SPECT IMAGING OF DOPAMINE TRANSPORTER SITES IN NORMAL AND MPTP-TREATED RHESUS-MONKEYS

Parkinson's disease is characterized by degeneration of dopamine (DA) neurons and their terminals. Since these neurons contain dopamine tran sporters (DAT), radioligands that bind to these sites are promising ra diopharmaceuticals for diagnosis and therapeutic monitoring of disease progression. We evaluated [I-123]-2 beta-carbomethoxy-3 beta-(4-fluor ophenyl)-N-(1 -iodoprop-1-en-3-yl)nortropane ([I-123]IACFT) for SPECT imaging in an MPTP model of parkinsonism. Methods: Three rhesus monkey s 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 [C-11]-2 beta-carbomethoxy-3 beta-aryltropane ([C-11] - CFT). Also, b iodistribution was measured by planar imaging. Results: In normal anim als, striatal accumulation of radioactivity was-rapid and peaked withi n 30 min. Striatal accumulation of [I-123]IACFT was nearly completely displaceable with unlabeled CFT (1 mg/kg) but was not affected by a si milar dose of the serotonin (5-HT) transport inhibitor, citalopram. Th e striatal to cerebellar ratio measured at 30 min. after injection of [I-123]IACFT was significantly higher (p < 0.01) than with [C-11]CFT; similar to 6: 1 versus similar to 2.5: 1. After MPTP treatment this ra tio decreased to 1.02:1 with IACFT and 1.23:1 with [C-11]CFT. Blood cl earance of [I-123]IACFT was rapid with a terminal t(1/2) of similar to 30 min. HPLC of plasma samples demonstrated that the concentration of intact ligand decreases rapidly, approaching zero by 60 min. Low leve ls of accumulation were measured in extracranial tissues. Conclusion: These results demonstrate that [I-123]IACFT is an excellent SPECT liga nd far dopamine transporter sites that combines the critical character istics of: (a) high striatal to cerebellar ratios, (b) high selectivit y for dopamine versus 5-HT transporter sites, (c) convenient preparati on at high-specific activity and radiochemical purity and (d) a striat al localization rate that is well matched to the physical t(1/2) of I- 123.