Further evaluation of the carbon11‐labeled D 2/3 agonist PET radiotracer PHNO: Reproducibility in tracer characteristics and characterization of extrastriatal binding

[ 11 C]‐(+)‐PHNO is a new dopamine D 2/3 receptor agonist radiotracer which has been successfully used to measure D 2/3 receptor availability in experimental animals and man. Here we report in vivo evaluation in the rat of the biodistribution, metabolism, specificity, selectivity, and dopamine sensitivity of carbon11‐labeled PHNO ([ 11 C]‐3‐PHNO) produced by an alternative radiochemical synthesis method. [ 11 C]‐3‐PHNO showed rapid metabolism and clearance from most peripheral organs and tissues. [ 11 C]‐3‐PHNO, but not its polar metabolite, readily crossed the blood‐brain barrier and showed high levels of uptake in the D 2/3 ‐rich striatum. Pretreatment with unlabeled PHNO and the D 2/3 receptor antagonist raclopride indicated that binding in the striatum was specific and selective to D 2/3 receptors. PET studies in anesthetized rats revealed significant reductions in [ 11 C]‐3‐PHNO binding in the striatum following amphetamine administration, indicating sensitivity to increases in endogenous dopamine concentrations. D 2/3 antagonist pretreatment additionally indicated moderate levels of [ 11 C]‐3‐PHNO specific binding in several extrastriatal brain areas—most notably the olfactory bulbs and tubercles, thalamus, and hypothalamus. Of particular interest, approximately 30% of [ 11 C]‐3‐PHNO signal in the cerebellum—a region often used as a “low‐binding” reference region for PET quantification—was attributable to specific signal. These data demonstrate that [ 11 C]‐3‐PHNO shows similar tracer characteristics to [ 11 C]‐(+)‐PHNO, but additionally indicate that radiolabeled PHNO may be used to estimate D 2/3 receptor availability in select extrastriatal brain regions with PET. Synapse 64:301–312, 2010. © 2009 Wiley‐Liss, Inc.