In vivo characterization of the pharmacokinetics and pharmacological properties of [11C]-(+)-PHNO in rats using an intracerebral beta-sensitive system

This study reports on the binding kinetics and pharmacological characterization of 11C]-(+)-PHNO ((+)-4-propyl-3,4,4a,5,6,10b-hexahydro-2H-naphtho1,2-b]1,4]oxazin-9-ol), a promising agonist radiotracer for in vivo evaluation of the D2-receptor. Its in vivo kinetics were monitored in rat striatum and cerebellum using a beta-sensitive Microprobe system. Control studies showed that 11C]-(+)-PHNO binding was reversible and reached a peak time equilibrium of specific binding in striatum 30 min after radiotracer injection. The binding potential (BP) calculated by the simplified reference tissue model was 3-fold higher than that measured with 11C]-(-)-NPA (2.14 +/- 0.50 vs. 0.66 +/- 0.01, respectively). In contrast, the methyl analog of (+)-PHNO, 11C]-(+)-MHNO, which displayed promising D2-agonist properties in vitro, showed no specific binding in the striatum in vivo. 11C]-(+)-PHNO binding was totally blocked by raclopride (1 mg/kg; i.v.) and 97% displaced by NPA (2 mg/kg; i.v.) suggesting that 11C]-(+)-PHNO was specific for the high affinity states of D2/D3-receptors. However, (+)-PHNO (1 mg/kg; i.v.) totally blocked and displaced 11C]-raclopride binding in striatum. Thus, (+)-PHNO at high concentrations might be able to bind to the low affinity states of D2/D3-receptors. After an amphetamine pretreatment (2 mg/kg; i.v.), a 69% decrease in BP value (P < 0.05) was observed for 11C]-(+)-PHNO indicating that its binding was highly sensitive to variations of endogenous DA. These results substantiate the use of 11C]-(+)-PHNO as an agonist radiotracer for D2-imaging. The sensitivity of its binding to competition with endogenous DA suggests an association with the subset of high affinity state D2-receptors.