n-iodoallyl-2-carbomethoxy-3-(4-fluorophenyl)tropane and Parkinson-Disease

Boston Life Sciences (BLS) is developing Altropane as a potential radio-imaging agent to be used with single photon emission tomography (SPECT), for the early diagnosis of Parkinson's disease (PD) and attention deficit hyperactivity disorder (ADHD) [329661]. Altropane is currently in phase III clinical trials for PD and phase II clinical trials for ADHD.

Topics: Animals; Attention Deficit Disorder with Hyperactivity; Clinical Trials as Topic; Cocaine; Humans; Parkinson Disease; Radiopharmaceuticals; Technology, Pharmaceutical; Tomography, Emission-Computed; Tomography, Emission-Computed, Single-Photon

Topics: Clinical Trials as Topic; Cocaine; Drug Industry; Humans; Parkinson Disease; Tomography, Emission-Computed, Single-Photon

Increasing evidence indicates that dopamine (DA) transporter density declines in Parkinson's disease (PD). 2Beta-carbomethoxy-3beta-(4-fluorophenyl)-n-(1-iodoprop-1-en -3-yl) nortropane (IACFT, Altropane) is a cocaine analog with high affinity and selectivity for dopamine transporter (DAT) sites in the striatum. In this study, single photon emission computed tomography (SPECT) with [123I]altropane was used to measure DAT density in seven healthy volunteers (five males, age 37-75, and two females, ages 26 and 39) and eight male patients with Parkinson's disease (age 14-79, Hoehn and Yahr stage: 1.5-3 (n = 5) and 4-5 (n = 3)). Dynamic SPECT images and arterial blood samples were acquired over 1.5-2 hr and plasma radioactivity was analyzed chromatographically to obtain metabolite corrected arterial input functions. Binding potential (BP, B'max/KD) for striatal (Str) DAT sites was calculated by two methods using occipital cortex (Occ) as a reference. In the first method, tissue time-activity curves (TAC) and metabolite corrected arterial input functions were analyzed by a linear graphical method developed for reversible receptor ligands. In the second method, the expression (Str(TAC) - Occ(TAC)) was fitted to a gamma variate function and the maximum divided by Occ(TAC) at the same time was used to estimate BP. In five of the PD patients, the SPECT data were compared with the results of PET with [18F] 6-fluoro DOPA (FD-PET). Plasma analysis indicated that [123I]altropane is rapidly converted to polar metabolites. SPECT images in healthy volunteers showed that [123I] altropane accumulated rapidly and selectively in the striatum and yielded excellent quality images within 1 h after injection. Both methods of analysis revealed a 7.6%/decade reduction in BP and average striatal values (corrected to age 25) were 1.83 +/- 0.22 and 2.09 +/- 0.20 by methods 1 and 2. In all the PD patients, striatal accumulation was markedly reduced and the pattern of loss was similar to that reported for DA; most profound in the posterior putamen with relative sparing of the caudate nuclei. A comparable pattern was observed with FD-PET. For total striatum, age-corrected BP was significantly (P < 0.001) reduced; 0.83 +/- 0.06 (method 1), 0.84 +/- 0.07 (method 2). BPs measured by the two methods were remarkably similar and highly correlated r2 = 0.88, (P < 0.001). These results indicate that [123I]altropane is an excellent SPECT ligand for imaging the DAT/DA neurons in human brain. The

Topics: Adolescent; Adult; Aged; Brain; Brain Chemistry; Carrier Proteins; Child; Cocaine; Dopamine Plasma Membrane Transport Proteins; Female; Humans; Iodine Radioisotopes; Ligands; Male; Membrane Glycoproteins; Membrane Transport Proteins; Middle Aged; Nerve Tissue Proteins; Parkinson Disease; Receptors, Dopamine D1; Tomography, Emission-Computed; Tomography, Emission-Computed, Single-Photon

To develop imaging biomarkers of diseases in the Lewy body spectrum and to validate these markers against postmortem neuropathologic findings.. Four cognitively normal participants with Parkinson disease (PD), 4 with PD with cognitive impairments, and 10 with dementia with Lewy bodies underwent amyloid imaging with [11C]Pittsburgh compound B (PiB) and dopamine transporter (DAT) imaging with [11C]Altropane. All 18 had annual neurologic examinations. All cognitively normal participants with PD developed cognitive impairment before death. Neuropathologic examinations assessed and scored Braak Lewy bodies, Thal distribution of amyloid, Consortium to Establish a Registry for Alzheimer's Disease neuritic amyloid plaques, Braak neurofibrillary tangles, and cerebral amyloid angiopathy, as well as total amyloid plaque burden in the superior frontal, superior parietal, occipital, and inferior temporal cortical regions. PET data were expressed as the standardized uptake value ratio with cerebellar reference. Analyses accounted for the interval between imaging and autopsy.. All 18 patients met neuropathologic criteria for Lewy body disease; the DAT concentration was low in each case. All patients with elevated [11C]PiB retention measured in a neocortical aggregate had β-amyloid deposits at autopsy. [11C]PiB retention significantly correlated with neuritic plaque burden and with total plaque burden. [11C]PiB retention also significantly correlated with the severity of both Braak stages of neurofibrillary tangle and Lewy body scores. Neuritic plaque burden was significantly associated with neurofibrillary tangle pathology.. Antemortem [11C]Altropane PET is a sensitive measure of substantia nigra degeneration. [11C]PiB scans accurately reflect cortical amyloid deposits seen at autopsy. These findings support the use of molecular imaging in the evaluation of patients with Lewy body diseases.

Topics: Aged; Aged, 80 and over; Amyloid beta-Peptides; Aniline Compounds; Autopsy; Brain; Cocaine; Contrast Media; Dopamine Plasma Membrane Transport Proteins; Female; Humans; Lewy Body Disease; Male; Middle Aged; Parkinson Disease; Positron-Emission Tomography; Thiazoles

Effective therapies for dementia with Lewy bodies (DLB) and Parkinson's disease (PD) dementia will require accurate diagnosis and an understanding of the contribution of distinct molecular pathologies to these diseases. We seek to use imaging biomarkers to improve diagnostic accuracy and to clarify the contribution of molecular species to cognitive impairment in DLB and PD.. We have performed cross-sectional and prospective cohort studies in subjects with DLB, PD with normal cognition, PD with mild cognitive impairment and PD with dementia, contrasted with Alzheimer's disease (AD) and healthy control subjects (HCS). Subjects underwent formal neurological examination, detailed neuropsychological assessments, MRI and PET scans with the radioligands altropane (a dopamine transporter, DAT) and Pittsburgh compound B (PiB; β-amyloid). Putamen DAT concentrations were similar in DLB and PD and differentiated them from HCS and AD. Decreased caudate DAT concentration related to functional impairment in DLB but not PD. PiB uptake was greatest in DLB. However, cortical PiB retention was common in PD and predicted cognitive decline. PET imaging of tau aggregates holds promise both to clarify the contribution of tau to cognitive decline in these diseases and to differentiate DLB and PD from the parkinsonian tauopathies.. Together, DAT and amyloid PET imaging discriminate DLB from PD and from other disease groups and identify pathological processes that contribute to their course. Multimodal PET imaging has the potential to increase the diagnostic accuracy of DLB and PD in the clinic, improve cohort uniformity for clinical trials, and serve as biomarkers for targeted molecular therapies.

Topics: Alzheimer Disease; Aniline Compounds; Brain; Carbolines; Cocaine; Cognitive Dysfunction; Cross-Sectional Studies; Diagnosis, Differential; Lewy Body Disease; Magnetic Resonance Imaging; Neuropsychological Tests; Parkinson Disease; Prospective Studies; Radionuclide Imaging; Radiopharmaceuticals; Survival Analysis; Thiazoles

This study used the dopamine transporter (DAT) probe, [(123)I]-2β-carbomethoxy-3β-(4-fluorophenyl)-N-(3-iodo-E-allyl)nortropane ([(123)I]altropane), to assess the DAT levels in the 6-hydroxydopamine rat model of Parkinson's disease. We sought to assess if the right to left [(123)I]altropane striatal ratios correlated with dopamine content in the striatum and substantia nigra and with behavioural outcomes.. [(123)I]altropane images taken pre- and postlesion were acquired before and after the transplantation of neural stem/progenitor cells. The images obtained using [(123)I]altropane and single photon emission computed tomography (SPECT) were compared with specific behavioural tests and the dopamine content assessed by high-performance liquid chromatography.. [(123)I]altropane binding correlated with the content of dopamine in the striatum; however, [(123)I]altropane binding did not correlate with the dopamine content in the substantia nigra. There was a significant correlation of altropane ratios with the cylinder test and the postural instability test, but not with amphetamine rotations. The low coefficient of determination (r(2)) for these correlations indicated that [(123)I]altropane SPECT was not a good predictor of behavioural outcomes.. Our data reveal that [(123)I]altropane predicts the integrity of the striatal dopamine nerve terminals, but does not predict the integrity of the nigrostriatal system. [(123)I]altropane could be a useful marker to measure dopamine content in cell replacement therapies; however, it would not be able to evaluate outcomes for neuroprotective strategies.

Topics: Animals; Behavior, Animal; Biomarkers; Cocaine; Disease Models, Animal; Dopamine; Dopamine Plasma Membrane Transport Proteins; Iodine Radioisotopes; Neostriatum; Neural Stem Cells; Oxidopamine; Parkinson Disease; Rats; Rats, Sprague-Dawley; Stem Cell Transplantation; Tomography, Emission-Computed, Single-Photon

Increasing evidence suggests that the dopamine transporter is situated almost exclusively on dopamine neurons. Accordingly, it is an valuable marker for Parkinson's disease and other pathological states of dopamine neurons. We previously demonstrated that the potent dopamine transport inhibitor [125I]altropane (IACFT:E-N-iodoallyl-2beta-carbomethoxy-3beta-(4-fluor ophenyl)tropane) is a high affinity selective probe for the dopamine transporter in monkey brain and an effective SPECT imaging agent in nonhuman primate brain. We now report the binding properties of [125I]altropane in postmortem tissue of normal human brain and compare the findings to Parkinson's diseased brain. In homogenates of human brain putamen, [125I]altropane bound with high affinity (KD: 4.96 +/- 0.38 nM, n = 4) and site density (BMAX: 212 +/- 41.1 pmol/g original wet tissue weight) well within the density range reported previously for the dopamine transporter in this brain region. Drugs inhibited [125I]altropane binding with a rank order of potency that corresponded closely to their rank order for blocking dopamine transport (r 0.98, P < 0.001). In postmortem Parkinson's diseased brain, bound [125I]altropane (1 nM) was markedly reduced (89%, 99% in putamen, depending on measures of nonspecific binding) compared with normal aged-matched controls (normal putamen: 49.2 +/- 8.1 pmol/g; Parkinson's diseased putamen: 0.48 +/- 0.33 pmol/g; n = 4). In vitro autoradiography, conducted in tissue sections at a single plane of the basal ganglia, revealed high levels of [125I]altropane binding the caudate nucleus and putamen, but lower levels (73% of the caudate-putamen) in the nucleus accumbens (n = 7). In Parkinson's diseased brains (n = 4), [125I]altropane binding was 13% of the levels detected in normal putamen, 17% of normal values in the caudate nucleus, and 25% of normal levels in nucleus accumbens. The association of [125I]altropane to the dopamine transporter in human postmortem tissue, the marked reduction of [125I]altropane binding in Parkinson's diseased brains, its rapid entry into brain and highly localized distribution in dopamine-rich brain regions, support its use as a probe for monitoring the dopamine transporter in vitro and in vivo by SPECT imaging.

Topics: Aged; Brain; Brain Chemistry; Carrier Proteins; Cocaine; Dopamine Plasma Membrane Transport Proteins; Female; Humans; Iodine Radioisotopes; Ligands; Male; Membrane Glycoproteins; Membrane Transport Proteins; Neostriatum; Nerve Tissue Proteins; Parkinson Disease; Putamen; Radioligand Assay; Receptors, Dopamine D1; Tomography, Emission-Computed; Tomography, Emission-Computed, Single-Photon

Parkinson's disease is characterized by degeneration of dopamine (DA) neurons and their terminals. Since these neurons contain dopamine transporters (DAT), radioligands that bind to these sites are promising radiopharmaceuticals for diagnosis and therapeutic monitoring of disease progression. We evaluated [123I]-2 beta-carbomethoxy- 3 beta-(4-fluorophenyl)-N-(1-iodoprop-1-en-3-yl)nortropane ([123I]IACFT) for SPECT imaging in an MPTP model of parkinsonism.. Three rhesus monkeys were imaged before and at 1 and 2 mo after treatment with MPTP. The SPECT results were correlated with motor behavior and PET imaging with [11C]-2 beta-carbomethoxy-3 beta-aryltropane ([11C]-CFT). Also, biodistribution was measured by planar imaging.. In normal animals, striatal accumulation of radioactivity was rapid and peaked within 30 min. Striatal accumulation of [123I]IACFT was nearly completely displaceable with unlabeled CFT (1 mg/kg) but was not affected by a similar dose of the serotonin (5-HT) transport inhibitor, citalopram. The striatal to cerebellar ratio measured at 30 min, after injection of [123I]IACFT was significantly higher (p < 0.01) than with [11C]CFT; approximately 6; 1 versus approximately 2.5; 1. After MPTP treatment this ratio decreased to 1.02:1 with IACFT and 1.23:1 with [11C]CFT. Blood clearance of [123I]IACFT was rapid with a terminal t1/2 of approximately 30 min. HPLC of plasma samples demonstrated that the concentration of intact ligand decreases rapidly, approaching zero by 60 min. Low levels of accumulation were measured in extracranial tissues.. These results demonstrate that [123I]IACFT is an excellent SPECT ligand for dopamine transporter sites that combines the critical characteristics of: (a) high striatal to cerebellar ratios, (b) high selectivity for dopamine versus 5-HT transporter sites, (c) convenient preparation at high-specific activity and radiochemical purity and (d) a striatal localization rate that is well matched to the physical t1/2 of 123I.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Binding Sites; Carrier Proteins; Cocaine; Contrast Media; Dopamine Agents; Dopamine Plasma Membrane Transport Proteins; Iodine Radioisotopes; Macaca mulatta; Membrane Glycoproteins; Membrane Transport Proteins; Nerve Tissue Proteins; Nortropanes; Parkinson Disease; Parkinson Disease, Secondary; Tissue Distribution; Tomography, Emission-Computed; Tomography, Emission-Computed, Single-Photon

Parkinson's disease is a progressive neurodegenerative disorder that is associated with the loss of nerve terminals from specific brain areas, particularly in the caudate and putamen, which contains the highest concentrations of dopamine transporter sites. Previously, we synthesized and evaluated a series of 11C-labeled 2 beta-carbomethoxy -3 beta-aryltropane (WIN 35,428; CFT) derivatives as markers for the dopamine transporter system. These ligands have high affinity and specificity for dopamine transporter sites in vitro and in vivo in laboratory animals. The goal of this study was the preparation and preliminary biological characterization of two new ligands based on the structure of WIN 35,428, the E and Z isomers of N-iodoallyl-2 beta -carbomethoxy-3 beta-(4-fluorophenyl)tropane (E and A IACFT).. E and Z IACFT were synthesized and radiolabeled with 125I. The ligands were characterized by in vitro assays of binding to dopamine and serotonin transporters and by autoradiography.. Iodine-125-IACFT was prepared in > 60% radiochemical yield, and > 98% radiochemical purity. Specific activity was 1500 Ci/mmole. In vitro, E-IACFT showed higher affinity for dopamine transporter sites than WIN 35,428 (6.6 versus 11 nM) and better selectivity than RTI-55. The Z isomer was found to have much lower affinity. One hour after an intravenous injection of 125I IACFT in monkeys, ex vivo autoradiographs of the brain revealed high concentrations of tracer in dopamine rich regions such as the caudateputamen. The striatum-to-cerebellum, striatum-to-cortex and striatum-to-thalamus ratios were 10.8, 7.2 and 8.3.. These result suggest that radiolabeled E-IACFT may be a useful radioligand for SPECT imaging of dopamine transporter sites. IACFT could prove to be extremely useful for the noninvasive evaluation of patients with early Parkinson's disease.

Topics: Animals; Autoradiography; Brain; Carrier Proteins; Citalopram; Cocaine; Dopamine; Dopamine Plasma Membrane Transport Proteins; Dopamine Uptake Inhibitors; Iodine Radioisotopes; Membrane Glycoproteins; Membrane Transport Proteins; Nerve Tissue Proteins; Parkinson Disease; Saimiri; Selective Serotonin Reuptake Inhibitors; Tomography, Emission-Computed, Single-Photon