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

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Abstract
[11C]‐(+)‐PHNO (4‐propyl‐9‐hydroxynaphthoxazine) is a new agonist radioligand that provides a unique opportunity to measure the high‐affinity states of the D2 receptors (D2‐high) using positron emission tomography (PET). Here we report on the distribution, displaceablity, specificity and modeling of [11C]‐(+)‐PHNO and compare it with the well characterized antagonist D2 radioligand, [11C]raclopride, in cat. [11C]‐(+)‐PHNO displayed high uptake in striatum with a mean striatal binding potential (BP) of 3.95 ± 0.85. Pre‐treatment with specific D1 (SCH23390), D2 (raclopride, haloperidol) and D3 receptor (SB‐277011) antagonists indicated that [11C]‐(+)‐PHNO binding in striatum is specific to D2 receptors. Within‐subject comparisons showed that [11C]‐(+)‐PHNO BP in striatum was almost 2.5‐fold higher than that measured with [11C]‐(–)‐NPA ([11C]‐(–)‐N‐propyl‐norapomorphine). Comparison of the dose‐effect of amphetamine (0.1, 0.5 and 2 mg/kg; i.v.) showed that [11C]‐(+)‐PHNO was more sensitive to the dopamine releasing effect of amphetamine than [11C]raclopride. Amphetamine induced up to 83 ± 4% inhibition of [11C]‐(+)‐PHNO BP and only up to 56 ± 8% inhibition of [11C]raclopride BP. Scatchard analyses of [11C]‐(+)‐PHNO and [11C]raclopride bindings in two cats showed that the Bmax 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 [11C]‐(+)‐PHNO in brain, its high signal‐to‐noise ratio, its favorable in vivo kinetics and its high sensitivity to amphetamine shows that [11C]‐(+)‐PHNO has highly suitable characteristics for probing the D2‐high with PET.

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