cinanserin and 2-((2-((dimethylamino)methyl)phenyl)thio)-5-iodophenylamine

Topics: Artifacts; Brain; Cinanserin; Computer Simulation; Humans; Image Interpretation, Computer-Assisted; Kinetics; Models, Biological; Protein Binding; Radiopharmaceuticals; Reproducibility of Results; Sensitivity and Specificity; Serotonin Plasma Membrane Transport Proteins; Tomography, Emission-Computed, Single-Photon

Several studies have reported low brain serotonin transporter (SERT) binding in individuals with major depression. We hypothesized that the SERT standardized uptake ratio (SUR) values using [(123) I]-ADAM single photon emission computed tomography would increase in depressed subjects who responded to cognitive behavior therapy (CBT) compared to CBT nonresponders. [(123) I]-ADAM scans were acquired before and after 12 weeks of CBT from 20 depressed subjects and on two occasions 12 weeks apart from 10 nondepressed, healthy volunteers. The primary outcome measure was change over time in SUR values in the midbrain, medial temporal lobe, and basal ganglia regions. Depressed subjects demonstrated low pretreatment mean SUR values that significantly increased over time in the midbrain (P = .011), right medial temporal lobe (P = .008), and left medial temporal lobe (P = .000) regions. Treatment responders showed a significant increase over time in SUR values in left medial temporal lobe (P = .029) and right medial temporal lobe (P = .007) regions. Partial and nonresponder subjects also showed a significant increase over time in SUR values in the left medial temporal region (P = .040) (vs. healthy volunteers), but to a lesser degree. The findings suggest that low pretreatment SERT binding may increase over time in some depressed individuals who experience symptom improvement.

Topics: Brain; Cinanserin; Cognitive Behavioral Therapy; Depressive Disorder, Major; Female; Humans; Male; Metabolic Clearance Rate; Radiopharmaceuticals; Reproducibility of Results; Sensitivity and Specificity; Serotonin Plasma Membrane Transport Proteins; Tissue Distribution; Tomography, Emission-Computed, Single-Photon; Treatment Outcome

Serotonin is one of the key neuromodulators involved in fundamental cerebral functions and behaviors. Previous study has demonstrated that somatization symptoms are probably associated with central serotonergic circuits, which are implicated in anxiety and nociception regulation. This study aims to examine the correlation between somatization subscale score and serotonin transporter (SERT) availability in healthy volunteers.. Sixty-four healthy participants, 26 males and 38 females, were enrolled from the community and were administered the single somatization subscale of the Chinese symptom checklist 90 revised (SCL90-R). Single photon emission computed tomography with [(123)I] 2-((2-((dimethylamino)methyl)phenyl)thio)-5-iodophenylamine was also performed to examine SERT availability.. The somatization scores were negatively correlated with SERT availability (Spearman's ρ = -0.35, p = 0.005), particularly in males (Spearman's ρ = -0.54, p = 0.004).. This result reconfirmed the correlation between central serotonergic activity and the intensity of somatization symptoms, even in healthy participants. However, a gender difference exists in this correlation.

Topics: Adult; Cinanserin; Female; Humans; Iodine Radioisotopes; Male; Middle Aged; Serotonin; Serotonin Plasma Membrane Transport Proteins; Sex Factors; Somatoform Disorders; Statistics, Nonparametric; Tomography, Emission-Computed, Single-Photon; Young Adult

Previous brain imaging studies have demonstrated a seasonal difference of serotonin transporter (SERT) binding in the human brain. However, the results were somewhat contradictory. We conducted test-retest study with single photon emission computed tomography (SPECT) with ¹²³I-ADAM as ligand in 28 healthy subjects. Ten of the subjects were studied within 1 month, whereas 18 were randomly assigned to be studied over a period of up to 1 year. The primary measure was the specific uptake ratio (SUR). Regions of interest included the midbrain, thalamus, putamen and caudate. The intra-class correlation coefficient (ICC) was 0.52-0.94 across different brain regions over 1 month, whereas the ICC was -0.24-0.63 over a 1-year period. The 1-month variability ranged from 6.5 ± 5.1% to 12.5 ± 10.6% across different brain regions, and the 1-year variability ranged from 16.5 ± 9.6% to 41.9 ± 35.5%. The Kruskal-Wallis test revealed a significant difference of variability across months. The Wilcoxon Signed Ranks Test showed the SUR between test-retest scans was of borderline significance. Curve fitting, using a 4th degree polynomial model, revealed a significant circadian correlation between the variability and interval of test-retest measurements. Our findings demonstrate the test-retest reproducibility of ¹²³I-ADAM in different time periods and suggest that circadian variation of SERT levels in the human brain might exist.

Topics: Adult; Brain; Brain Mapping; Cinanserin; Female; Follow-Up Studies; Humans; Magnetic Resonance Imaging; Male; Protein Binding; Radiopharmaceuticals; Reproducibility of Results; Serotonin Plasma Membrane Transport Proteins; Statistics, Nonparametric; Time Factors; Tomography, Emission-Computed, Single-Photon; Young Adult

The tracer (123)I-2-([2-({dimethylamino}methyl)phenyl]thio)-5-iodophenylamine ([(123)I]ADAM) has been developed to image serotonin transporters (SERTs) with SPECT. Preclinical studies have shown that [(123)I]ADAM binds selectively to SERTs. Moreover, initial human studies have shown that [(123)I]ADAM binding could be blocked by selective serotonin reuptake inhibitors (SSRIs). However, in humans it has not been proven that [(123)I]ADAM binds selectively to SERTs.. We examined the in vivo availability of SERTs in 12 healthy young volunteers 5 h after bolus injection of [(123)I]ADAM. To evaluate the selectivity of binding, four participants were pretreated (double-blinded design) with placebo, four with paroxetine (20 mg) and four with the dopamine/norepinephrine blocker methylphenidate (20 mg). SPECT studies were performed on a brain-dedicated system (Neurofocus), and the SPECT images were coregistered with individual MR scans of the brain. ADAM binding in SERT-rich brain areas and cerebellar cortex (representing non-specific binding) was assessed by drawing regions of interest (ROIs) on the individual MR images. Specific to non-specific ratios were used as the outcome measure.. We found that specific to non-specific ratios were statistically significantly lower in paroxetine-pretreated participants than in placebo- or methylphenidate-pretreated participants. No such difference was found between groups pretreated with placebo or methylphenidate.. Our preliminary findings suggest that [(123)I]ADAM binds selectively to SERTs in human brain.

Topics: Adult; Brain; Cinanserin; Double-Blind Method; Health; Humans; Male; Protein Binding; Radioactive Tracers; Serotonin Plasma Membrane Transport Proteins; Substrate Specificity; Tomography, Emission-Computed, Single-Photon; Young Adult

I-123 ADAM single-photon emission tomography (SPECT) analysis is usually performed by drawing regions of interest or by directly registering the SPECT image to a magnetic resonance image (MRI). Each method is limited by an observer or registration bias.. Eleven healthy volunteers were recruited for I-123 ADAM SPECT using a triple-headed gamma camera with fan-beam collimators after an intravenous injection of 185 MBq of I-123 ADAM. We propose two new registration methods: sequential registration and a two-step registration. Reconstructed images were registered to MRIs using mutual information with sequential and two-step methods.. The sequential and two-step method mean counts of midbrain activity were not significantly different (166.1+/-4.3 vs. 164.2+/-4.1, P=0.273), but they were significantly higher than the direct method mean count (132.8+/-3.7, P<0.001). Sequential and two-step method midbrain/cerebellum ratios were not significantly different (4.40+/-0.37 vs. 4.28+/-0.34, P=0.277), but they were significantly higher than the direct method midbrain/cerebellum ratio (1.68+/-0.16, P<0.001).. The accuracy of the sequential method of registration was significantly better than that of drawing regions of interest or directly coregistering the SPECT image to an MRI. It is, however, tedious and time-consuming. The simplified two-step method yields similar results and is more practical for clinical I-123 ADAM SPECT studies.

Topics: Cerebellum; Cinanserin; Female; Humans; Image Processing, Computer-Assisted; Magnetic Resonance Imaging; Male; Reproducibility of Results; Time Factors; Tomography, Emission-Computed, Single-Photon; Young Adult

Previous studies have investigated the occupancy of the serotonin reuptake transporter (SERT) after clinical doses of citalopram and other selective serotonin reuptake inhibitors. In the present study, the occupancies of SERT after multiple doses of escitalopram and citalopram were compared using the radioligand [(123)I]ADAM and single photon emission computed tomography (SPECT).. Fifteen healthy subjects received escitalopram 10 mg/day (n = 6) or citalopram 20 mg/day (n = 9) for a total of 10 days. SERT occupancies in midbrain were determined with SPECT and [(123)I]ADAM at three different time points: at baseline (no medication) and at 6 and 54 h after last drug intake.. At 6 h after the last dose, mean SERT occupancies were 81.5 +/- 5.4% (mean+/-SD) for escitalopram and 64.0 +/- 12.7% for citalopram (p < 0.01). At 54 h after the last dose, mean SERT occupancies were 63.3 +/- 12.1% for escitalopram and 49.0 +/- 11.7% for citalopram (p < 0.05). The plasma concentrations of the S-enantiomer were of the same magnitude in both substances. For both drugs, the elimination rate of the S-enantiomer in plasma was markedly higher than the occupancy decline rate in the midbrain.. The significantly higher occupancy of SERT after multiple doses of escitalopram compared to citalopram indicates an increased inhibition of SERT by escitalopram. The results can also be explained by an attenuating effect of R-citalopram on the occupancy of S-citalopram at the SERT.

Topics: Adult; Area Under Curve; Brain; Cerebellum; Cinanserin; Citalopram; Dose-Response Relationship, Drug; Drug Administration Schedule; Humans; Male; Mesencephalon; Radiopharmaceuticals; Selective Serotonin Reuptake Inhibitors; Serotonin Plasma Membrane Transport Proteins; Stereoisomerism; Time Factors; Tissue Distribution; Tomography, Emission-Computed, Single-Photon

We studied the midbrain SERT availability in patients with major depression and assessed the relation of SERT occupancy by citalopram to the treatment response. 21 non-medicated patients with major depression and 13 healthy controls were examined by [(123)I]-ADAM SPECT. The midbrain SERT availability (SERT V(3)'') was calculated using individual MRI scans. In 13/21 patients SPECT was repeated 7 days after oral medication with citalopram (10 mg/day). We found no significant difference in the mean midbrain SERT availability between the studied patients with major depression and healthy controls (0.86 +/- 0.27 vs. 0.71 +/- 0.44, p = 0.069). The mean SERT occupancy accounted to 61%. The degree of SERT blockade by citalopram did not correlate with the reduction in HAMD total score. Treatment with low-dosed citalopram caused individually variable occupancy of the midbrain-SERT and a rapid clinical improvement in 54% of the investigated patients.

Topics: Adult; Brain Mapping; Cinanserin; Citalopram; Depressive Disorder, Major; Female; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Radiopharmaceuticals; Selective Serotonin Reuptake Inhibitors; Serotonin Plasma Membrane Transport Proteins; Tissue Distribution; Tomography, Emission-Computed, Single-Photon

Recently, the tracer (123)I-2-([2-({dimethylamino}methyl)phenyl]thio)-5-iodophenylamine ([(123)I]ADAM) has been developed for selective imaging of serotonin transporters (SERTs) with single photon emission computed tomography (SPECT). The purpose of this study was to develop an [(123)I]ADAM SPECT protocol for clinical studies in young adults.. We examined the time course of [(123)I]ADAM binding to central SERTs in eight healthy young volunteers up to 6 h postinjection.. We found that the time of peak-specific [(123)I]ADAM binding was highly variable among subjects, but specific binding in the SERT-rich (hypo)thalamus peaked within 5 h postinjection in all subjects. Moreover, in this brain area, binding ratios of specific to nonspecific binding did not significantly change between 3 and 6 h postinjection, and peaked 5 h postinjection.. Five hours postinjection may be optimal for single-scan [(123)I]ADAM SPECT studies in humans, but more work is needed to assess the accuracy of the 5-h tissue ratio as a measure of SERT in the brain.

Topics: Adult; Brain; Cinanserin; Female; Humans; Kinetics; Male; Metabolic Clearance Rate; Organ Specificity; Radiopharmaceuticals; Reference Values; Serotonin Plasma Membrane Transport Proteins; Tissue Distribution; Tomography, Emission-Computed, Single-Photon

[(123)I]-2-((2-((dimethylamino)methyl)phenyl)thio)-5-iodophenylamine ([(123)I]ADAM), a novel radiotracer, has promising application in the imaging of the serotonin transporter (SERT) in the human brain. In this study, the optimal scanning time for acquiring brain single photon emission computed tomography (SPECT) images was determined by performing dynamic SPECT studies at intervals from 0 to 6 h postinjection of [(123)I]ADAM. Additionally, radiation-absorbed doses were determined for three healthy human subjects using attenuation-corrected images.. Twelve subjects were randomized into one of three study groups as follows: whole-body distribution imaging (n=3), dynamic SPECT imaging (n=3) and brain SPECT imaging (n=6). The radiation-absorbed dose was calculated using MIRDOSE 3.0 software with attenuation-corrected data. The specific binding (SB) ratio of the brain stem was measured from dynamic SPECT images to determine the optimal scanning time.. Dynamic SPECT images showed that the SB of the brain stem gradually increased to a maximum 4 h postinjection. Single photon emission computed tomography images at 4 h postinjection showed a high uptake of the radiotracer (SB) in the hypothalamus (1.40+/-0.12), brain stem (1.44+/-0.16), pons (1.13+/-0.14) and medial temporal lobe (0.59+/-0.10). The mean adult male value of effective dose was 3.37 x 10(-2) mSv/MBq with a 4.8-h urine-voiding interval. Initial high uptake in SERT-rich sites was demonstrated in the lung and brain. A prominent washout of the radiotracer from the lung further increased brain radioactivity that reached a peak value of 5.03% of injected dose 40 min postinjection.. [(123)I]ADAM is a promising radiotracer for SPECT imaging of SERT in humans with acceptable dosimetry and high uptake in SERT-rich regions. Brain SPECT images taken within 4 h following injection show optimal levels of radiotracer uptake in known SERT sites. However, dynamic changes in lung SERT distribution must be carefully evaluated.

Topics: Adult; Brain; Cinanserin; Female; Humans; Kinetics; Male; Metabolic Clearance Rate; Organ Specificity; Radiopharmaceuticals; Reference Values; Serotonin Plasma Membrane Transport Proteins; Tissue Distribution; Tomography, Emission-Computed, Single-Photon; Whole Body Imaging

Escitalopram is a dual serotonin reuptake inhibitor (SSRI) approved for the treatment of depression and anxiety disorders. It is the S-enantiomer of citalopram, and is responsible for the serotonin reuptake activity, and thus for its pharmacological effects. Previous studies pointed out that clinically efficacious doses of other SSRIs produce an occupancy of the serotonin reuptake transporter (SERT) of about 80% or more. The novel radioligand [123I]ADAM and single photon emission computer tomography (SPECT) were used to measure midbrain SERT occupancies for different doses of escitalopram and citalopram.. Twenty-five healthy subjects received a single dose of escitalopram [5 mg (n=5), 10 mg (n=5), and 20 mg (n=5)] or citalopram [(10 mg (n=5) and 20 mg (n=5)]. Midbrain SERT binding was measured with [(123)I]ADAM and SPECT on two study days, once without study drug and once 6 h after single dose administration of the study drug. The ratio of midbrain-cerebellum/cerebellum was the outcome measure (V3") for specific binding to SERT in midbrain. Subsequently, SERT occupancy levels were calculated using the untreated baseline level for each subject. An Emax model was used to describe the relationship between S-citalopram concentrations and SERT occupancy values. Additionally, four subjects received placebo to determine test-retest variability.. Single doses of 5, 10, or 20 mg escitalopram led to a mean SERT occupancy of 60+/-6, 64+/-6, and 75+/-5%, respectively. SERT occupancies for subjects treated with single doses of 10 and 20 mg citalopram were 65+/-10 and 70+/-6%, respectively. A statistically significant difference was found between SERT occupancies after application of 10 and 20 mg escitalopram, but not for 10 and 20 mg citalopram. There was no statistically significant difference between the SERT occupancies of either 10 mg citalopram or 10 mg escitalopram, or between 20 mg citalopram and 20 mg escitalopram. Emax was slightly higher after administration of citalopram (84%) than escitalopram (79%). In the test-retest study, a mean SERT "occupancy" of 4% was found after administration of placebo, the intraclass correlation coefficient was 0.92, and the repeatability coefficient was 0.25.. SPECT and [123I]ADAM were used to investigate SERT occupancies after single doses of escitalopram or citalopram. The test-retest study revealed good reproducibility of SERT quantification. Similar SERT occupancies were found after administration of equal doses (in respect to mg) of escitalopram and citalopram, giving indirect evidence for a fractional blockade of SERT by the inactive R-citalopram.

Topics: Administration, Oral; Adult; Akathisia, Drug-Induced; Area Under Curve; Cerebellum; Cinanserin; Citalopram; Dose-Response Relationship, Drug; Humans; Iodine Radioisotopes; Male; Mesencephalon; Metabolic Clearance Rate; Nausea; Protein Binding; Selective Serotonin Reuptake Inhibitors; Serotonin Plasma Membrane Transport Proteins; Sleep Wake Disorders; Stereoisomerism; Time Factors; Tomography, Emission-Computed, Single-Photon; Xerostomia

Serotonergic brain regions play a crucial role in the modulation of emotion, and serotonergic dysfunction may contribute to several neurological disorders. [123I]ADAM is a novel SPECT tracer which binds with high affinity to serotonin transporters (SERT). The objective of this study was to compare different methods for the quantification of tracer binding and to develop a simplified single-scan protocol for this tracer, as well as to investigate its potential for characterisation of the transporter occupancy versus plasma concentration curve of a selective serotonin re-uptake inhibitor (SSRI).. Dynamic SPECT scans were performed on 16 healthy volunteers after administration of approximately 150 MBq [123I]ADAM. Data were acquired from the time of injection until approximately 5.5 h after injection in 30- or 45-min sessions. Each subject was scanned twice: with and without pre-treatment with the SSRI citalopram in various dosage regimens. The plasma concentration of citalopram (C(p)) was determined from venous samples. Images were reconstructed by filtered back-projection with scatter and attenuation correction. Tracer binding was quantified for midbrain, striatum and thalamus using cerebellum as a reference region. Quantification was done by kinetic modelling, graphical analysis and multi-linear regression, as well as by the ratio method, with binding potential (BP2) as the outcome measure. The SERT occupancy by citalopram was determined relative to the baseline scan for each subject, and the occupancy versus C(p) curve was fitted with the E(max) model.. The highest binding of [123I]ADAM was in midbrain (mean baseline BP2+/-SD=1.31+/-0.29), with lower binding in thalamus (0.79+/-0.16) and striatum (0.66+/-0.13). There was good agreement between BP2 values obtained by different quantification methods. Using the ratio method, the best agreement with kinetic modelling was obtained with data from the time interval [200,260] min after injection. The fitting of the midbrain occupancy curve yielded a maximum occupancy of 84% and a plasma concentration required to reach 50% of the maximum of 2.5 ng/ml, with a goodness-of-fit variability of 13% (SD).. Binding of [123I]ADAM to SERT in midbrain can be quantified with a single scan starting 200 min after injection. However, the variability of estimated occupancy values may be too high for critical assessment of occupancy of SERT by SSRI.

Topics: Adult; Cinanserin; Citalopram; Humans; Image Interpretation, Computer-Assisted; Male; Mesencephalon; Metabolic Clearance Rate; Middle Aged; Radiopharmaceuticals; Selective Serotonin Reuptake Inhibitors; Serotonin Plasma Membrane Transport Proteins; Tissue Distribution; Tomography, Emission-Computed, Single-Photon

[(123)I]ADAM [2-((2-((dimethylamino)methyl)phenyl)thio)-5-iodophenylamine (ADAM)] has recently been shown to be a very promising imaging ligand for the detection of serotonin transporters (SERT) in human brain, because of its high specificity for SERT. [(123)I]ADAM has previously been used only for animal studies. In this work, we investigated the radiation dosimetry and biodistribution of [(123)I]ADAM based on whole-body scans in healthy human volunteers. Following the administration of 196+/-20 MBq (range 157-220 MBq) [(123)I]ADAM, serial whole-body images were performed up to 24 h. Estimates of radiation absorbed dose were calculated using the MIRDOSE 3.0 program with a dynamic bladder model. Twelve source organs were considered in estimating absorbed radiation doses for organs of the body. The highest absorbed organ doses were found to the lower large intestine wall (8.3.10(-2) mGy/MBq), kidneys (5.2.10(-2) mGy/MBq), urinary bladder wall (4.9.10(-2) mGy/MBq) and thyroid (4.3.10(-2) mGy/MBq). The effective dose was estimated to be 2.2.10(-2) mSv/MBq. The results suggest that [(123)I]ADAM is of potential value as a tracer for single-photon emission tomography imaging of serotonin receptors in humans, with acceptable dosimetry and high brain uptake.

Topics: Adult; Body Burden; Carrier Proteins; Cinanserin; Feasibility Studies; Female; Humans; Iodine Radioisotopes; Male; Membrane Glycoproteins; Membrane Transport Proteins; Metabolic Clearance Rate; Middle Aged; Nerve Tissue Proteins; Organ Specificity; Radiation Dosage; Radiometry; Radiopharmaceuticals; Serotonin Plasma Membrane Transport Proteins; Tissue Distribution; Whole-Body Counting

Cerebral serotonin metabolism has an important but controversial role in obesity. However, it is not given enough attention in morbidly obese young adults. We used single photon emission computed tomography (SPECT) with [I-123]-labeled 2-((2-((dimethylamino)methyl)phenyl)thio)-5-iodophenylamine (ADAM) to investigate changes in serotonin transporter (SERT) availability in 10 morbidly obese young adults without an eating disorder (M/F = 5/5, body mass index (BMI): 40.3 ± 4.1 kg/m2, percentage of body fat (BF%): 46.0 ± 3.9%) and 10 age- and sex-matched non-obese controls (BMI: 20.3 ± 1.2 kg/m2, BF%: 20.6 ± 8.9%). All participants underwent SPECT at 10 min and 6 h after an injection of 200 MBq of [I-123]-ADAM. The SERT binding site (midbrain) was drawn with cerebellum normalization. The BF% and fat distribution were measured using dual-energy X-ray absorptiometry. The midbrain/cerebellum SERT binding ratios (2.49 ± 0.46 vs. 2.47 ± 0.47; p = 0.912) at 6 h were not significantly different between groups, nor was the distribution of the summed images at 10 min (1.36 ± 0.14 vs. 1.35 ± 0.11; p = 0.853). There were no significant correlations between midbrain/cerebellum SERT binding ratio and age, BMI, BF%, or fat distribution. No significant difference in SERT availability in the midbrain between morbidly obese and non-obese young adults without an eating disorder indicates an unmet need for investigating the role of cerebral serotonin in obesity.

Topics: Adult; Brain; Case-Control Studies; Cinanserin; Female; Humans; Male; Obesity; Radiopharmaceuticals; Serotonin Plasma Membrane Transport Proteins; Tomography, Emission-Computed, Single-Photon

Reduced brain serotonin transporter (SERT) has been demonstrated in bipolar disorder (BD). The aim of this study was to explore the potential role of cytokines on reduced SERT in BD.. Twenty-eight BD type I patients and 28 age- and gender-matched healthy controls (HCs) were recruited. Single photon emission computed tomography with the radiotracer 123I ADAM was used for SERT imaging. Regions of interest included the midbrain, thalamus, putamen and caudate. Seven cytokines, including tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), interleukin-1α (IL-1α), IL-1β, IL-4, IL-6 and IL-10, were measured using an enzyme linked immune-sorbent assay.. SERT availability in the midbrain and caudate was significantly lower in BD compared to HCs. IL-1β was significantly lower, whereas IL-10 was significantly higher in BD compared to HCs. Multiple linear regression analyses revealed that there were associations between cytokines, IL-1α, IL-1β, IL-6 and SERT availability in the midbrain but not in the thalamus, putamen and caudate. Furthermore, linear mixed effect analyses demonstrated that these associations were not different between HCs and BD.. While many cytokines have been proposed to be important in the pathophysiology of BD, our results demonstrated that significant associations between cytokines and SERT availability may explain the role of cytokines in mood regulation. However, these associations were not different between HCs and BD, which imply the role of these cytokines is not specific for BD.

Topics: Adult; Bipolar Disorder; Brain; Cinanserin; Cytokines; Female; Functional Neuroimaging; Humans; Male; Serotonin Plasma Membrane Transport Proteins; Tomography, Emission-Computed, Single-Photon; Young Adult

Converging evidence indicates the hypothalamus-pituitary-adrenal axis and serotonergic neurons exert reciprocal modulatory actions. Likewise, brain-derived neurotrophic factor (BDNF) has been implicated as a growth and differentiation factor in the development of serotonergic neurons. The aim of this study was to examine the interaction of cortisol and BDNF on serotonin transporter (SERT) in bipolar disorder (BD). Twenty-eight BD and 28 age- and gender-matched healthy controls (HCs) were recruited. (123)I-ADAM with single-photon emission computed tomography (SPECT) was applied for measurement of SERT availability in the brain, which included the midbrain, thalamus, putamen and caudate. Ten milliliters of venous blood was withdrawn, when the subject underwent SPECT, for the measurement of the plasma concentration of cortisol and BDNF. SERT availability was significantly decreased in the midbrain and caudate of BD compared with HCs, whereas plasma concentration of cortisol and BDNF did not show a significant difference. The linear mixed-effect model revealed that there was a significant interaction of group and cortisol on SERT availability of the midbrain, but not BDNF. Linear regression analyses by groups revealed that cortisol was associated with SERT availability in the midbrain in the HCs, but not in BD. Considering previous studies, which showed a significant association of cortisol with SERT availability in the HCs and major depressive disorder (MDD), our result replicated a similar finding in HCs. However, the negative finding of the association of cortisol and SERT availability in BD, which was different from MDD, suggests a different role for cortisol in the pathophysiology of mood disorder.

Topics: Adult; Bipolar Disorder; Brain; Brain-Derived Neurotrophic Factor; Case-Control Studies; Cinanserin; Female; Humans; Hydrocortisone; Linear Models; Magnetic Resonance Imaging; Male; Protein Binding; Radiochemistry; Serotonin Plasma Membrane Transport Proteins; Tomography, Emission-Computed, Single-Photon

3,4-Methylenedioxymethamphetamine (MDMA), a common recreational drug, is known to cause serotonergic neurotoxicity in the brain. Dextromethorphan (DM) is a widely used antitussive reported to exert anti-inflammatory effect in vivo. In this study, we examined the long-term effect of MDMA on the primate serotonergic system and the protective property of DM against MDMA-induced serotonergic abnormality using single photon emission computed tomography (SPECT). Nine monkeys (Macaca cyclopis) were divided into three groups, namely control, MDMA and co-treatment (MDMA/DM). [

Topics: Animals; Brain; Cinanserin; Dextromethorphan; Iodine Radioisotopes; Magnetic Resonance Imaging; N-Methyl-3,4-methylenedioxyamphetamine; Primates; Serotonin; Time Factors; Tomography, Emission-Computed, Single-Photon

Serotonin may play an important role in the pathology of major depressive disorder (MDD). However, the relationship between serotonin transporter (SERT) availability and the medical outcome of antidepressant treatment is uncertain.. In this naturalistic study, SERT availability (expressed as the specific uptake ratio, SUR) in the midbrain of 17 drug-free patients with MDD and 17 controls matched for age and gender was measured using SPECT with [(123)I]ADAM. The severity of MDD was measured by the Hamilton Depression Rating Scale before, and after 6 weeks of non-standardized antidepressant treatment.. A total of 12 patients completed the study. The SUR of the patients with MDD was significantly lower than that of the healthy controls. The SUR of SERT was not found to have a linear relationship with the treatment outcome; however, supplemental analysis found a curvilinear relationship between treatment outcome and the SUR of SERT.. The findings indicate that the SUR of SERT is lower in patients with MDD; however it did not predict treatment outcome in a linear fashion. Studies with larger sample sizes are required.

Topics: Adult; Antidepressive Agents; Case-Control Studies; Cinanserin; Depressive Disorder, Major; Female; Functional Neuroimaging; Humans; Iodine Radioisotopes; Male; Mesencephalon; Middle Aged; Radiopharmaceuticals; Serotonin Plasma Membrane Transport Proteins; Tomography, Emission-Computed, Single-Photon; Treatment Outcome; Young Adult

It was found that serotonin transporter (SERT) gene (5-HTTLPR) polymorphism may moderate the association between perceiving stress and depressive tendency. Although SERT availability in the central nervous system could be associated with 5-HTTLPR polymorphism, whether SERT availability moderates the association between stress and depressive tendency is unclear. This study aimed to investigate whether there is a SERT availability×environmental stress interaction effect, as well as a gene-by-environmental (G×E) interaction effect, using single-photon emission computed tomography (SPECT) with a serotonin transporter radiotracer, [(123)I]ADAM. 87 healthy volunteers were enrolled. The SERT availability was approximated using SPECT with [(123)I]ADAM. Stress and depressive tendencies were measured by the Recent Life Change Questionnaire (RLCQ) and the Taiwanese Depression Questionnaire (TDQ), respectively. A significant interaction of sex×RLCQ×thalamic SERT availability on the TDQ was found, and this effect was robust after controlling for the effect of the SS genotype. The interaction of RLCQ×thalamic SERT availability on the TDQ was significant among males. In particular, a significant association between RLCQ and TDQ (Spearman correlation, ρ=0.64, p<0.01) was found among male subjects with a lower level of thalamic SERT availability. SERT availability may play a role in depressive tendency when under perceived stress among healthy individuals, independent of G×E. This finding provides new evidence that confirms the role of the serotonergic system in the association between stress and depression. Males with lower levels of SERT availability may be more vulnerable to the effects of negative life events.

Topics: Adult; Cinanserin; Depression; Female; Genotype; Humans; Life Change Events; Male; Mesencephalon; Middle Aged; Polymorphism, Single Nucleotide; Serotonin Plasma Membrane Transport Proteins; Sex Factors; Statistics, Nonparametric; Stress, Psychological; Surveys and Questionnaires; Taiwan; Tomography, Emission-Computed, Single-Photon; Young Adult

Serotonin transporter (SERT) and dopamine transporter (DAT) levels differ in patients with major depressive disorder (MDD) who are in a depressed state in comparison with healthy controls. In addition, a family history of depression is a potent risk factor for developing depression, and inherited vulnerability to serotonergic and dopaminergic dysfunction is suspected in this. The aim of this study was to examine the availabilities of midbrain SERT and striatal DAT in healthy subjects with and without a first-degree family history of MDD.. Eight healthy subjects with first-degree relatives with MDD and 16 sex- and age-matched healthy controls were recruited. The availabilities of SERT and DAT were approximated using SPECT, employing [¹²³I] 2-((2-((dimethylamino) methyl) phenyl)thio)-5-iodophenylamine (ADAM) and [(⁹⁹m)Tc] TRODAT-1 as the ligands, respectively. There are missing data for one participant with a first-degree family history of MDD from the ADAM study, due to a lack of the radio-ligand at the time of experiment.. SERT availability in the midbrain was significantly lower in subjects with a first-degree family history of MDD than in healthy subjects. However, DAT availability was no different between two groups.. The results with regard to the midbrain SERT level suggest the heritability of MDD.

Topics: Adult; Cinanserin; Depressive Disorder, Major; Dopamine Plasma Membrane Transport Proteins; Family; Female; Healthy Volunteers; Humans; Iodine Radioisotopes; Male; Mesencephalon; Middle Aged; Neostriatum; Organotechnetium Compounds; Radiopharmaceuticals; Serotonin Plasma Membrane Transport Proteins; Tomography, Emission-Computed, Single-Photon; Tropanes

The pharmacokinetic properties of radiotracers are crucial for successful in vivo single-photon emission computed tomographic (SPECT) imaging. Our goal was to determine if MDR1A-deficient animals could allow better SPECT imaging outcomes than wild-type (WT) animals for a selection of serotoninergic radioligands. Thus, we compared the performances of 123I-p-MPPI, 123I-R91150, 123I-SB207710, and 123I-ADAM radioligands, for imaging of their respective targets (5-hydroxytryptamine [5-HT]1A, 5-HT2A, 5-HT4, and serotonin transporter [SERT]), in WT and Mdr1a knockout (KO) rats. With 123I-SB207710, virtually no SPECT signal was recorded in the brain of WT or KO animals. For 123I-p-MPPI, low nondisplaceable binding potentials (BPND, mean ± SD) were observed in WT (0.49 ± 0.25) and KO (0.89 ± 0.52) animals. For 123I-ADAM, modest imaging contrast was observed in WT (1.27 ± 0.02) and KO (1.31 ± 0.09) animals. For 123I-R91150, the BPND were significantly higher in Mdr1a KO (3.98 ± 0.65) animals compared to WT animals (1.22 ± 0.26). The pharmacokinetics of 123I-SB207710 and 123I-p-MPPI do not make them ideal tracers for preclinical SPECT neuroimaging. 123I-ADAM showed adequate brain uptake regardless of Mdr1a expression and appeared suitable for preclinical SPECT neuroimaging in both animal strains. The use of Mdr1a KO animals significantly improved the brain penetration of 123I-R91150, making this animal strain an interesting option when considering SPECT neuroimaging of 5-HT2A receptors in rat.

Topics: Aminopyridines; Animals; ATP Binding Cassette Transporter, Subfamily B; Brain; Cinanserin; Gene Knockout Techniques; Iodine Radioisotopes; Male; Organ Specificity; Piperazines; Piperidines; Radiopharmaceuticals; Rats; Rats, Sprague-Dawley; Receptors, Serotonin; Selective Serotonin Reuptake Inhibitors; Tissue Distribution; Tomography, Emission-Computed, Single-Photon

The association between hypothalamo-pituitary-adrenal (HPA) axis function and the serotonergic system could be involved in the mechanism of depression. However, neuroimaging evidence is scarce. The aim of the present study was to probe the association between dexamethasone suppression test response and serotonin transporter (SERT) availability in drug-free patients with major depressive disorder (MDD). Seventeen MDD patients (five males and twelve females) were recruited. SPECT with [(123)I] ADAM was used to measure the midbrain SERT availability, and HPA axis function was measured by the dexamethasone suppression test (DST). The association was significant when considering all participants (ρ=0.69, p=0.002). This association may have clinical implications for the treatment of MDD.

Topics: Adult; Cinanserin; Depressive Disorder, Major; Dexamethasone; Female; Humans; Hydrocortisone; Male; Mesencephalon; Pituitary-Adrenal Function Tests; Serotonin Plasma Membrane Transport Proteins; Tomography, Emission-Computed, Single-Photon

Accumulating evidence suggests that dysfunction of the amygdala is related to abnormal fear processing, anxiety, and social behaviors noted in autistic spectrum disorders (ASDs). In addition, studies have shown that disrupted brain serotonin homeostasis is linked to ASD. With a valproate (VPA)-induced rat ASD model, we investigated the possible role of amygdala serotonin homeostasis in autistic phenotypes and further explored the underlying mechanism. We first discovered that the distribution of tryptophan hydroxylase immunoreactivity in the caudal raphe system was modulated on postnatal day (PD) 28 of the VPA-exposed offspring. Then, we found a significantly higher serotonin transporter availability in the amygdala of the VPA-exposed offspring on PD 56 by using single photon emission computed tomography and computed tomography co-registration following injection of (123)I-labeled 2-((2-(dimethylamino)methyl)phenyl)thio)-5-iodophenylamine((123)I[ADAM]). Furthermore, treatment with 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), a 5-HT1A receptor agonist, increased social interaction and improved fear memory extinction in the VPA-exposed offspring. 8-OH-DPAT treatment also reversed the characteristics of miniature excitatory post-synaptic currents as well as paired pulse facilitation observed in lateral amygdala slices. These results provided further evidence to support the role of the amygdala in characteristic behavioral changes in the rat ASD model. The serotonergic projections that modulate the amygdala function might play a certain role in the development and treatment of behavioral symptoms exhibited in individuals with ASD.

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Amygdala; Animals; Autistic Disorder; Behavior, Animal; Cinanserin; Disease Models, Animal; Excitatory Postsynaptic Potentials; Extinction, Psychological; Fear; Female; Male; Memory; Miniature Postsynaptic Potentials; Multimodal Imaging; Pregnancy; Prenatal Exposure Delayed Effects; Radiopharmaceuticals; Rats; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT1A; Serotonin 5-HT1 Receptor Agonists; Serotonin Plasma Membrane Transport Proteins; Social Behavior; Time Factors; Tomography, Emission-Computed, Single-Photon; Tomography, X-Ray Computed; Tryptophan Hydroxylase; Valproic Acid

Serotonin modulates human behavior and emotion. Recent evidence implies that a higher level of serotonergic activity could be associated with a higher level of perceived social support. This study aimed to examine the correlation between serotonin transporter (SERT) availability and perceived social support scores in healthy volunteers.. 111 healthy participants, 50 males and 61 females, were enrolled from the community and completed the Measurement of Support Function questionnaire. Single photon emission computed tomography (SPECT) with [(123)I] ADAM was performed to examine SERT availability.. Perceived social support was positively correlated with SERT availability (Spearman's ρ=0.29, p<0.01; χ(2)=7.57, p<0.01), particularly in males (Spearman's ρ=0.37, p<0 .01; χ(2)=11.77, p<0.01). Censored regressions indicated that these associations are not influenced by a ceiling effect and remained significant after controlling the effect of age.. This result confirmed the correlation between perceived social support and central serotonergic activity. However, this correlation was present only in males.

Topics: Adult; Cinanserin; Female; Healthy Volunteers; Humans; Male; Mesencephalon; Reference Values; Serotonin Plasma Membrane Transport Proteins; Social Support; Surveys and Questionnaires; Tomography, Emission-Computed, Single-Photon

Purpose of the study was to investigate alterations in midbrain serotonin transporter (SERT) binding in patients with epilepsy and symptoms of depression compared to patients with epilepsy with no symptoms of depression.. We studied 12 patients with epilepsy (7 patients had focal and 5 had generalized epilepsy syndromes). The presence of self-reported symptoms of depression was assessed using Beck Depression Inventory (BDI) and the Emotional State Questionnaire (EST-Q). The binding potential of the SERT was assessed by performing brain single photon emission tomography (SPET) using the SERT radioligand 2-((2-((dimethylamino)methyl)phenyl)thio)-5-(123)iodophenylamine (123I-ADAM).. Seven patients had BDI and EST-Q subscale scores greater than 11 points, which was interpreted as the presence of symptoms of depression. We found that 123I-ADAM binding was not significantly different between patients with epilepsy with and without symptoms of depression. In addition, 123I-ADAM binding did not show a significant correlation to either BDI or EST-Q depression subscale scores and did not differ between patients with focal vs. generalized epilepsy.. The results of our study failed to demonstrate alterations of SERT binding properties in patients with epilepsy with or without symptoms of depression.

Topics: Adult; Cinanserin; Comorbidity; Depression; Epilepsy; Female; Humans; Male; Middle Aged; Psychiatric Status Rating Scales; Radiopharmaceuticals; Serotonin Plasma Membrane Transport Proteins; Tomography, Emission-Computed, Single-Photon; Young Adult

Neuroimaging evidence supporting an association between either dopamine or serotonin and time to relapse of heroin users is limited. In this two-isotope SPECT small sample (N=9) pilot study, the relationship between the availability of serotonin transporter (SERT) and dopamine transporter (DAT) and the relapse of heroin users was investigated. A significant negative association between SERT availability and time to relapse among those who relapsed (N=7) was found.

Topics: Adult; Cinanserin; Corpus Striatum; Dopamine Plasma Membrane Transport Proteins; Female; Functional Neuroimaging; Heroin Dependence; Humans; Male; Mesencephalon; Organotechnetium Compounds; Pilot Projects; Radiopharmaceuticals; Recurrence; Serotonin Plasma Membrane Transport Proteins; Time Factors; Tomography, Emission-Computed, Single-Photon; Tropanes

Most common psychiatric diseases have been found to be associated with disturbance of both the hypothalamic-pituitary-adrenal (HPA) axis and the brain serotonergic system. The aim of this study was to explore the neuroendocrine relationships between the dexamethasone suppression test (DST) and serotonin transporter (SERT) availability in healthy volunteers. Sixty-six participants (30 males and 36 females) were recruited from the community. The DST suppression rate (D%) is the reduction in cortisol level from Day 1 (D1) to Day 2 (D2) in proportion to the Day 1 cortisol level (D%=(D1-D2)/D1×100%). SPECT with [(123)I] ADAM was used to measure SERT availability. A significant correlation between D% and SERT availability was noted in all subjects (Spearman's ρ=0.26, p=0.03) and in the male subjects (Spearman's ρ=0.41, p=0.02). SERT availability may be sensitive to changes in DST, especially in males.

Topics: Adult; Brain; Cinanserin; Dexamethasone; Female; Functional Neuroimaging; Humans; Hydrocortisone; Iodine Radioisotopes; Male; Pituitary-Adrenal Function Tests; Serotonin Plasma Membrane Transport Proteins; Sex Characteristics; Tomography, Emission-Computed, Single-Photon

We examined midbrain, medial temporal lobe, and basal ganglia serotonin transporter (SERT) distribution volume ratio (DVR) values in subjects with major depressive disorder versus healthy volunteers using a selective SERT radioligand and single photon emission computed tomography (SPECT). We hypothesized that the DVR value for SERT binding would be lower in depressed versus non-depressed subjects. [(123)I]-ADAM SPECT scans were acquired from 20 drug free, depressed subjects and 20 drug-free depressed subjects and 10 drug-free healthy volunteers. The primary outcome measure was the DVR value for [(123)I]-ADAM uptake in the midbrain, medial temporal lobe, and basal ganglia regions. Depressed subjects demonstrated significantly lower DVR values in the midbrain, right and left medial temporal lobe, and right and left basal ganglia. There was significant probability that lower DVR values could distinguish between depressed and non-depressed subjects in the midbrain, medial temporal lobe, and the right and left basal ganglia. These findings confirm prior observations of lower SERT binding in depression, and suggest that low SERT binding may represent a putative biomarker of depression. Future studies are needed to confirm these observations.

Topics: Adult; Brain; Brain Mapping; Cinanserin; Depressive Disorder, Major; Female; Functional Laterality; Humans; Iodine Radioisotopes; Male; Middle Aged; Predictive Value of Tests; Protein Binding; ROC Curve; Serotonin Plasma Membrane Transport Proteins; Tomography, Emission-Computed, Single-Photon

Serotonin transport abnormalities are implicated in neuropsychiatric disorders. [(123)I]ADAM ([(123)I]-2-([2-({dimethylamino}methyl)phenyl]thio)-5-iodophenylamine) is a novel radiotracer that targets serotonin transporters. We assessed the toxicity of [(123)I]ADAM (18.5 MBq) administered in early- and late-phases (8 and 14 day postfertilization, respectively) of pregnancy. The mortality, clinical status, and gross necropsy were measured in pregnant rats, and the fertility index was measured in rat offspring (weight, clinical observations). We found no dosing-related clinical signs. In conclusion, [(123)I]ADAM was not toxic in an animal pregnancy model.

Topics: Animals; Cinanserin; Female; Fertility; Iodine Radioisotopes; Pregnancy; Pregnancy, Animal; Radiopharmaceuticals; Rats; Rats, Sprague-Dawley; Serotonin Plasma Membrane Transport Proteins

Although loudness dependence of auditory evoked potentials (LDAEPs) had been suggested as a noninvasive measure of central serotonin functions, recent studies suggest that LDAEP may be modulated by multiple neuromodulatory systems, such as dopamine. Here, we explore the relationship between LDAEP and dopamine and serotonin in the level of monoamine transporter availability.. Forty-nine healthy volunteers received LDAEP and single-photon emission computed tomography (SPECT) using [(99m)Tc] TRODAT and [(123)I] ADAM to approximate the availability of dopamine transporters (DATs) and serotonin transporters (SERTs).. LDAEP was found to be positively associated with DAT, after adjusting for age and gender, and the log-transformed slope of loudness dependence at Cz was negatively associated with SERT.. Our findings provide further evidence for the possible involvement of dopamine and serotonins in the genesis of LDAEP.

Topics: Acoustic Stimulation; Adult; Brain; Brain Mapping; Cinanserin; Dopamine Plasma Membrane Transport Proteins; Evoked Potentials, Auditory; Female; Humans; Loudness Perception; Male; Middle Aged; Organotechnetium Compounds; Radiopharmaceuticals; Regression Analysis; Serotonin Plasma Membrane Transport Proteins; Tomography, Emission-Computed, Single-Photon; Tropanes; Young Adult

Image analysis of 123I ADAM single photon emission computed tomography is used to evaluate the functional activities in apparatus or in the brain regions. We have earlier proposed a two-step registration method for registering intrasubject long-time 2-[(2-((dimethyl-amino) methyl)phenyl)thio]-5-iodophenylamine (ADAM) images. However, this method requires acquisition of individual MRI, 10-min ADAM, and 6-h ADAM images.. In this study, we propose using standard (std) brains to replace the individual MRI and 10-min ADAM images. We first use the MRI std instead of the individual MRI. We then use the 10-min ADAM std to replace the individual 10-min ADAM image.. The results produced using the MRI std method are close to the original two-step registration method (specific/nonspecific binding ratio, 4.211 vs. 4.326, P=0.055); and the 10 min ADAM std method is close to the MRI std method (specific/nonspecific binding ratio, 4.095 vs. 4.211, P=0.070).. The proposed 10-min ADAM std method yields acceptable quantitative measurements and significantly reduces patient loading by eliminating the additional individual MRI and 10-min ADAM imaging. More important, the interobserver problem can be solved because the area of interest (AOI) is drawn on the MRI std once; the AOI drawn on the MRI std can be mapped onto the registered 10-min ADAM std, and the individual 6 h ADAM image can then be automatically evaluated with the AOI on the 10-min ADAM std after the proposed registration. Thus, the examination of 123I ADAM thus becomes less expensive, more convenient, and useful for clinical applications.

Topics: Brain; Cinanserin; Female; Humans; Image Processing, Computer-Assisted; Magnetic Resonance Imaging; Male; Middle Aged; Reference Standards; Time Factors; Tomography, Emission-Computed, Single-Photon

Sunlight exposure is considered responsible for seasonal serotonin changes. Sixty-six healthy participants were recruited, and single photon emission computed tomography ([¹²³I]-ADAM SPECT) was used to investigate the association between serotonin transporter (SERT) availability and duration of sunlight exposure in Taiwan, a subtropical country. No significant correlation between SERT availability and the duration of sunlight exposure was found.

Topics: Adult; Cinanserin; Female; Humans; Iodine Radioisotopes; Male; Mesencephalon; Seasons; Serotonin Plasma Membrane Transport Proteins; Taiwan; Tomography, Emission-Computed, Single-Photon; Young Adult

It is predicted that depression will become the most common neurological disease in the new millennium. Its incidence is currently about 3% of diseases worldwide. Serotonin is an essential neurotransmitter for the central and peripheral nervous systems and plays a crucial role in neuropsychiatric disorders. (123)I-labeled ADAM was developed to facilitate an early diagnosis of serotonin transporter (SERT) abnormalities in the brain. Many studies have confirmed that the binding of this radiotracer to SERTs is associated with depression. The aim of this study was to evaluate the acute and subacute toxicity of ADAM and to determine its no observed adverse effect level (NOAEL) by administering it via intravenous injection to Sprague-Dawley rats for 14 consecutive days. None of the animals died, and no treatment-related clinical signs were observed. Urinalysis, hematology, and clinical chemistry analysis revealed that daily administration of ADAM (2-2-dimethylaminomethylphenylthio-5-iodophenylamine) for 2 weeks had no toxicological effects. It is concluded that ADAM exerts no adverse toxic effects on this animal model. The NOAEL was 155 microg/kg/day.

Topics: Animals; Cinanserin; Female; Iodine Radioisotopes; Male; No-Observed-Adverse-Effect Level; Radiopharmaceuticals; Rats; Rats, Sprague-Dawley; Serotonin Plasma Membrane Transport Proteins; Toxicity Tests, Acute; Toxicity Tests, Chronic

Previous positron emission tomography studies have demonstrated that serotonin transporter (SERT) binding in the midbrain is decreased in the depressive state of bipolar disorder (BD). The aim of this study was to assess SERT binding in the midbrain of patients in a euthymic state of BD.. Twenty-eight healthy controls and 24 patients in a euthymic state of medicated BD were recruited. Euthymic state was defined as Montgomery-Asberg Depression Rating Scale scores < 10 and Young Mania Rating Scale scores < 7 within a consecutive eight-week period. Single photon emission computed tomography with the radiotracer (123)I-ADAM was used to measure SERT binding in the midbrain. An equilibrium ratio model was used for data analysis. Specific uptake ratio (SUR), which represents availability of SERT binding in the midbrain, was the primary measurement outcome.. The averaged SURs were not different between healthy controls and BD patients in euthymic state (p = 0.27). However, a three-way ANCOVA analysis comparing SURs in healthy controls, bipolar I disorder (BD I) patients, and bipolar II disorder (BD II) patients, covarying education duration and sex, showed that the averaged SURs were significantly lower in BD I than BD II patients and healthy controls (p = 0.042). The decreased SURs in BD I patients were well correlated with duration of illness (R = -0.742, p = 0.014) only.. Our findings demonstrate that there is differential biological regulation in BD I and BD II patients after stable treatment, which may support the existence of a dichotomy in BD.

Topics: Analysis of Variance; Antidepressive Agents; Antipsychotic Agents; Bipolar Disorder; Brain; Cinanserin; Humans; Iodine Radioisotopes; Magnetic Resonance Imaging; Protein Binding; Psychiatric Status Rating Scales; Serotonin Antagonists; Serotonin Plasma Membrane Transport Proteins; Tomography, Emission-Computed, Single-Photon

Serotonin transporter (SERT) and dopamine transporter (DAT) levels differ in patients with major depression who are in a depressed state in comparison with healthy controls. The aim of this study was to examine the distribution volume ratios (DVRs) of SERT and DAT in drug-free and euthymic patients with a history of major depression. Subjects comprised 13 patients with a history of major depression and 26 sex- and age-matched healthy controls. The euthymic state of depression was defined as a score of 7 or less on the Hamilton Depression Rating Scale. The DVRs of SERT and DAT were approximated using SPECT, with [(123)I] 2-((2-((dimethylamino)methyl)phenyl)thio)-5-iodophenylamine (ADAM) and [(99m)Tc] TRODAT-1 as the ligands, respectively. There were no significant differences in the DVRs of SERT or DAT between healthy subjects and euthymic patients with a history of major depression; hence, the SERT and DAT DVRs may not therefore be trait markers for patients with major depression, which helps us to understand more about the pathophysiology of depression.

Topics: Adult; Brain; Brain Mapping; Case-Control Studies; Cinanserin; Depressive Disorder, Major; Dopamine Plasma Membrane Transport Proteins; Female; Humans; Male; Middle Aged; Organotechnetium Compounds; Psychiatric Status Rating Scales; Radiopharmaceuticals; Serotonin Plasma Membrane Transport Proteins; Tomography, Emission-Computed, Single-Photon; Tropanes

The aim of this study was to examine the feasibility of (123)I-ADAM to image the serotonin transporter (SERT) in Asian (Taiwanese) subjects. Single photon emission computed tomography (SPECT) scans were performed on nine healthy volunteers who were s-allele carriers at the polymorphism within the serotonin transporter promoter region (SERTPR) after intravenous bolus injection of (123)I-ADAM. Quantification of (123)I-ADAM binding was performed using the ratio equilibrium method (REM) with specific uptake ratio (SUR) and a simplified reference tissue model (SRTM). Curve-fitting techniques were used to obtain the peak equilibrium point from 241 to 301 min (average 264+/-20 min) after injection of (123)I-ADAM for the midbrain and from 215 to 270 min (average 235+/-18 min) after injection of (123)I-ADAM for the striatum. Two sets of SUR were obtained by either curve fitting (estimated values) or integrated period from 240 to 270 min (observed values). The estimated values of SUR were 2.11+/-0.51 for the midbrain and 1.50+/-0.44 for the striatum, whereas the observed values were 2.11+/-0.83 for the midbrain and 1.24+/-0.31 for the striatum. The SRTM showed that the binding potential (BP) was 2.10+/-0.66 for the midbrain and 1.35+/-0.25 for the striatum. There was a good correlation between estimated SUR, observed SUR and SRTM in the midbrain but not in the striatum. The optimal scanning duration for both the midbrain and the striatum should be 220 to 280 min similar to that suggested by previous studies in Caucasians. However, due to the low signal-to-noise ratio in the striatum, (123)I-ADAM could be an ideal tracer for imaging SERT in the midbrain but not in the striatum.

Topics: Adult; Brain; Cinanserin; Corpus Striatum; Female; Humans; Image Interpretation, Computer-Assisted; Iodine Radioisotopes; Radioligand Assay; Receptor, Serotonin, 5-HT2A; Serotonin Plasma Membrane Transport Proteins; Tomography, Emission-Computed, Single-Photon

Parkinson's disease (PD) affects both dopaminergic and serotonergic systems. In this study, we simultaneously evaluated dopamine and serotonin transporters in primates using dual-isotope single-photon emission computed tomography (SPECT) imaging and compared the results with traditional single-isotope imaging.. Four healthy and one 6-OHDA-induced PD monkeys were used for this study. SPECT was performed over 4 h after individual or simultaneous injection of [(99m)Tc]TRODAT-1 (a dopamine transporter imaging agent) and [(123)I]ADAM (a serotonin transporter imaging agent).. The results showed that the image quality and uptake ratios in different brain regions were comparable between single- and dual-isotope studies. The striatal [(99m)Tc]TRODAT-1 uptake in the PD monkey was markedly lower than that in normal monkeys. The uptake of [(123)I]ADAM in the midbrain of the PD monkey was comparable to that in the normal monkeys, but there were decreased uptakes in the thalamus and striatum of the PD monkey.. Our results suggest that dual-isotope SPECT using [(99m)Tc]TRODAT-1 and [(123)I]ADAM can simultaneously evaluate changes in dopaminergic and serotonergic systems in a PD model.

Topics: Animals; Brain; Cinanserin; Dopamine Plasma Membrane Transport Proteins; Feasibility Studies; Macaca; Organotechnetium Compounds; Oxidopamine; Parkinson Disease; Serotonin Plasma Membrane Transport Proteins; Time Factors; Tomography, Emission-Computed, Single-Photon; Tropanes

Parkinson's disease (PD) affects multiple neurotransmitter systems. The purpose of this study was to investigate differences in the serotonin transport system between normal and parkinsonian monkeys using 2-([2-([di-methylamino]methyl)phenyl]thio)-5-[(123)I] iodophenyl-amine([(123)I]ADAM), a serotonin transporters (SERT) radioligand. The brain single photon emission computed tomography (SPECT) was performed on two normal and one parkinsonian monkey. The parkinsonian monkey was induced by bilateral injection of 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle under magnetic resonance imaging (MRI) guidance. Each monkey underwent two [(99m)Tc] TRODAT-1 (a dopamine transporters imaging agent) and two [(123)I] ADAM brain SPECT scans. After a bolus injection of the radioligand, the SPECT data were acquired over 4h using a dual-head gamma camera equipped with ultra-high resolution fan-beam collimators. The striatal uptake of [(99m)Tc]TRODAT-1 was 46% lower in the parkinsonian monkey than those of normal monkeys at 210-240 min post-injection. [(123)I]ADAM uptake in the midbrain of the parkinsonian monkey was comparable to those of the controls. The uptakes of [(123)I]ADAM in the striatum, thalamus, and frontal cortex of the parkinsonian monkey, were 31%, 31%, and 23% lower than those of normal monkeys at 210-240 min post-injection, respectively. Our results suggest that [(123)I]ADAM SPECT has potential for evaluating the serotonin transporter changes in human PD.

Topics: Animals; Brain; Cinanserin; Disease Models, Animal; Macaca; Parkinsonian Disorders; Radiopharmaceuticals; Serotonin Plasma Membrane Transport Proteins; Tomography, Emission-Computed, Single-Photon

The in vivo assessment of brain serotonergic function might be of clinical relevance in neuropsychiatry. The loudness dependence of auditory evoked potentials (LD) has been proposed as an indirect indicator of cortical serotonergic activity, whereas single photon emission computed tomography (SPECT) and [123I]ADAM allow the selective assessment of brain serotonin transporters (SERT). The aim of this study was to investigate LD and SERT availability as independent variables of the brain serotonergic system in healthy volunteers. Fifteen (six male, nine female) subjects received both neurophysiological and imaging investigations. Evoked potentials were recorded following the application of acoustic stimuli with increasing intensities; the LD was analyzed using dipole source analysis. SPECT was performed four hours after injection of 137 +/- 11.4 MBq [123I]ADAM. As a measure of SERT availability specific ADAM brainstem binding was used. LD correlated significantly with SERT availability (Pearson's correlations: rho = -0.57, p < 0.05). The correlations remained significant after controlling for the effects of age or gender (partial correlations: rho = -0.60, p < 0.05) but were pronounced in the female group (rho = -0.83, p < 0.01). Associations between LD and SERT availability contribute to the understanding of the central serotonergic system and further validate the use of neurophysiological approaches as indirect measures of neurochemical brain activity.

Topics: Acoustic Stimulation; Adult; Brain Stem; Cinanserin; Evoked Potentials, Auditory, Brain Stem; Female; Humans; Image Processing, Computer-Assisted; Male; Radiopharmaceuticals; Serotonin; Tomography, Emission-Computed, Single-Photon

Imaging serotonin transporters in the living human brain is important in several fields, such as normal psychophysiology, mood disorders, eating disorders, and neurodegenerative disorders. The aim of this study was to compare different kinetic and semiquantitative methods for assessing serotonin transporters using (123)I-labeled 2-((2-((dimethylamino)methyl)phenyl)thio)-5-iodophenylamine (ADAM) in humans: an arterial plasma input model, simplified and Logan reference tissue models, and standardized uptake value ratios.. Nine subjects were scanned with dynamic (123)I-ADAM SPECT (mean age, 31 y; range, 24-43 y), and metabolite-corrected arterial input was measured. Tissue reference models (simplified reference tissue model, Logan reference tissue model, and ratio method) were validated against the outcome of a 1-tissue-compartment model, and performance with decreasing scan length was evaluated. The specificity of (123)I-ADAM binding was investigated in a blocking experiment.. Binding estimates from the simplified reference tissue and Logan reference tissue models correlated tightly with full kinetic modeling when based on a 240- or 360-min dynamic acquisition (r = 0.99); however, there were slight underestimations (3%-5%), especially in high-binding regions. Application of the ratio method to data from 200 to 240 min overestimated specific binding (on average, by 10% +/- 28%) and correlated only moderately with estimates from the 1-tissue-compartment model (r = 0.94). With an acquisition time of 0-120 min, the Logan model still yielded an acceptable outcome when a fixed clearance rate constant (k2') from the cerebellum was applied. Intravenously injected citalopram was not associated with a decrease in cerebellar binding. A lipophilic metabolite that did not seem to bind specifically to serotonin transporter was seen in 2 of 7 subjects.. Serotonin transporter binding with (123)I-ADAM SPECT can be assessed with the Logan model based on a 120-min acquisition when a constant k2' is applied. This model, because it allows for more accurate and less biased binding estimates and thus reduces the required sample size, is advantageous over the ratio method used in clinical studies so far. A single blocking experiment supported the use of the cerebellum as a reference region.

Topics: Adult; Artifacts; Brain; Cinanserin; Computer Simulation; Female; Humans; Image Interpretation, Computer-Assisted; Kinetics; Male; Models, Biological; Protein Binding; Radiopharmaceuticals; Reproducibility of Results; Sensitivity and Specificity; Serotonin Plasma Membrane Transport Proteins; Tomography, Emission-Computed, Single-Photon

Night eating syndrome (NES) represents a delay in the circadian pattern of food intake, manifested by evening hyperphagia and/or nocturnal awakenings accompanied by ingestions of food. A neurobiological marker of NES has been implicated with the recently discovered therapeutic response to the selective serotonin reuptake inhibitor (SSRI) sertraline. This pilot SPECT (single photon emission computed tomography) study compared the serotonin transporter (SERT) uptake ratios of night eaters with those of healthy controls. Six night eaters underwent SPECT imaging using the radiopharmaceutical (123)I-ADAM. Uptake, compared with that of the cerebellum, was obtained for the midbrain, basal ganglia, and temporal lobes; uptake ratios in night eaters were compared with those of six healthy controls. Night eaters had significantly greater SERT uptake ratios in the midbrain than healthy controls. These findings, in conjunction with the therapeutic response of NES to sertraline, indicate that the serotonin system is involved in the pathophysiology of NES.

Topics: Adult; Basal Ganglia; Binding Sites; Brain; Bulimia Nervosa; Cerebellum; Cinanserin; Circadian Rhythm; Diagnostic and Statistical Manual of Mental Disorders; Female; Humans; Iodides; Iodine Radioisotopes; Male; Mesencephalon; Protein Binding; Serotonin Plasma Membrane Transport Proteins; Surveys and Questionnaires; Temporal Lobe; Thyroid Gland; Tomography, Emission-Computed, Single-Photon

The serotonin (5-hydroxytryptamine, or 5-HT) transporters (5-HTT) are target-sites for commonly used antidepressants. [(123)I] ADAM is a novel radiotracer that selectively binds the 5-HTT of the central nervous system. The aim for this study was to compare four-parameter model (FPM) with three-parameter model (TPM) from non-invasive reference tissue model (RTM) for 5-HTT quantification using the cerebellum as indirect input function. Furthermore, we compared tracer kinetic model with the tissue ratio (TR) method. The binding potential (BP) values derived from both models were almost the same, but ratio of delivery (R(1)) in TPM had smaller standard deviation than the FPM. There was also significant correlation between BP and specific uptake ratio (SUR). In conclusion, simplified reference tissue model (SRTM) was the better choice because of its stability and convenient implementation for non-invasive quantification of brain SPECT studies. The correlation found between BP and SUR supports the use of TR method for quantification of 5-HTT to avoid arterial sampling in dynamic SPECT scan.

Topics: Adult; Algorithms; Cerebellum; Cinanserin; Female; Humans; Magnetic Resonance Imaging; Male; Models, Biological; Protein Binding; Radiopharmaceuticals; Serotonin Plasma Membrane Transport Proteins; Tissue Distribution; Tomography, Emission-Computed, Single-Photon; Young Adult

[123I]ADAM (2-((2-((dimethylamino)methyl)phenyl)thio)-5-iodophenylamine) is a promising radioligand for in-vivo quantification of serotonin transporters (SERT) using single photon emission computed tomography (SPECT) in man. We performed tracer kinetic analysis in various brain regions to determine the optimum equilibrium time for SERT quantification with [123I]ADAM and SPECT. Radiosyntheses of [123I]ADAM were performed at MAP Medical Technologies Oy, Tikkakoski, Finland. Thirty healthy male volunteers (21-41 yr) received between 104 and 163 MBq [123I]ADAM intravenously as a bolus. Consecutively, multiple SPECT scans were performed between 14 and 420 min post-injection (p.i.) using a Siemens Multispect 3 camera. Reconstruction was performed applying filtered back projection with a Butterworth filter (cut-off 0.7, order 7) in 128x128 matrices. Regions of interest (ROI) were drawn manually on the individual T1-weighted magnetic resonance image (MRI) comprising midbrain/hypothalamus for specific binding to SERT, and the cerebellum as reference region. After re-orientation to the MRI, the ROI template was applied to SPECT studies. We generated time-activity curves for the ROI and calculated the ratio countstarget/countscerebellum minus 1 (=V3'') as a measure for specific SERT binding. Counts were corrected for applied activity, acquisition time and body-weight. Peak uptakes were observed between 14 and 50 min after bolus injection. Counts per voxel were highest in the midbrain/hypothalamus, 798 (max. 872, min. 728), whereas 462 counts per voxel (max. 599, min. 412) were measured in the cerebellum at a mean time of 31 min p.i. Stable values for V3'' reached 205-320 min p.i. Mean peak V3'' value was 1.43 (95% CI 171-230) for the midbrain/hypothalamus at 205 min p.i. [123I]ADAM is a useful ligand for in-vivo quantification of human SERT by means of SPECT, with a comparatively better signal-to-noise ratio compared to beta-CIT. Our data suggest that the acquisition time for the SPECT scan is optimally, under pseudo-equilibrium conditions, between 205-320 min post-bolus injection of the tracer.

Topics: Adult; Brain; Cinanserin; Humans; Hypothalamus; Magnetic Resonance Imaging; Male; Mesencephalon; Protein Binding; Radiopharmaceuticals; Reproducibility of Results; Serotonin Plasma Membrane Transport Proteins; Tomography, Emission-Computed, Single-Photon

The present study examined the relationship between serotonin transporter (SERT) availability and hostility scores in healthy volunteers. SERT availability was measured by using SPECT with [(123)I] ADAM in 10 healthy participants. Hostility was measured with the Cook-Medley Hostility Scale. Hostile attribution, but not the other subscales of hostility, was negatively correlated with SERT availability. Central serotoninergic activities may play a role in hostility.

Topics: Adult; Brain; Cinanserin; Female; Hostility; Humans; Injections, Intravenous; Iodine Radioisotopes; Male; Serotonin Plasma Membrane Transport Proteins; Tomography, Emission-Computed, Single-Photon

Bulimia Nervosa (BN) is believed to be caused by an interaction of genetic and environmental factors. Previous studies support the existence of a bulimia-related endophenotype as well as disturbances in serotonin (5-HT) transmission. We studied serotonin transporter (SERT) binding in BN, and to investigate the possibility of a SERT-related endophenotype for BN, did this in a sample of female twins. We hypothesized clearly reduced SERT binding in BN women as opposed to healthy women, and intermediate SERT binding in unaffected co-twins.. We studied 13 female twins with BN (9 with purging and 4 with non-purging BN) and 25 healthy women, including 6 healthy twin sisters of BN patients and 19 women from 10 healthy twin pairs. [123I]ADAM, a selective SERT radioligand for single photon emission tomography (SPET) imaging, was used to assess SERT availability in the midbrain and the thalamus.. No differences in SERT binding were evident when comparing the BN women, their unaffected co-twins and the healthy controls (p = 0.14). The healthy sisters of the BN patients and the healthy control women had similar SERT binding in both brain regions. In a post hoc subgroup analysis, the purging bulimics had higher SERT binding than the healthy women in the midbrain (p = 0.03), but not in the thalamus.. Our finding of increased SERT binding in the midbrain in the purging BN women raises the possibility that this subgroup of bulimics might differ in serotonergic function from the non-purging ones. The similarity of the unaffected co-twins and the healthy controls doesn't support our initial assumption of a SERT-related endophenotype for BN. Due to the small sample size, our results need to be interpreted with caution and verified in a larger sample.

Topics: Adult; Bulimia; Cinanserin; Female; Humans; Longitudinal Studies; Phenotype; Serotonin; Serotonin Plasma Membrane Transport Proteins

Serotonergic dysfunction is considered to be involved in the pathophysiology of borderline personality disorder (BPD). The aim of this study was to investigate serotonin transporter availability in patients with BPD as a marker of the central serotonergic system.. Eight unmedicated patients with BPD and 9 healthy control subjects received single photon emission computed tomography (SPECT) 4 hours after injection of 185 MBq [I-123] ADAM (2-([2-([dimethylamino]methyl)phenyl]thio)). As a measure of brain serotonin transporter (SERT) availability, ratios of specific-to-nonspecific [I-123] ADAM binding for the brainstem and hypothalamus were calculated with an occipital reference. Levels of impulsiveness and depressive symptoms were assessed with the Barratt Impulsiveness Scale and the Beck Depression Inventory.. Mean specific-to-nonspecific ratios showed a 43% higher brainstem and a 12% higher hypothalamus ADAM binding in patients, compared with control subjects. We found significant correlations of ADAM binding with both age and impulsiveness but not depression. Associations of BIS scores with ADAM binding remained significant after controlling for age and depression (r = 0.69, p < 0.01).. The study provides evidence of a serotonergic dysfunction in patients with BPD and suggests a serotonergic component in the pathophysiology of the disorder. SERT binding reflected the level of impulsiveness as a common feature in BPD.

Topics: Adolescent; Adult; Borderline Personality Disorder; Brain Stem; Cinanserin; Female; Humans; Hypothalamus; Magnetic Resonance Imaging; Male; Psychiatric Status Rating Scales; Radiopharmaceuticals; Serotonin; Serotonin Plasma Membrane Transport Proteins; Surveys and Questionnaires; Tomography, Emission-Computed, Single-Photon

Blood platelets are thought to be a useful peripheral model for investigating the central serotoninergic mechanisms associated with the serotonin transporter (SERT). On the other hand, an in vivo investigation of SERT in the human brain has been made possible by the development of several promising SPECT radioligands, such as [123I]-ADAM. The aim of the present study was to investigate the possible correlation between the SERT measurements in the brain and those in platelets. Forty-four subjects (14 healthy subjects and 30 patients with the diagnosis of major depression or schizoaffective disorder) were examined. The [123I]-ADAM binding was assessed 4h after injection using MR-guided regions of interest (ROIs) in the midbrain and cerebellum. In a parallel investigation, serotonin (5HT) concentration and kinetic characteristics of 5HT uptake activity (Vmax and Km) were determined in platelet-rich plasma. Overall, there was no significant correlation between the V(max) of 5HT uptake in platelets and the specific to nonspecific partition coefficient of [123I]-ADAM (V''3) in the midbrain. However, low but significant Pearson correlation coefficients were found for V(max) and normalised activities measured in the midbrain (r=0.310, p=0.043). The correlation was stronger and significant in females (n=20, r=0.629, p=0.003) but low and non-significant in the 24 males (r=0.104). Although confirmation is necessary, it seems that the relationship between different indices of [123I]-ADAM binding in the brain and 5HT uptake characteristics in platelets is complex, nonuniform, and possibly gender-specific.

Topics: Adult; Blood Platelets; Brain; Cinanserin; Depression; Female; Humans; Iodine Radioisotopes; Male; Middle Aged; Psychotic Disorders; Radiopharmaceuticals; Serotonin; Serotonin Plasma Membrane Transport Proteins; Sex Factors; Tomography, Emission-Computed, Single-Photon

To assess the paroxetine-induced serotonin transporter (SERT) occupancy (SERTocc) using in vivo (123)I-ADAM SPECT.. (123)I-ADAM SPECT was used to investigate the SERTocc induced by paroxetine in major depression disorder (MDD) patients, to compare the SERT availability in drug-free MDD patients and healthy volunteers, and to study the relationship between paroxetine plasma concentrations (Cp) and SERTocc.. Measures of SERT availability by means of (123)I-ADAM SPECT were obtained in ten MDD patients before and after 4- to 6-week treatment with paroxetine 20 mg/day. (123)I-ADAM SPECT measures of SERT availability from a group of ten previously studied age-matched healthy volunteers were used for comparison. The relationship between percentages of SERTocc and paroxetine Cp was studied using an E (max) model.. Mean SERTocc values were 66.4 +/- 9.5% in midbrain, 63.0 +/- 9.6% in thalamus, and 61.3 +/- 10.9% in striatum. No significant differences in SERTocc were found among these three regions. No significant differences in mean SERT availability were found in any region between drug-free MDD patients (midbrain = 1.14 +/- 0.15; thalamus = 0.85 +/- 0.13; striatum = 0.70 +/- 0.07) and healthy volunteers (midbrain = 1.19 +/- 0.22; thalamus = 0.96 +/- 0.14; striatum = 0.67 +/- 0.15). The E (max) model returned a SERTocc(max) = 70.5% and a Cp(50) = 2.7 ng/ml.. Using (123)I-ADAM SPECT, treatment with paroxetine 20 mg/day leads to more than 60% SERTocc on average in cerebral regions with known high SERT density. Data from this study do not support the existence of SERT availability differences between drug-free MDD patients and healthy volunteers. Finally, the E (max) model is suitable for the study of paroxetine Cp relationship to (123)I-ADAM SPECT-measured SERTocc. This approach may be useful for pharmacokinetic-pharmacodynamic relationships in drug development.

Topics: Adult; Brain; Cinanserin; Corpus Striatum; Depressive Disorder; Female; Humans; Iodine Radioisotopes; Male; Mesencephalon; Middle Aged; Paroxetine; Radioligand Assay; Selective Serotonin Reuptake Inhibitors; Serotonin Antagonists; Serotonin Plasma Membrane Transport Proteins; Thalamus; Tomography, Emission-Computed, Single-Photon; Treatment Outcome

The serotonergic system may play an important role in the pathophysiology of major depressive disorder (MDD). Few imaging studies have examined serotonin transporter (SERT) binding in patients with MDD. We hypothesized that SERT binding activity may be altered in patients with MDD. This study compared SERT binding in patients with MDD with that in healthy controls.. We studied SERT activity in 7 patients (22-50 y old) with moderate to severe MDD and 6 healthy controls (24-56 y old) using (123)I-labeled 2-((2-((dimethylamino)methyl) phenyl)thio)-5-iodophenylamine (ADAM) and SPECT brain imaging. Subjects underwent SPECT 4 h after intravenous administration of 185 MBq (5 mCi) of (123)I-ADAM. Images were reconstructed in the axial plane, and region-of-interest demarcations were placed on the midbrain, medial temporal region, and basal ganglia region.. (123)I-ADAM binding to SERT in the midbrain was significantly lower (P = 0.01) in MDD patients (1.81 +/- 0.07) than in controls (1.95 +/- 0.13). Age-adjusted (123)I-ADAM binding in the midbrain correlated significantly with scores on the Hamilton Depression Rating Scale (r = 0.82; P = 0.02). A significant negative correlation was observed between (123)I-ADAM SERT binding in the midbrain and age in the healthy control group (r = 0.98; P = 0.0002). SERT binding in the basal ganglia or medial temporal regions of interest did not significantly differ between groups.. The findings from this preliminary study suggest the possibility of decreased SERT binding in the midbrain region of patients with MDD, with the degree of decrease correlating with the severity of depressive symptoms. There also appears to be an age-related decline in midbrain (123)I-ADAM SERT binding in healthy subjects.

Topics: Adult; Age Factors; Cinanserin; Depressive Disorder, Major; Female; Humans; Iodine Radioisotopes; Male; Membrane Glycoproteins; Membrane Transport Proteins; Mesencephalon; Middle Aged; Nerve Tissue Proteins; Protein Binding; Radiopharmaceuticals; Serotonin Antagonists; Serotonin Plasma Membrane Transport Proteins; Tomography, Emission-Computed, Single-Photon

(123)I-ADAM (2-([2-([dimethylamino]methyl)phenyl]thio)-5-(123)I-iodophenylamine) has been recently proposed as a new serotonin transporter (SERT) ligand for SPECT. The objective of this study was to characterize (123)I-ADAM in healthy volunteers. (123)I-ADAM distribution in the normal brain, pseudoequilibrium interval after a single injection, normal specific uptake values, and long-term test-retest variability and reliability were investigated.. Ten healthy volunteers underwent 2 SPECT sessions under the same conditions 47.6 +/- 24.0 d apart. Scans were sequentially acquired from the time of (123)I-ADAM intravenous injection up to 12 h after injection. Regions of interest (ROIs) for cerebellum (C), midbrain, thalamus, striatum, mesial temporal region, and cortex were drawn on MR images and pasted to corresponding SPECT slices after coregistration. Specific uptake ratios (SURs) at pseudoequilibrium and the simplified reference tissue model (SRTM) methods were used for quantification. SURs were obtained as ([region - C]/C) at each time point. Test-retest variability and reliability (intraclass correlation coefficient [ICC]) were calculated.. The highest (123)I-ADAM specific uptake was found in the midbrain and thalamus, followed by the striatum and mesial temporal region. Quantification results using SUR and SRTM were correlated with R = 0.93 (test) and R = 0.94 (retest). SURs remained stable in all regions from 4 to 6 h after injection. Using SUR, test-retest variability/ICC were 13% +/- 11%/0.74 in midbrain, 16% +/- 13%/0.63 in thalamus, 19% +/- 18%/0.62 in striatum, and 22% +/- 19%/0.05 in mesial temporal region.. (123)I-ADAM accumulates in cerebral regions with high known SERT density. The optimal imaging time for (123)I-ADAM SPECT quantification is suggested to be from 4 to 6 h after a single injection. Long-term test-retest variability and reliability found in the midbrain are comparable to that reported with other (123)I-labeled SPECT ligands. These results support the use of (123)I-ADAM SPECT for SERT imaging after a single injection in humans.

Topics: Adult; Aged; Brain; Cinanserin; Female; Follow-Up Studies; Humans; Image Enhancement; Injections, Intravenous; Male; Membrane Glycoproteins; Membrane Transport Proteins; Metabolic Clearance Rate; Middle Aged; Nerve Tissue Proteins; Radiopharmaceuticals; Reference Values; Reproducibility of Results; Sensitivity and Specificity; Serotonin Plasma Membrane Transport Proteins; Time Factors; Tissue Distribution; Tomography, Emission-Computed, Single-Photon

123I-ADAM is a novel radioligand for imaging of the brain serotonin transporters (SERTs). Traditionally, the analysis of brain receptor studies has been based on observer-dependent manual region of interest definitions and visual interpretation. Our aim was to create a template for automated image registrations and volume of interest (VOI) quantifications and to show that an automated quantification method of 123I-ADAM is more repeatable than the manual method.. A template and a predefined VOI map was created from 123I-ADAM scans done for healthy volunteers (n = 15). Scans of another group of healthy persons (HS, n = 12) and patients with bulimia nervosa (BN, n = 10) were automatically fitted to the template and specific binding ratios (SBRs) were calculated by using the VOI map. Manual VOI definitions were done for the HS and BN groups by both one and two observers. The repeatability of the automated method was evaluated by using the BN group.. For the manual method, the interobserver coefficient of repeatability was 0.61 for the HS group and 1.00 for the BN group. The introobserver coefficient of repeatability for the BN group was 0.70. For the automated method, the coefficient of repeatability was 0.13 for SBRs in midbrain.. An automated quantification gives valuable information in addition to visual interpretation decreasing also the total image handling time and giving clear advantages for research work. An automated method for analysing 123I-ADAM binding to the brain SERT gives repeatable results for fitting the studies to the template and for calculating SBRs, and could therefore replace manual methods.

Topics: Automation; Cinanserin; Humans; Image Processing, Computer-Assisted; Iodine Radioisotopes; Observer Variation; Reference Values; Reproducibility of Results; Tomography, Emission-Computed, Single-Photon

ADAM, 2-((2-((dimethylamino)methyl)phenyl)thio)-5-iodophenylamine, is a recently described SPECT tracer for exploration of the serotonin transporter. We evaluated its potential to detect abnormalities in serotonergic function in the rat using 1) a model of serotonergic neuron lesion induced with 5,7-dihydroxytryptamine (5,7-DHT), and 2) experimental induction of acute decrease in endogenous brain serotonin levels. Cerebral biodistribution studies of [125I]ADAM were performed in normal conditions, in 5,7-DHT-lesioned rats, and after acute serotonin depletion obtained with p-chlorophenylalanine (pCPA). Around 50% reduction in accumulation of ADAM was observed in the hypothalamus and hippocampus 3 weeks after lesion of serotonergic neurons, whereas a more modest decrease of 15-30% occurred in the thalamus, frontal cortex, and striatum. This demonstrated the ability of the tracer to detect serotonergic neuron loss in vivo. After inducing acute 5-HT depletion with pCPA, we observed an increase in in vivo [125I]ADAM binding in all brain areas studied. The higher in vivo binding of [125I]ADAM in pCPA-treated rats than in controls was mainly due to an increase in specific binding to the SERT, as demonstrated by greatly reduced binding in the presence of a saturating dose of paroxetine. This may indicate in vivo competition between ADAM and 5-HT for binding to the SERT. The present findings thus demonstrate that ADAM is a specific SERT radioligand which can be used for in vivo study of central serotonin systems, and supports its use as a tracer for SPECT studies in human disorders involving dysfunction of serotonergic neurotransmission.

Topics: Animals; Brain; Carrier Proteins; Cinanserin; Male; Membrane Glycoproteins; Membrane Transport Proteins; Nerve Tissue Proteins; Radioactive Tracers; Rats; Rats, Wistar; Serotonin; Serotonin Plasma Membrane Transport Proteins

Imaging of serotonin transporter (SERT) in the central nervous system may provide an important tool to evaluate some psychiatric disorders. Recently, a novel (123)I-labeled radiotracer, 2-((2-((dimethylamino)methyl)phenyl)thio)-5-iodophenylamine ((123)I-ADAM), has been developed that exhibited a high selectivity for SERT. The aim of this study was to characterize the biodistribution and specificity of (123)I-ADAM to SERT using quantitative autoradiography in both control and neurotoxin-treated animals.. (123)I-ADAM (74 MBq) was injected intravenously into the mice to access its biodistribution in the brain via quantitative autoradiography. Further, rats with serotonin depleted by intraperitoneal injection of p-chloroamphetamine (PCA) were used to evaluate the specificity of (123)I-ADAM to SERT. The levels of biogenic amines were then measured and correlated with quantitative (123)I-ADAM labeling in control and PCA-treated rat brains.. The autoradiographic results showed that (123)I-ADAM accumulated in SERT-rich brain areas after systemic injection, including the globus pallidus, thalamus, hypothalamus, substantia nigra, interpeduncular nucleus, amygdala, and raphe nucleus. The dorsal raphe nucleus had the highest initial uptake with a peak specific binding ratio (i.e., [target - cerebellum]/cerebellum) at 120 min after injection. (123)I-ADAM uptake was dramatically decreased in the hippocampus, thalamus, amygdala, geniculate nuclei, hypothalamus, raphe nucleus, and substantia nigra in PCA-lesioned rats. The decrement in radioactivity was more prominent at higher dosages of PCA and was in parallel with the changes in amounts of serotonin and 5-hydroxyindoleacetic acid in the prefrontal cortex.. This study demonstrates that regional distribution of (123)I-ADAM radioactivity is similar to the SERT localization in both rat and mouse brains. We also validated that destruction on central serotonergic neurons after PCA treatment inhibits the uptake of (123)I-ADAM in serotonin-rich brain regions. High specific binding to SERT in vivo makes (123)I-ADAM an appropriate radiotracer for solitary studies of serotonin functions in living humans.

Topics: Animals; Autoradiography; Binding Sites; Biogenic Amines; Brain; Carrier Proteins; Cinanserin; Iodine Radioisotopes; Male; Membrane Glycoproteins; Membrane Transport Proteins; Metabolic Clearance Rate; Mice; Mice, Inbred ICR; Nerve Tissue Proteins; p-Chloroamphetamine; Protein Binding; Radionuclide Imaging; Radiopharmaceuticals; Rats; Serotonin Plasma Membrane Transport Proteins; Tissue Distribution

Serotonin transporters (SERTs) play a major role in modulating serotonergic neuronal function and are the target of many antidepressant drugs used in neuro-psychiatric disorders. To gain more information on the temporal distribution of SERTs, 2-([2-([dimethylamino]methyl)phenoxyl]thio)-5-[I]iodophenylamine (I-ADAM) single photon emission computed tomography (SPECT) was utilized in an in vivo imaging study using non-human primates.. Two female monkeys (Macaca cyclopis) were studied. Eight brain SPECT imaging examinations, each 30 min in duration, were obtained after injection of 185 MBq of I-ADAM. Images were obtained using a dual-head gamma camera equipped with ultra-high resolution fan-beam collimators. In addition to visual inspection, the radio-uptake and specific uptake ratios (SURs) of midbrain (MB), thalamus (TH), striatum (ST), temporal and frontal cortices and the whole brain in reference to the corresponding magnetic resonance image at the eight time points were measured. The SUR of MB, using cerebellum (CB) as the reference tissue, was calculated as (MB - CB)/CB, in mean counts/pixel. The SURs of the other brain regions were similarly measured.. There was relatively high uptake of I-ADAM in the MB and TH, moderate uptake in ST, lower uptake in the cerebral cortex, and almost no uptake in the CB. The image of MB could be easily identified at the first 30 min time point. It appeared that the SURs of MB, TH and ST reached equilibrium around 210 min after injection. No adverse reactions of the primates were found during and after imaging. Brain distribution of I-ADAM in the primate appeared consistent with the known distribution of SERTs.. In conjunction with a high SUR in MB, TH and ST, we speculate that I-ADAM may be a potential radioligand for SPECT studies of serotonin transporters in humans.

Topics: Animals; Brain; Cinanserin; Female; Humans; Iodine Radioisotopes; Macaca; Membrane Glycoproteins; Membrane Transport Proteins; Metabolic Clearance Rate; Nerve Tissue Proteins; Primates; Radionuclide Imaging; Radiopharmaceuticals; Serotonin Plasma Membrane Transport Proteins; Tissue Distribution

2-((2-((Dimethylamino)methyl)phenyl)thio)-5-(123)I-iodophenylamine ((123)I-ADAM) is a new radiopharmaceutical that selectively binds the central nervous system serotonin transporters. The purpose of this study was to measure its whole-body biokinetics and estimate its radiation dosimetry in healthy human volunteers. The study was conducted within a regulatory framework that required its pharmacologic safety to be assessed simultaneously.. The sample included 7 subjects ranging in age from 22 to 54 y old. An average of 12.7 whole-body scans were acquired sequentially on a dual-head camera for up to 50 h after the intravenous administration of 185 MBq (5 mCi) (123)I-ADAM. The fraction of the administered dose in 13 regions of interest (ROIs) was quantified from the attenuation-corrected geometric mean counts in conjugate views. Multiexponential functions were iteratively fit to each time-activity curve using a nonlinear, least-squares regression algorithm. These curves were numerically integrated to yield source organ residence times. Gender-specific radiation doses were then estimated with the MIRD technique. SPECT brain scans obtained 3 h after injection were evaluated using an ROI analysis to determine the range of values for the region to cerebellum.. There were no pharmacologic effects of the radiotracer on any of the subjects, including no change in heart rate, blood pressure, or laboratory results. Early planar images showed differentially increased activity in the lungs. SPECT images demonstrated that the radiopharmaceutical localized in the midbrain in a distribution that is consistent with selective transporter binding. The dose-limiting organ in both men and women was the distal colon, which received an average of 0.12 mGy/MBq (0.43 rad/mCi) (range, 0.098-0.15 mGy/MBq). The effective dose equivalent and effective dose for (123)I-ADAM were 0.037 +/- 0.003 mSv/MBq and 0.036 +/- 0.003 mSv/MBq, respectively. The mean adult male value of effective dose for (123)I-ADAM is similar in magnitude to that of (111)In-diethylenetriaminepentaacetic acid (0.035 mGy/MBq), half that of (111)In-pentetreotide (0.81 mGy/MBq), and approximately twice that of (123)I-inosine 5'-monophosphate (0.018 mGy/MBq). The differences in results between this study and a previous publication are most likely due to several factors, the most prominent being this dataset used attenuation correction of the scintigraphic data. Region-to-cerebellum ratios for the brain SPECT scans were 1.95 +/- 0.13 for the midbrain, 1.27 +/- 0.10 for the medial temporal regions, and 1.11 +/- 0.07 for the striatum.. (123)I-ADAM may be a safe and effective radiotracer for imaging serotonin transporters in the brain and the body.

Topics: Adult; Brain; Carrier Proteins; Cinanserin; Female; Humans; Iodine Radioisotopes; Male; Membrane Glycoproteins; Membrane Transport Proteins; Middle Aged; Nerve Tissue Proteins; Radiation Dosage; Radiopharmaceuticals; Serotonin; Serotonin Plasma Membrane Transport Proteins; Tissue Distribution; Tomography, Emission-Computed, Single-Photon

A radiopharmaceutical, (123)I-labeled 2-((2-((dimethylamino)methyl)phenyl)thio)-5-iodophenylamine ([(123)I]ADAM), has been developed recently for evaluation of how serotonin transporters (SERT) function in the brain. However, the detailed biodistribution and specific binding in certain brain areas are not well investigated. In this study, both phosphor plate imaging and microautoradiography were applied to explore the binding characteristics of [(123)I]ADAM in SERT neurons. The effect of two psychotropics and one narcotic on the binding of [(123)I]ADAM to SERT was also studied. Fluoxetine and desipramine, both are psychotropics and specific SERT ligands and decreased the affinity of [(123)I]ADAM, while p-chloroamphetamine (PCA), a narcotic, destroyed most of serotonergic neurons, as well as reducing the concentration of serotonin and the number of SERT in the brain as shown by the biodistribution of [(123)I]ADAM. Significant and selective accumulation of [(123)I]ADAM in the areas from midbrain to brain stem in normal mice with maximum target-to-background ratio was found at 90 minutes postinjection. A rapid clearance of [(131)I]ADAM at 120 minutes postinjection was found in the CA1, CA3 and ThN brain areas. In addition, the inhibition effect on binding ability of [(123)I]ADAM to SERT by the psychotropics and the narcotic was found to have the order of: PCA > fluoxetine > desipramine.

Topics: Adrenergic Uptake Inhibitors; Animals; Autoradiography; Brain; Cinanserin; Desipramine; Fluoxetine; Male; Membrane Glycoproteins; Membrane Transport Proteins; Metabolic Clearance Rate; Mice; Mice, Inbred ICR; Nerve Tissue Proteins; p-Chloroamphetamine; Radionuclide Imaging; Radiopharmaceuticals; Selective Serotonin Reuptake Inhibitors; Serotonin; Serotonin Agents; Serotonin Plasma Membrane Transport Proteins; Tissue Distribution

A novel radioiodine ligand [(123)I] ADAM (2-((2-((dimethylamino)methyl)phenyl)thio)-5-iodophenylamine) has been suggested as a promising serotonin transporter (SERT) imaging agent for the central nervous system. In this study, the biodistribution of SERTs in the rabbit brain was investigated using [(123)I] ADAM and mapping images of the same animal produced by both single-photon emission computed tomography (SPECT) and microautoradiography. A semiquantification method was adopted to deduce the optimum time for SPECT imaging, whereas the input for a simple fully quantitative tracer kinetic model was provided from arterial blood sampling data.. SPECT imaging was performed on female rabbits postinjection of 185 MBq [(123)I] ADAM. The time-activity curve obtained from the SPECT images was used to quantify the SERTs, for which the binding potential was calculated from the kinetic modeling of [(123)I] ADAM. The kinetic data were analyzed by the nonlinear least squares method. The effects of the selective serotonin reuptake inhibitors fluoxetine and p-chloroamphetamine (PCA) on rabbits were also evaluated. After scanning, the same animal was sacrificed and the brain was removed for microautoradiography. Regions-of-interest were analyzed using both SPECT and microautoradiography images. The SPECT images were coregistered manually with the corresponding microautoradiography images for comparative study.. During the time interval 90-100 min postinjection, the peak specific binding levels in different brain regions were compared and the brain stem was shown to have the highest activity. The target-to-background ratio was 1.89+/-0.02. Similar studies with fluoxetine and PCA showed a background level for SERT occupation. Microautoradiography demonstrated a higher level of anatomical details of the [(123)I] ADAM distribution than that obtained by SPECT imaging of the rabbit brain.. SPECT imaging of the rabbit brain with [(123)I] ADAM showed high affinity, high specificity, and favorable kinetics. The time-activity curve showed that the accumulation of the [(123)I] ADAM in the brain stem reached a maximum between 90 and 100 min postinjection. The microautoradiography provides high-resolution images of the rabbit brain. Our results for the [(123)I] ADAM biodistribution in the rabbit brains demonstrate that this new radioligand is suitable as a selective SPECT imaging agent for SERTs.

Topics: Algorithms; Animals; Brain; Cinanserin; Female; Image Interpretation, Computer-Assisted; Metabolic Clearance Rate; Models, Biological; Rabbits; Radiopharmaceuticals; Receptors, Serotonin; Tissue Distribution; Tomography, Emission-Computed, Single-Photon

Iodine-123 labeled 2-((2-((dimethylamino)methyl)phenyl)thio)-5-iodophenylamine ([(123)I] ADAM) has been suggested as a promising serotonin transporter (SERT) imaging agent. Much research has been accomplished, mainly focusing on the SERT binding sites in the central nervous system (CNS). However, the biodistribution of [(123)I] ADAM using whole body autoradiography (WBAR) has never been previously described, to the best of our knowledge. In this study, we assayed the biodistribution of [(123)I] ADAM in tissues/organs removed from mice, and measured their radioactivity with a scintillation counter (SC). The results showed that the liver has the highest uptake. On the other hand, the WBAR clearly demonstrated that [(123)I] ADAM was bound to SERT-rich sites including those in the brain stem, lung, adrenal glands and intestinal mucosa. This radiotracer also accumulated in the liver, kidney, and thyroid. The results from both methods were compared; each has its own complementary role in the biodistribution studies. The SC method revealed the total amount of radiotracer accumulation in each organ, and the WBAR demonstrated more anatomical details of the radiotracer's distribution. The whole body distribution results of the radioligand using both methods explore the usage of this novel radioligand for most possible SERT binding sites, not only in the CNS but also in the peripheral nervous system and neuroendocrine tissues. These findings suggest that [(123)I] ADAM is a potentially useful imaging agent for SERT.

Topics: Animals; Autoradiography; Biomarkers; Carrier Proteins; Cinanserin; Iodine Radioisotopes; Male; Membrane Glycoproteins; Membrane Transport Proteins; Mice; Mice, Inbred ICR; Nerve Tissue Proteins; Radiopharmaceuticals; Reproducibility of Results; Sensitivity and Specificity; Serotonin Plasma Membrane Transport Proteins; Statistics as Topic; Tissue Distribution; Whole-Body Counting

We reported recently a highly selective radioligand, 2-([2-([dimethylamino]methyl)phenyl]thio)-5-[(123)I]iodophenylamine (ADAM), for SPECT imaging of serotonin transporters (SERT). In this article we describe the kinetic modeling of [(123)I]ADAM and its ability to quantitatively and reproducibly measure the concentrations of SERT in the nonhuman primate brain. We also investigate simplified models of tracer behavior that do not require invasive arterial blood sampling.. Three female baboons each underwent 3 [(123)I]ADAM SPECT studies. The studies consisted of a dynamic sequence of seventy-two 5-min scans after injection of 330 +/- 50 MBq (mean +/- SD) [(123)I]ADAM. Rapid arterial blood samples were obtained and corrected for the presence of labeled metabolites. Dynamic imaging and metabolite-corrected plasma data were analyzed using graphic analysis to give the distribution volumes (DVs) of different brain regions. DV ratios (DVRs) of target to cerebellum were derived and compared against a kinetic reference tissue model and simple target-to-background ratio.. Averaged over all 9 scans, the mean DV in the midbrain was 4.86 +/- 1.06 mL/mL and the mean DV in the cerebellum was 2.25 +/- 0.48 mL/mL. The mean test-retest repeatability of the midbrain DV was 14.5%. The reference tissue model gave a mean midbrain DVR of 2.01 +/- 0.17 and correlated strongly with the DVR calculated from the full kinetic model (correlation coefficient [R(2)] = 0.94; P < 0.001), but with much improved repeatability (test-retest, 5.4%; intersubject variability, 5.2%). Similarly, the simple ratio method gave strong correlations with the full kinetic model (R(2) = 0.89; P < 0.001) and a test-retest of 7.6%.. Accurate, repeatable quantification of SERT in the nonhuman primate brain is possible using kinetic modeling of dynamic [(123)I]ADAM SPECT scans. Simplified models, which do not require arterial blood sampling, gave accurate results that correlated strongly with the full kinetic model. The test-retest reliability of the simplified reference region models was excellent. Quantification of SERT is possible using full kinetic modeling and also with simpler reference region methods.

Topics: Animals; Brain; Carrier Proteins; Cinanserin; Female; Membrane Glycoproteins; Membrane Transport Proteins; Nerve Tissue Proteins; Papio; Radiopharmaceuticals; Serotonin; Serotonin Plasma Membrane Transport Proteins; Tomography, Emission-Computed, Single-Photon

Serotonin transporters (SERT) are target-sites for commonly used antidepressants, such as fluoxetine, paroxetine, sertraline, and so on. Imaging of these sites in the living human brain may provide an important tool to evaluate the mechanisms of action as well as to monitor the treatment of depressed patients. Synthesis and characterization of an improved SERT imaging agent, ADAM (2-((2-((dimethylamino)methyl)phenyl)thio)-5-iodophenylamine)(7) was achieved. The new compound, ADAM(7), displayed an extremely potent binding affinity toward SERT ( K(i)=0.013 nM, in membrane preparations of LLC-PK(1)-cloned cell lines expressing the specific monoamine transporter). ADAM(7) also showed more than 1,000-fold selectivity for SERT over norepinephrine transporter (NET) and dopamine transporter (DAT) ( K(i)=699 and 840 nM, for NET and DAT, respectively). The radiolabeled compound [(125)I]ADAM(7) showed an excellent brain uptake in rats (1.41% dose at 2 min post intravenous [IV] injection), and consistently displayed the highest uptake (between 60-240 min post IV injection) in hypothalamus, a region with the highest density of SERT. The specific uptake of [(125)I]ADAM(7) in the hypothalamus exhibited the highest target-to-nontarget ratio ([hypothalamus - cerebellum]/cerebellum was 3.97 at 120 min post IV injection). The preliminary imaging study of [(123)I]ADAM in the brain of a baboon by single photon emission computed tomography (SPECT) at 180-240 min post IV injection indicated a specific uptake in midbrain region rich in SERT. These data suggest that the new ligand [(123)I]ADAM(7) may be useful for SPECT imaging of SERT binding sites in the human brain.

Topics: Animals; Carrier Proteins; Cinanserin; Dopamine; Dopamine Plasma Membrane Transport Proteins; Iodine Radioisotopes; Ligands; LLC-PK1 Cells; Magnetic Resonance Imaging; Membrane Glycoproteins; Membrane Transport Proteins; Membranes; Nerve Tissue Proteins; Norepinephrine; Norepinephrine Plasma Membrane Transport Proteins; Radiopharmaceuticals; Rats; Serotonin; Serotonin Plasma Membrane Transport Proteins; Spectrophotometry, Infrared; Swine; Symporters; Tissue Distribution; Tomography, Emission-Computed, Single-Photon

An improved iodinated tracer, ADAM (2-((2-((dimethylamino)methyl)- phenyl)thio)-5-iodophenylamine) for imaging serotonin transporters (SERT) with single photon emission computerized tomography (SPECT), was prepared and characterized. Scatchard analysis of saturation binding of [(125)I]ADAM to rat frontal cortical membrane homogenates gave a K(d) value of 0.15 +/- 0.03 nM and a B(max) value of 194 +/- 65 fmol/mg protein. Biodistribution of [(125)I]ADAM in rat brain after an iv injection showed a high specific binding in the regions of hypothalamus, cortex, striatum, and hippocampus, where SERT are concentrated and the specific binding peaked at 120-240 min postinjection [(hypothalamus-cerebellum)/cerebellum = 4.3 at 120 min post-iv injection]. Moreover, the specific hypothalamic uptake was blocked by pretreatment with SERT selective competing drugs, such as paroxetine and (+)McN5652, while other noncompeting drugs, such as ketanserin, raclopride, and methylphenidate, showed no effect. The radioactive material recovered from rat brain homogenates at 120 min after [(125)I]ADAM injection showed primarily the original compound (>90%), a good indication of in vivo stability in the brain tissues. Both male and female rats showed similar and comparable organ distribution pattern and regional brain uptakes. Ex vivo autoradiograms of rat brain sections (120 min after iv injection of [(125)I]ADAM) showed intense labeling in several regions (olfactory tubercle, lateral septal nucleus, hypothalamic and thalamic nuclei, globus pallidus, central gray, superior colliculus, substantia nigra, interpeduncular nucleus, dorsal and median raphes, and locus coerulus), which parallel known SERT density. These results strongly suggest that the novel tracer ADAM is superior to the congers (i.e., IDAM) reported previously. When labeled with I-123, ADAM will be an improved and useful SPECT imaging agent for SERT in the brain.

Topics: Animals; Autoradiography; Brain; Carrier Proteins; Cinanserin; Female; Humans; In Vitro Techniques; Iodine Radioisotopes; Male; Membrane Glycoproteins; Membrane Transport Proteins; Nerve Tissue Proteins; Radioligand Assay; Rats; Rats, Sprague-Dawley; Serotonin Plasma Membrane Transport Proteins; Sex Characteristics; Tissue Distribution