Aripiprazole exhibits a unique occupancy profile as compared with other conventional and atypical antipsychotics. The threshold for response appears to be higher than 60%, extrapyramidal side effects appear to be uncommon even at occupancies that exceed the conventional extrapyramidal side effects threshold of 80%, and 5-HT(2) occupancy is lower than D(2) occupancy. Implications for aripiprazole's mechanism of action are discussed.

Imaging the competition between D(2/3) radioligands and endogenous dopamine is so far the only way to measure dopamine release in the living human brain. The dopamine D(2) receptor exists in a high (D(2)(high)) and a low-affinity state for dopamine. Under physiological conditions, dopamine is expected to bind to D(2)(high) only. [(11)C]-(+)-4-propyl-9-hydroxynaphthoxazine ((+)-PHNO) is the first D(2/3) agonist radioligand for positron emission tomography (PET) imaging in humans. Since [(11)C]-(+)-PHNO is expected to bind preferentially to D(2)(high), it should be particularly vulnerable to competition with endogenous dopamine. Nine healthy subjects participated in two PET scans, one after administration of d-amphetamine and one after placebo. [(11)C]-(+)-PHNO PET test re-test variability was determined in 11 healthy subjects. Binding potentials (BPs) were calculated for caudate, putamen, ventral striatum, and globus pallidus. d-Amphetamine led to a significant decrease of [(11)C]-(+)-PHNO BPs in caudate (-13.2%), putamen (-20.8%), and ventral striatum (-24.9%), but not in globus pallidus (-6.5%). d-Amphetamine-induced displacement correlated with serum d-amphetamine levels in all regions but caudate. This is the first report on competition between endogenous dopamine and a D(2/3) agonist radioligand in humans. [(11)C]-(+)-PHNO PET might be a superior measure for release of endogenous dopamine than PET employing conventional D(2/3) antagonist radioligands.

The kinetic modeling of [ 11 C]-( + )-PHNO binding to the dopamine D 2/3 receptors in six human volunteers using positron emission tomography (PET) is described. [ 11 C]-( + )-PHNO is the first agonist radioligand for the D 2/3 in humans and as expected showed high uptake in caudate, putamen, globus pallidus (GP) and ventral striatum, and low uptake in cerebellum. A two-tissue compartment model (2CM) with four parameters was necessary to adequately fit time-activity data in all regions. Although a 2CM provided an excellent estimation of total distribution volumes, which were highly correlated with those obtained with the invasive Logan approach, it provided a poor identification of the k 3 /k 4 ratios. Coupling K 1 /k 2 between brain regions (Method C) or fixing K 1 /k 2 to the value obtained in cerebellum (Method D) enabled more stable estimates of k 3 /k 4 as compared with an unconstrained 2CM. The k 3 /k 4 obtained with Method D ranged from 0.1260.03 in cerebellum to 3.9360.77 in GP and were similar to those obtained when coupling K 1 /k 2 . Binding potentials (BPs) obtained using the simplified reference tissue model (BP SRTM ) ranged from 2.0860.34 in caudate to 3.5560.78 in GP and were highly correlated with k 3 /k 4 estimates obtained with Method D (r = 0.98). However, BP SRTM were 11%65% lower than values obtained with Method D. BPs derived using the noninvasive Logan approach were slightly lower but not significantly different than BP SRTM . This study demonstrates that [ 11 C]-( + )-PHNO can be used for the quantitative measurement of D 2/3 densities and should enable further studies of potential D 2/3 dysregulation in several important psychiatric and neurologic illnesses.