Binding characteristics and sensitivity to endogenous dopamine of [11C]-(+)-PHNO, a new agonist radiotracer for imaging the high-affinity state of D2 receptors in vivo using positron emission tomography (original) (raw)

2006, Journal of Neurochemistry

11 C]-(+)-PHNO (4-propyl-9-hydroxynaphthoxazine) is a new agonist radioligand that provides a unique opportunity to measure the high-affinity states of the D 2 receptors (D 2 -high) using positron emission tomography (PET). Here we report on the distribution, displaceablity, specificity and modeling of [ 11 C]-(+)-PHNO and compare it with the well characterized antagonist D 2 radioligand, [ 11 C]raclopride, in cat. [ 11 C]-(+)-PHNO displayed high uptake in striatum with a mean striatal binding potential (BP) of 3.95 ± 0.85. Pre-treatment with specific D 1 (SCH23390), D 2 (raclopride, haloperidol) and D 3 receptor (SB-277011) antagonists indicated that [ 11 C]-(+)-PHNO binding in striatum is specific to D 2 receptors. Withinsubject comparisons showed that [ 11 C]-(+)-PHNO BP in striatum was almost 2.5-fold higher than that measured with [ 11 C]-(-)-NPA ([ 11 C]-(-)-N-propyl-norapomorphine). Compar-ison of the dose-effect of amphetamine (0.1, 0.5 and 2 mg/kg; i.v.) showed that [ 11 C]-(+)-PHNO was more sensitive to the dopamine releasing effect of amphetamine than [ 11 C]raclopride. Amphetamine induced up to 83 ± 4% inhibition of [ 11 C]-(+)-PHNO BP and only up to 56 ± 8% inhibition of [ 11 C]raclopride BP. Scatchard analyses of [ 11 C]-(+)-PHNO and [ 11 C]raclopride bindings in two cats showed that the B max obtained with the agonist (29.6 and 32.9 pmol/mL) equalled that obtained with the antagonist (30.6 and 33.4 pmol/mL). The high penetration of [ 11 C]-(+)-PHNO in brain, its high signal-to-noise ratio, its favorable in vivo kinetics and its high sensitivity to amphetamine shows that [ 11 C]-(+)-PHNO has highly suitable characteristics for probing the D 2 -high with PET.