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Binding characteristics and sensitivity to endogenous dopamine of [ 11 C]‐(+)‐PHNO, a new agonist radiotracer for imaging the high‐affinity state of D 2 receptors in vivo using positron emission tomography

2006; Wiley; Volume: 97; Issue: 4 Linguagem: Inglês

10.1111/j.1471-4159.2006.03840.x

1471-4159

Nathalie Ginovart, Laurent Galineau, Matthäus Willeit, Romina Mizrahi, P Bloomfield, Philip Seeman, Sylvain Houle, Shitij Kapur, Alan A. Wilson,

Neuroscience and Neuropharmacology Research

Abstract [ 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. Within‐subject 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). Comparison 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.