Janet Sangare

Small effect of dopamine release and no effect of dopamine depletion on [18F]fallypride binding in healthy humans

Molecular imaging has been used to estimate both drug‐induced and tonic dopamine release in the striatum and most recently extrastriatal areas of healthy humans. However, to date, studies of drug‐induced and tonic dopamine release have not been performed in the same subjects. This study performed positron emission tomography (PET) with [18F]fallypride in healthy subjects to assess (1) the reproducibility of [18F]fallypride and (2) both D‐amphetamine‐induced and α‐methyl‐p‐tyrosine (AMPT)‐induced changes in dopamin release on [18F]fallypride binding in striatal and extrastriatal areas. Subjects underwent [18F]fallypride PET studies at baseline and following oral D‐amphetamine administration (0.5 mg/kg) and oral AMPT administration (3 g/70 kg/day over 44 h). Binding potential (BP) (BPND) of [18F]fallypride was calculated in striatal and extrastriatal areas using a reference region method. Percent change in regional BPND was computed and correlated with change in cognition and mood. Test–retest variability of [18F]fallypride was low in both striatal and extrastriatal regions. D‐Amphetamine significantly decreased BPND by 8–14% in striatal subdivisions, caudate, putamen, substantia nigra, medial orbitofrontal cortex, and medial temporal cortex. Correlation between change in BPND and verbal fluency was seen in the thalamus and substantia nigra. In contrast, depletion of endogenous dopamine with AMPT did not effect [18F]fallypride BPND in both striatum and extrastriatal regions. These findings indicate that [18F]fallypride is useful for measuring amphetamine‐induced dopamine release, but may be unreliable for estimating tonic dopamine levels, in striatum and extrastriatal regions of healthy humans. Synapse 62:399–408, 2008. Published 2008 Wiley‐Liss, Inc.

Widespread decrease of nicotinic acetylcholine receptors in Parkinson's disease

Nicotinic acetylcholine receptors have close interactions with the dopaminergic system and play critical roles in cognitive function. The purpose of this study was to compare these receptors between living PD patients and healthy subjects.

Pre- and post-synaptic dopamine imaging and its relation with frontostriatal cognitive function in Parkinson disease: PET studies with [11C]NNC 112 and [18F]FDOPA

Frontostriatal cognitive dysfunction is common in Parkinson disease (PD), but the explanation for its heterogeneous expressions remains unclear. This study examined the dopamine system within the frontostriatal circuitry with positron emission tomography (PET) to investigate pre- and post-synaptic dopamine function in relation to the executive processes in PD. Fifteen non-demented PD patients and 14 healthy controls underwent [(18)F]FDOPA (for dopamine synthesis) and [(11)C]NNC 112 (for D(1) receptors) PET scans and cognitive testing. Parametric images of [(18)F]FDOPA uptake (K(i)) and [(11)C]NNC 112 binding potential (BP(ND)) were calculated using reference tissue models. Group differences in K(i) and BP(ND) were assessed with both volume of interest and statistical parametric mapping, and were correlated with cognitive tests. Measurement of [(18)F]FDOPA uptake in cerebral cortex was questionable because of higher K(i) values in white than adjacent gray matter. These paradoxical results were likely to be caused by violations of the reference tissue model assumption rendering interpretation of cortical [(18)F]FDOPA uptake in PD difficult. We found no regional differences in D(1) receptor density between controls and PD, and no overall differences in frontostriatal performance. Although D(1) receptor density did not relate to frontostriatal cognition, K(i) decreases in the putamen predicted performance on the Wisconsin Card Sorting Test in PD only. These results suggest that striatal dopamine denervation may contribute to some frontostriatal cognitive impairment in moderate stage PD.

Disulfiram Inhibits Defluorination of 18F-FCWAY, Reduces Bone Radioactivity, and Enhances Visualization of Radioligand Binding to Serotonin 5-HT1A Receptors in Human Brain

18F-trans-4-Fluoro-N-2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl]-N-(2-pyridyl)cyclohexanecarboxamide (18F-FCWAY) is a PET radioligand for imaging serotonin 5-hydroxytryptamine-1A receptors in brain. 18F-FCWAY undergoes significant defluorination, with high uptake of radioactivity in the skull and resulting spillover contamination in the underlying neocortex. The cytochrome P450 enzyme CYP2E1 defluorinates many drugs. We previously showed that miconazole, an inhibitor of CYP2E1, blocks defluorination of FCWAY in rats. Here, we used 18F-FCWAY to test the ability of the less toxic agent disulfiram to inhibit defluorination in humans. Methods: Eight healthy volunteers underwent a PET scan before and after administration of 500 mg of disulfiram (n = 6) or 2,000 mg of cimetidine (n = 2). Seven of the subjects had arterial blood sampling during both scans. Results: Although cimetidine had relatively small and variable effects on 2 subjects, disulfiram reduced skull radioactivity by about 70% and increased peak brain uptake by about 50% (n = 5). Disulfiram decreased plasma-free 18F-fluoride ion (from peak levels of 340% ± 62% standardized uptake value (SUV) to 62% ± 43% SUV; P < 0.01) and increased the concentration of the parent 18F-FCWAY (with a corresponding decrease of clearance from 14.8 ± 7.8 L·h−1 at baseline to 7.9 ± 2.8 L·h−1 after drug treatment (P < 0.05). Using compartmental modeling with input of both 18F-FCWAY and the radiometabolite 18F-FC (trans-4-fluorocyclohexanecarboxylic acid), distribution volumes attributed to the parent radioligand unexpectedly decreased about 40%–60% after disulfiram, but the accuracy of the radiometabolite correction is uncertain. Disulfiram changed the shape of the brain time–activity curves in a manner that could occur with inhibition of the efflux transporter P-glycoprotein (P-gp). However, disulfiram showed no in vivo efficacy in monkeys to enhance the uptake of the known P-gp substrate 11C-loperamide, suggesting that the effects of disulfiram in humans were mediated entirely by inhibition of CYP2E1. Conclusion: A single oral dose of disulfiram inhibited about 70% of the defluorination of 18F-FCWAY, increased the plasma concentration of 18F-FCWAY, increased brain uptake of activity, and resulted in better visualization of 5-HT1A receptor in the brain. Disulfiram is a safe and well-tolerated drug that may be useful for other radioligands that undergo defluorination via CYP2E1.