title: Long-term treatment with the tetrahydropyridine analog (HPTP) of haloperidol influences dopamine ligand binding in baboon brain. An [123I]iodobenzamide (IBZM) SPECT study.
abstract: Haloperidol (HP) and its tetrahydropyridine dehydration product 4-(4-chlorophenyl)-[4-(fluorophenyl)-4-oxobutyl]-1,2,3,6-tetrahydropyrid ine (HPTP) are both metabolized in vivo to several pyridinium metabolites with potential neurotoxic properties similar to the neurotoxin 1-methyl-4-phenylpyridinium (MPP+), a metabolite of the parkinsonian-inducing agent 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The effect of long-term HPTP treatment on the central nervous system of baboons (Papio ursinus) was studied using [123I]iodobenzamide (IBZM) and single photon emission computed tomography (SPECT) at 1-14 weeks after termination of HPTP treatment. Striatal dopamine receptor binding was measured semiquantitatively by calculating the IBZM count rate ratios of the basal ganglia to frontal cortex and basal ganglia to cerebellum. Relative striatal perfusion was assessed by similar 99mTc-HMPAO (hexamethylpropylene amine oxime) ratios. Time activity curves of IBZM from the brain structures suggest that HPTP treatment results in a marked reduction in central dopamine ligand binding, and in particular D2-like receptor binding. Increased washout of the ligand from all the brain structures investigated was seen in the HPTP-treated animals, also consistent with reduced binding. Cerebral blood flow in the control and HPTP-treated groups was similar, indicating that this did not account for the reduced dopamine receptor binding of the IBZM ligand. These data suggest that treatment with HPTP induces significant effects on dopamine receptor binding that may contribute to some of the neurological disorders observed in humans undergoing chronic HP treatment.
authors.affiliation: Department of Pharmaceutical Chemistry, Potchefstroom University for Christian Higher Education, South Africa. vanders@vt.edu
authors.forename: C J
authors.initials: CJ
authors.lastname: Van der Schyf
authors.forename: I C
authors.initials: IC
authors.lastname: Dormehl
authors.forename: D W
authors.initials: DW
authors.lastname: Oliver
authors.forename: N
authors.initials: N
authors.lastname: Hugo
authors.forename: R
authors.initials: R
authors.lastname: Keeve
authors.forename: H W
authors.initials: HW
authors.lastname: Müller-Gärtner
authors.forename: S M
authors.initials: SM
authors.lastname: Pond
authors.forename: N
authors.initials: N
authors.lastname: Castagnoli
mesh_terms: D000818:Animals; D001549:Benzamides; D001667:Binding, Competitive; D001921:Brain / Q000000981:diagnostic imaging*; D004298:Dopamine / Q000494:pharmacology*; D006220:Haloperidol / Q000031:analogs & derivatives / Q000494:pharmacology*; D008297:Male; D010215:Papio; D011725:Pyridines / Q000494:pharmacology*; D011759:Pyrrolidines; D013997:Time Factors; D015899:Tomography, Emission-Computed, Single-Photon
chemical_list: D001549:Benzamides; D011725:Pyridines; D011759:Pyrrolidines; C055743:3-iodo-2-hydroxy-6-methoxy-N-((1-ethyl-2-pyrrolidinyl)methyl)benzamide; D006220:Haloperidol; C023666:pyridine; D004298:Dopamine