n-(3-iodopropen-1-yl)-2-carbomethoxy-3-(4-chlorophenyl)tropane and Parkinson-Disease

We evaluated the patterns of dopamine transporter loss in the striatum of ten controls, twenty patients with Parkinson's disease (PD), and nine with progressive supranuclear palsy (PSP) using (123)I-IPT single photon emission tomography (SPECT). Four ROIs in the striatum correspond to the head of caudate nucleus (ROI 1), a transitional region between head of caudate and putamen (ROI 2), anterior putamen (ROI 3), and posterior putamen (ROI 4). A striatal ratio of specific to nondisplaceable uptake (V3'') was calculated normalizing the activity of the ROIs to that of occipital cortex. V3'' values were significantly reduced in all ROIs of PD and PSP patients, compared with controls (p=0.001). V3'' value in ROI 2 was significantly lower in PSP group, compared with PD group (p=0.02). The percent reductions of striatal uptake in ROI 1, ROI 2, ROI 3 and ROI 4 were 56%, 53%, 64% and 78% in PD patients, whereas 75%, 72%, 75% and 77% in PSP patients, respectively. The reduction patterns of uptake were significantly different between PD and PSP groups (p=0.001). In PD patients, the percent reductions of (123)I-IPT uptake were significantly greater in ROI 3 and 4 compared with ROI 1 or 2, whereas those were similar in all ROIs of PSP patients. In addition, PD patients showed a significantly higher posterior putamen/caudate ratio of reduced (123)I-IPT uptake than the anterior putamen/caudate ratio (p=0.005). Our results implicate that (123)I-IPT SPECT is a relatively simple and reliable technique that may be useful in differentiating PD from PSP.

Topics: Adult; Aged; Basal Ganglia; Caudate Nucleus; Diagnosis, Differential; Dopamine; Dopamine Plasma Membrane Transport Proteins; Female; Humans; Iodine Radioisotopes; Male; Middle Aged; Parkinson Disease; Predictive Value of Tests; Putamen; Reference Values; Supranuclear Palsy, Progressive; Tomography, Emission-Computed, Single-Photon; Tropanes

Putative neurotoxic actions of levodopa and neuroprotective effects of dopamine agonists, as indicated by laboratory and animal studies, provide the rationale to study their effect on the progression of Parkinson's disease. Aim of this pilot study was to compare the effects of monotherapy with the dopamine agonist alpha-dihydroergocryptine (DEC) versus monotherapy with levodopa on nigrostriatal dopaminergic neurons as measured with dopamine transporter (DAT) SPECT. 25 PD patients (H&Y stages 1 to 2.5) entered this study and were treated in a randomized fashion either with DEC (101+/-39 mg) or levodopa (369+/-51 mg) monotherapy. 16/25 patients (8 per group) terminated the study after 52 weeks. In each patient SPECT investigations with [123I]IPT were performed at baseline and after 52 weeks to assess changes of specific DAT binding over time. Changes in clinical symptoms were assessed by UPDRS score. The mean annual decline rate in striatal IPT-binding was lower in the DEC group (8.4%) compared to the levodopa group (10.4%). The difference was most accentuated in the putamen (DEC: 7.3%; levodopa: 16.2%; p = 0.16). Due to the small sample size and the relatively short observation period, however, group differences did not reach a statistical significant level. The results of this pilot study suggest that as compared to levodopa monotherapy DEC may have beneficial effects on decline of dopamine transporter binding similar to those recently described for pramipexole.

Topics: Adolescent; Aged; Caudate Nucleus; Dihydroergocryptine; Dopamine Plasma Membrane Transport Proteins; Double-Blind Method; Female; Follow-Up Studies; Humans; Levodopa; Male; Membrane Glycoproteins; Membrane Transport Proteins; Middle Aged; Neostriatum; Nerve Tissue Proteins; Parkinson Disease; Putamen; Radiopharmaceuticals; Tomography, Emission-Computed, Single-Photon; Tropanes

Imaging of striatal dopamine transporter binding allows differentiation between patients with Parkinson's disease and controls. We investigated the use of this technique to monitor disease progression. We used N-(3-iodopropen-2-yl)-2beta-carbomethoxy-3beta-(4-chlorophenyl) tropane (IPT) and single photon emission computed tomography (SPECT) to determine dopamine transporter function in eight patients with Parkinson's disease Hoehn and Yahr stage I to III over time. Patients were recruited from the movement disorder clinic and were studied at entry and after a follow-up period of 1 and 2 years. Specific striatal IPT binding was measured with a manual region of interest technique. At entry, all patients showed a reduction of striatal IPT uptake of approximately 50% compared to controls, with a mean striatum to background ratio of 3.61 +/- 0.72 (controls, 7.34 +/- 1.18). Putamen to background ratios were initially measured as 2.42 +/- 0.74 and caudate to background ratios as 5.00 +/- 0.73 (controls, 6.46 +/- 1.22 for putamen and 8.58 +/- 1.36 for caudate). Specific striatal IPT binding decreased by a mean of 6.6% in the first year and another 5.3% in the second year. Changes of specific IPT binding over time were similar in caudate and putamen. In patients with clinically asymmetric disease, differences between the rate of decline in the ipsilateral and contralateral sides could not be detected. The findings suggest that IPT SPECT can quantify the reduction of dopamine transporter binding over time. This technique seems to be a useful tool in monitoring the intra-individual progression of dopaminergic cell loss in patients with Parkinson's disease and may help to follow the effects of putative neuroprotective drugs in future clinical trials.

Topics: Adult; Aged; Carrier Proteins; Caudate Nucleus; Disease Progression; Dopamine Plasma Membrane Transport Proteins; Female; Humans; Male; Membrane Glycoproteins; Membrane Transport Proteins; Middle Aged; Neostriatum; Nerve Tissue Proteins; Parkinson Disease; Putamen; Radiopharmaceuticals; Tomography, Emission-Computed, Single-Photon; Tropanes

Specific binding to dopamine transporters may serve as a tool to detect early loss of nigrostriatal dopaminergic neurons in patients with Parkinson's disease.. To determine striatal dopamine transporter binding using the cocaine analogue [I-123]N-(3-iodopropen-2-yl)-2beta-carbomethoxy-3beta-(4-chl orophenyl) tropane ([I-123]IPT) and single photon emission computed tomography.. We studied 9 control subjects (mean age, 58 years; range, 41-69 years) and 28 patients with early Parkinson's disease (Hoehn and Yahr stages I [n = 14] and II [n = 14] [symptom duration, <5 years]; mean age, 55.5 years; range, 36-71 years). Single photon emission computed tomography was performed 90 minutes after injection of 120 to 150 MBq of radioactive [I-123]IPT.. Specific striatal [I-123] IPT binding (mean +/- SD) was significantly reduced in patients with early Parkinson's disease (ipsilateral striatum: 4.09+/-0.97; range, 2.46-6.40; contralateral striatum: 3.32+/-0.76; range, 1.80-5.13) compared with controls (left striatum: 7.28+/-0.94; range, 5.78-8.81; right striatum: 7.41+/-1.28; range, 5.58-9.44). IPT binding ratios (mean +/- SD) were significantly lower in patients with Hoehn and Yahr stage II (ipsilateral striatum: 3.47+/-0.75; contralateral striatum: 2.96+/-0.73) compared with those with Hoehn and Yahr stage I (ipsilateral striatum: 4.72+/-0.75; contralateral striatum: 3.69+/-0.61) (P<.001). The ipsilateral striatum of patients with Hoehn and Yahr stage I showed a significant mean+/-SD reduction of IPT binding (ipsilateral striatum: 4.72+/-0.75) compared with either right or left striatum of controls (P<.001). Only in 1 patient was IPT binding to the ipsilateral striatum (ratio, 6.40) higher than the lowest value observed in the striatum of a control subject (ratio, 5.58).. Use of [I-123] IPT and single photon emission computed tomography demonstrates a reduction of dopamine transporter binding in patients with early Parkinson's disease. Significantly reduced IPT binding already observed in the ipsilateral striatum of patients with Hoehn and Yahr stage I demonstrates the potential of this method to detect preclinical disease.

Topics: Adult; Aged; Carrier Proteins; Dopamine; Dopamine Plasma Membrane Transport Proteins; Female; Humans; Male; Membrane Glycoproteins; Membrane Transport Proteins; Middle Aged; Neostriatum; Nerve Tissue Proteins; Parkinson Disease; Radiopharmaceuticals; Tomography, Emission-Computed, Single-Photon; Tropanes

To investigate nigral neuronal damage in patients with isolated postural tremor and those with postural and rest tremor without parkinsonism.. Using [123I]-N-(3-iodopropen-2-yl)-2 -carbomethoxy-3beta-(4-chlorophenyl) tropane SPECT, we measured the basal ganglia-occipital cortex/occipital cortex ([BG-OCC]/OCC) uptake ratios in 21 control subjects and patients with isolated postural tremor (n = 9), postural and rest tremor (n = 6), and PD (n = 11).. In the patients with PD, the means (+/-SD) of the (BG-OCC)/OCC ratios of the ipsilateral (2.35+/-0.37) and the contralateral (1.97+/-0.33) sides to the more severely affected limbs were significantly lower than the mean of the bilateral (BG-OCC)/OCC ratios of the age-matched control subjects (3.83+/-0.66). The mean (+/-SD) of the bilateral (BG-OCC)/OCC ratios of the patients with isolated postural tremor (3.60+/-0.83) was comparable with that of the age-matched control subjects. However, the mean (+/-SD) of the bilateral (BG-OCC)/OCC ratios of the patients with postural and rest tremor (2.61+/-0.18) was lower than that of the control subjects (p < 0.05). The mean of the bilateral (BG-OCC)/OCC ratios of the patients with postural and rest tremor was comparable with that of the side ipsilateral to the severely affected limbs of the patients with PD. However, it was higher than that of the side contralateral to the limbs more severely affected by PD. Four of the six patients with postural and rest tremor had (BG-OCC)/OCC ratios lower than 2 standard deviations from the mean of the age-matched control subjects.. Later in their clinical courses, some patients with postural tremor may acquire rest tremor in association with mild substantia nigra neuronal loss.

Topics: Adult; Aged; Aged, 80 and over; Analysis of Variance; Brain; Female; Humans; Iodine Radioisotopes; Male; Middle Aged; Parkinson Disease; Tomography, Emission-Computed, Single-Photon; Tropanes

This study evaluated the striatal specific binding ratio (SBR), the anterior to posterior ratio of the striatum (APR) and its reproducibility by employing a template-based registration (TBR) method using the coregistered to the standard T1 magnetic resonance (MR) template (SMRT) as a replacement for the MR image of each patient. The 123I-IPT single photon emission computed tomography (SPECT) images of 30 patients with Idiopathic Parkinson's disease (IPD) and 11 normal controls were analyzed. The region of interest (ROI) was positioned manually in the same slice showing the highest striatal activity using the manual ROI method, while the ROI were positioned automatically in the mid striatal slice of the SPECT image coregistered to the SMRT. The SBR obtained using the TBR method showed a strong correlation with those using the manual method in all groups: normal controls (r = 0.851, P = 0.001), early IPD (r = 0.841, P < 0.001), and severe IPD (r = 0.702, P = 0.007). The APR obtained by the TBR correlated with those using the manual method in only the early IPD (r = 0.72, P = 0.001), while those obtained using the manual method showed no correlation in the three groups (P > 0.05). The reproducibility (rmsCV) of the TBR method was 7.2% (normal controls, 5.2%; mild IPD, 4.2%; severe IPD, 10.8%), while the reproducibility of the manual method was 31% (normal controls, 19.7%; mild IPD, 21.7%; severe IPD, 46.2%). This shows that the use of 123I-IPT SPECT for assessing IPD is affected by the method used to position the striatal ROI. This study showed that the TBR method using the SMRT is useful in diagnosing the IPD and assessing the disease severity with a high reproducibility, indicating a possibility of using the TBR method as a good replacement for the manual method.

Topics: Adult; Aged; Caudate Nucleus; Corpus Striatum; Dopamine Plasma Membrane Transport Proteins; Female; Humans; Image Processing, Computer-Assisted; Iodine Radioisotopes; Magnetic Resonance Imaging; Male; Mathematical Computing; Middle Aged; Occipital Lobe; Parkinson Disease; Putamen; Radiopharmaceuticals; Reference Values; Substantia Nigra; Tomography, Emission-Computed, Single-Photon; Tropanes

Rapid eye movement (REM) sleep behaviour disorder (RBD) is characterized by complex behaviour during REM sleep. The aetiology of this disorder is still unknown, but a recent study showed an association between RBD and Parkinson's disease. We therefore studied striatal postsynaptic dopamine D2 receptor density with [123I](S)-2-hydroxy-3-iodo-6-methoxy-(1-ethyl-2-pyrrolidinylmethyl ) benzamide ([123I]IBZM) and the striatal presynaptic dopamine transporter with (N)-(3-iodopropene-2-yl)-2beta-carbomethoxy-3beta-(4-chlorop henyl) tropane ([123I]IPT) using single-photon emission computed tomography (SPECT) in patients with idiopathic RBD. We compared the [123I]IPT-SPECT results of five patients with polysomnographically confirmed idiopathic RBD with the [123I]IPT-SPECTs of seven age- and sex-matched controls without a history of sleep disorders, and of 14 patients with Parkinson's disease (Hoehn and Yahr stage I). All RBD patients had significantly reduced striatal [123I]IPT binding compared with the controls (RBD: right, 2.94 +/- 0.32, left, 3.03 +/- 0.41; controls: right, 4.41 +/- 0.17, left, 4.34 +/- 0.21; P = 0.003), but significantly higher striatal [123I]IPT binding compared with the striatum contralateral to the symptomatic body side of the Parkinson's disease patients (Parkinson's disease: ipsilateral, 3.17 +/- 0.36, P = 0.298; contralateral, 2.51 +/- 0.31, P = 0.019). Uptake of [123I]IBZM was not significantly different in the RBD group compared with the controls. This study demonstrates that [123I]IPT-SPECT is a useful diagnostic tool in RBD and that reduced striatal dopamine transporters may be a pathophysiological mechanism of idiopathic RBD. (Results are given as mean +/- standard deviation.)

Topics: Adult; Aged; Benzamides; Carrier Proteins; Corpus Striatum; Dopamine Antagonists; Dopamine Plasma Membrane Transport Proteins; Eye Movements; Humans; Iodine Radioisotopes; Membrane Glycoproteins; Membrane Transport Proteins; Middle Aged; Nerve Tissue Proteins; Parkinson Disease; Presynaptic Terminals; Pyrrolidines; Receptors, Dopamine D2; Sleep Wake Disorders; Sleep, REM; Tomography, Emission-Computed, Single-Photon; Tropanes

Imaging the presynaptic dopamine transporter with cocaine analogues and single-photon emission tomography (SPET) has proven to be a potential diagnostic tool for classifying the extent and degree of dopaminergic nerve cell loss. For correct interpretation of scan results, however, knowledge of the intra-/interobserver variation of data evaluation is mandatory. Iodine-123 labelled N-(3-iodopropen-2-yl)-2beta-carbomethoxy-3beta-(chlorophenyl)tropane ([123I]IPT) SPET data of 10 controls and 30 parkinsonian patients with varying degrees of reduced IPT binding were analysed twice by an expert (intraobserver) and once by a less experienced physician in training (interobserver). For semiquantitative evaluation of specific IPT binding, ratios between total striatum, caudate and putamen and a background region were calculated. No significant differences were observed for either the intra- or the interobserver analyses. Variation was lower in controls than in the patient group. Overall variation indices were below 5%. Variation in interobserver results was only slightly higher than that in intraobserver results. The intra-/interobserver results showed highly significant correlations (r = 0.99). The intraclass correlation was higher than 0.9 for all evaluations. Our results indicate that the specific presynaptic striatal dopamine transporter binding assessed with IPT-SPET may be reproducibly analysed by the same and different observers in controls as well as in patients with varying degrees of reduced binding.

Topics: Carrier Proteins; Dopamine Plasma Membrane Transport Proteins; Humans; Iodine Radioisotopes; Membrane Glycoproteins; Membrane Transport Proteins; Neostriatum; Nerve Tissue Proteins; Observer Variation; Parkinson Disease; Radiopharmaceuticals; Receptors, Presynaptic; Tomography, Emission-Computed, Single-Photon; Tropanes

We investigated the availability of dopamine reuptake sites in the striata of two patients with productive symptoms and neuroleptic therapy as well as progressive parkinsonism using the new dopamine transporter ligand [123I]N-(3-iodopropen-2-yl)-2beta-carbo-methoxy-3beta- (4-chlorophenyl)tropane (IPT) and single photon emission computed tomography (SPECT). Normal specific binding in the caudate nucleus was 8.6 +/- 1.2 and in the putamen 6.5 +/- 1.3 (mean +/- S.D.; n = 8; mean age, 56.7 years; range 41-67 years). Patient 1 (age 43) was admitted to our clinic at age 38 because of left-sided parkinsonism. At age 40, she developed paranoid psychosis without change after cessation of L-DOPA and lisuride treatment for 3 months. She was diagnosed as a schizophrenic, paranoid subtype (DSM-III-R). IPT-SPECT showed a loss of dopaminergic nerve terminals (right caudate/putamen, 5.16/2.0; left caudate/putamen, 5.92/2.66). Patient 2 (age, 61 years) had a history of paranoid psychosis for approx. 30 years. He experienced progressive right-sided parkinsonism since age 57 when treated with clozapine. IPT-SPECT showed a marked reduction of striatal dopamine transporter binding (right caudate/putamen, 5.06/1.65; left caudate/putamen, 3.8/1.12). Our findings indicate that patients may suffer contemporaneously from Parkinson's disease and schizophrenia. In these patients, the proof of a nigrostriatal dopaminergic deficit justifies treatment with neuroleptics and dopaminergic drugs. Imaging of dopamine transporters with SPECT and IPT or a related compound represents an attractive alternative to the more complex measurements of fluorodopa uptake with positron emission tomography (PET).

Topics: Adult; Aged; Antipsychotic Agents; Caudate Nucleus; Dopamine; Female; Humans; Iodine Radioisotopes; Male; Middle Aged; Neostriatum; Parkinson Disease; Putamen; Schizophrenia, Paranoid; Tomography, Emission-Computed, Single-Photon; Tropanes

IPT [N-(3-iodopropen-2-yl)- 2beta-carbomethoxy-3beta-(4-chlorophenyl) tropane] is a new cocaine analogue which allows the presynaptic dopamine transporters to be imaged with single-photon emission tomography (SPET) as early as 1-2 h post injection. In the present study [123I]IPT SPET was performed in patients with Parkinson's disease (PD) to analyse the relationship between specific dopamine tansporter binding and clinical features of the disease. Twenty-six PD patients (Hoehn and Yahr stages I-IV, age range 40-79 years) and eight age-matched controls were studied. SPET imaging was performed 90-120 min after injection of 160-185 MBq [123I]IPT using a triple-head camera. For semiquantitative evaluation of specific [123I]IPT binding, ratios between caudate, putamen and background regions were calculated. Specific [123I]IPT uptake was significantly reduced in PD patients compared to controls. Most patients showed a marked asymmetry with a more pronounced decrease in [123I]IPT binding on the side contralateral to the predominant clinical findings. The putamen was always more affected than the caudate. [123I]IPT binding was significantly correlated with disease duration (r=-0.7, P<0.0001) but not with the age of PD patients (r=-0.10, P=0. 61). Specific [123I]IPT uptake in the caudate and putamen, and putamen to caudate ratios, decreased with increasing Hoehn and Yahr stage. Our findings indicate that [123I]IPT SPET may be a useful technique to estimate the extent of nigrostriatal degeneration in PD patients. Close relationships between striatal [123I]IPT binding and clinical features of the disease suggest that this method can be used to objectively follow the course and progression of PD. The reduced putamen to caudate ratios observed even in patients with mild, newly recognized symptoms indicate that particularly this parameter may help to establish the correct diagnosis in the early course of PD.

Topics: Adult; Aged; Brain; Carrier Proteins; Case-Control Studies; Dopamine Plasma Membrane Transport Proteins; Female; Humans; Iodine Radioisotopes; Male; Membrane Glycoproteins; Membrane Transport Proteins; Middle Aged; Nerve Tissue Proteins; Parkinson Disease; Tomography, Emission-Computed, Single-Photon; Tropanes

Iodine-123-N-(3-iodopropene-2-yl)-2beta-carbomethoxy-3beta-( 4-chlorophenyl) tropane (123I-IPT) is a new dopamine transporter ligand that selectively binds the dopamine reuptake sites. Transporter concentrations have been known to decrease in Parkinson's disease patients. The purpose of this study was to evaluate the usefulness of IPT as an imaging agent for measuring changes in transporter concentrations in Parkinson's disease.. IPT labeled with 6.78 +/- 0.67 mCi 123I was injected intravenously as a bolus into eight normal controls (mean age 41 +/- 12 yr) and 17 Parkinson's disease patients (mean age 55 +/- 9 yr). Dynamic SPECT scans of the brain were then performed for 5 min each over 120 min on a triple-headed gamma camera equipped with medium-energy collimators. Regions of interest were drawn on the middle set of the image at the level of the basal ganglia (BG) for each subject. Time-activity curves were generated for the left BG, right BG and occipital cortex (OCC). The empirical ratios between BG-OCC and OCC, which represent specific-to-nonspecific binding ratios, were computed at various time points. The statistical parameter k3/k4 was estimated by two methods: a variation of the graphic method that derives the ratio of ligand distribution volumes (R[V]) and the area ratio method (R[A]), in which the ratio is calculated from the areas under the specific and nonspecific binding activity curves.. The mean (BG-OCC)/OCC ratio for normal controls (3.07 +/- 0.73) was significantly higher than that for Parkinson's disease patients at 115 min (1.10 +/- 0.56) (p = 2.76 x 10[-5]). The mean R(V) and R(A) for normal controls were 2.06 +/- 0.27 and 1.50 +/- 0.15, respectively. The mean R(V) and R(A) for Parkinson's disease patients were 0.78 +/- 0.31 and 0.65 +/- 0.24, respectively. Both R(V) and R(A) for normal controls were significantly higher than those for Parkinson's disease patients (p values for R(V) and R(A) were 1.91 x 10(-8) and 3.46 x 10(-10), respectively). The R(V) has linear relationships with both R(A) and (BG-OCC)/OCC ratio at 115 min. The R(V) has a higher correlation (r = 0.99) with R(A) than it does with (BG-OCC)/OCC (r = 0.93).. The R(V), R(A) and (BG-OCC)/OCC for Parkinson's disease patients were clearly separated from those of normal controls, and they may be useful outcome measures for clinical diagnosis. The simplest (BG-OCC)/OCC ratio, requiring a single late time point, could be useful in clinical situations, whereas R(V) or R(A) is preferred when the dynamic data are available. The findings suggest that 123I-IPT is a useful tracer for diagnosing Parkinson's disease and studying dopamine reuptake sites.

Topics: Adult; Brain; Carrier Proteins; Case-Control Studies; Dopamine; Dopamine Plasma Membrane Transport Proteins; Female; Humans; Iodine Radioisotopes; Male; Membrane Glycoproteins; Membrane Transport Proteins; Middle Aged; Nerve Tissue Proteins; Parkinson Disease; Time Factors; Tomography, Emission-Computed, Single-Photon; Tropanes