EFFECT OF THE HALOPERIDOL TETRAHYDROPYRIDINE METABOLITE UOROPHENYL)-4-OXOBUTYL]-1,2,3,6-TETRAHYDROPYRIDINE ON DOPAMINE-RECEPTOR AND TRANSPORTER BINDING - A NONHUMAN PRIMATE I-123 IODOBENZAMIDE AND 2-BETA-CARBOMETHOXY-3-BETA-(4-IODOPHENYL)TROPANE SINGLE-PHOTON EMISSION COMPUTED TOMOGRAPHIC STUDY

Researching the biological activities and toxicities of metabolites of drugs is of growing importance and has received increasing attention during the last decade in order to gain a better understanding of the efficacy and safety profile of drugs in clinical use. HPTP orophenyl)- 4-oxobutyl]-1,2,3,6-tetrahydropyridine, CAS 52659-92-8), the tetrahydr opyridine metabolite of the classical neuroleptic, haloperidol (GAS 52 -86-8), has recently been the focus for further understanding the well -known side effect profile of haloperidol. The current study was aimed at investigating the effect of HPTP treatment on dopamine receptor an d transporter binding in the nonhuman primate, i.e. the baboon Papio u rsinus. The study was performed using the dopamine receptor ligand, (1 23)-I-iodobenzamide (IBZM) and the dopamine transporter ligand, [(123) ]2 beta-carbomethoxy-3 beta-(4-iodophenyl)tropane (beta-CIT) in planar scintigraphy and single photon emission computed tomographic (SPECT) protocols. Dopamine receptor binding in the striatum was measured from the time activity curves by calculating the IBZM ratios of the basal ganglia to frontal cortex and of the basal ganglia to cerebellum. Tc-9 9m-HMPAO (hexamethylpropylene amine oxime) SPECT detected no changes i n striatal perfusion during HPTP treatment. The transporter binding wa s measured by dynamic imaging of the basal ganglia, frontal cortex and cerebellum using beta-CIT. IBZM dopamine receptor binding is initiall y (as measured after 18 weeks treatment) decreased by HPTP treatment i n the basal ganglia, frontal cortex (not significantly) and cerebellum but reversed to control values in the frontal cortex, as measured aft er 58 weeks treatment with HPTP. The binding to the basal ganglia and to a lesser degree the cerebellum is still affected after 58 weeks tre atment with HPTP but indicates a tendency to return towards the contro l values. The results of the planar dynamic study with beta-CIT indica te a decrease in the beta-CIT binding to the dopamine transporters in the basal ganglia and to a lesser extent the cerebellum as measured by the time activity and percentage washout rate of the beta-CIT in the HPTP treated baboons. The effect of HPTP on the serotonin transporters appears to be minimal as observed from the results obtained from the frontal cortex. These results indicate that HPTP treatment influences both presynaptic and postsynaptic neurofunction in the dopaminergic ne urones.