Synapse 2006 May 19; 60(2): 172-183 (Read article online)

Galineau L, Wilson AA, Garcia A, Houle S, Kapur S, Ginovart N

This study reports on the binding kinetics and pharmacological characterization of [(11)C]-(+)-PHNO ((+)-4-propyl-3,4,4a,5,6,10b-hexahydro-2H-naphtho[1,2-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 [(11)C]-(+)-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 [(11)C]-(-)-NPA (2.14 +/- 0.50 vs. 0.66 +/- 0.01, respectively). In contrast, the methyl analog of (+)-PHNO, [(11)C]-(+)-MHNO, which displayed promising D2-agonist properties in vitro, showed no specific binding in the striatum in vivo. [(11)C]-(+)-PHNO binding was totally blocked by raclopride (1 mg/kg; i.v.) and 97% displaced by NPA (2 mg/kg; i.v.) suggesting that [(11)C]-(+)-PHNO was specific for the high affinity states of D2/D3-receptors. However, (+)-PHNO (1 mg/kg; i.v.) totally blocked and displaced [(11)C]-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 [(11)C]-(+)-PHNO indicating that its binding was highly sensitive to variations of endogenous DA. These results substantiate the use of [(11)C]-(+)-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. Synapse 60:172-183, 2006. (c) 2006 Wiley-Liss, Inc.