Further evaluation of the carbon11-labelled D2/3 agonist PET radiotracer PHNO: reproducibility in tracer characteristics and characterization of extrastriatal binding

摘要

[¹¹C]-(+)-PHNO is a new dopamine D2/3 receptor agonist radiotracer which has been successfully used to measure D2/3 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 carbon-11 labeled PHNO ([¹¹C]-3-PHNO) produced by an alternative radiochemical synthesis method. [¹¹C]-3-PHNO showed rapid metabolism and clearance from most peripheral organs and tissues. [¹¹C]-3-PHNO, but not its polar metabolite, readily crossed the blood-brain barrier and showed high levels of uptake in the D2/3 -rich striatum. Pre-treatment with unlabelled PHNO and the D2/3 receptor antagonist raclopride indicated that binding in the striatum was specific and selective to D2/3 receptors. PET studies in anaesthetized rats revealed significant reductions in [¹¹C]-3-PHNO binding in the striatum following amphetamine administration, indicating sensitivity to increases in endogenous dopamine concentrations. D2/3 antagonist pre-treatment additionally indicated moderate levels of [¹¹C]-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 [¹¹C]-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 [¹¹C]-3-PHNO shows similar tracer characteristics to [¹¹C]-(+)-PHNO, but additionally indicate that radiolabeled PHNO may be used to estimate D2/3 receptor availability in select extrastriatal brain regions with PET.