No direct correlation between behaviorally active doses of the dopamine D 2 agonist LY 171555 and displacement of [ 123 I]IBZM as measured with SPECT in MPTP monkeys

Almost no information is available concerning the link between clinical effects of dopamine D 2 receptor agonists in the treatment of Parkinson's disease (PD) and the extent of D 2 receptor occupancy in the brain. Therefore, we investigated the possible correlation between adminis tration of behaviorally active doses of the selective D 2 agonist LY 171555 and in vivo D 2 receptor occupancy in the unilateral 1‐methyl‐4‐phenyl 1,2,3,6‐tetrahydropyridine(MPTP)‐lesioned rhesus monkey model of PD. Single photon emission computed tomography (SPECT) with the D 2 receptor antagonist ( 123 I)IBZM (iodobenzamide) as radioligand was used to estimate the receptor occupancy. The MPTP‐lesioned monkeys consistenty showed signs of unilateral parkinsonism. LY 171555 (0.01 or 0.3 mg/kg) significantly increased contralateral rotation (away from the lesion), being most effective at the lower dose. In the MPTP‐lesioned monkeys [ 123 ]IBZM activity in the left (lesioned) striatum was significantly higher as compared to that in the right striatum. Only upon administration of 0.3 mg/kg LY 171555 a significant amount of receptor occupancy by LY 171555, as measured with [ 123 I]IBZM SPECT, at both lesioned and non‐lesioned side, was detected. Using D 2 receptor mediated inhibition of the evoked release of [ 3 H]acetylcholine from rat striatal tissue as a functional model, we showed that the lack of effect with 0.01 mg/kg LY 171555 was not due to non‐competitive interaction between LY 171555 and IBZM at the D 2 receptor. We conclude that the D 2 antagonist [ 123 I]IBZM is not a suitable SPECT ligand to study the relationship between behavioral effects of the selective D 2 agonist LY 171555 in unilaterally MPTP‐lesioned monkeys and the D 2 receptor occupancy in vivo in this animal model of PD. © 1994 Wiley‐Liss. Inc.