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 [C-11]-(+)-PHNO ((+)-4-propyl-3,4,4a,5,6,10b-hexahydro-2H-naphtho[1,2-b][1,41oxazin-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 [C-11]-(+)-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 Mold higher than that measured with [C-11]-(-)-NPA (2.14 +/- 0.50 vs. 0.66 +/- 0.01, respectively). In contrast, the methyl analog of (+)-PHNO, [C-11]-(+)-MHNO, which displayed promising D2-agonist properties in vitro, showed no specific binding in the striatum in vivo. [C-11]-(+)-PHNO binding was totally blocked by raclopride (1 mg/kg; i.v.) and 97% displaced by NPA (2 mg/kg; i.v.) suggesting that [C-11]-(+)-PHNO was specific for the high affinity states of D2/D3-receptors. However, (+)-PHNO (1 mg/kg; i.v.) totally blocked and displaced [C-11]-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 [C-11]-(+)-PHNO indicating that its binding was highly sensitive to variations of endogenous DA. These results substantiate the use of [C-11]-(+)-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.