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.
Egerton
Alice
A
Division of Neuroscience and Psychological Medicine, Department of Neuroscience and Mental Health, Imperial College London, London, United Kingdom. Alice.Egerton@iop.kcl.ac.uk
Hirani
Ella
E
Ahmad
Rabia
R
Turton
David R
DR
Brickute
Diana
D
Rosso
Lula
L
Howes
Oliver D
OD
Luthra
Sajinder K
SK
Grasby
Paul M
PM
D000818:Animals; D001667:Binding, Competitive; D002250:Carbon Radioisotopes / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D003342:Corpus Striatum / Q000000981:diagnostic imaging* / Q000187:drug effects*; D018491:Dopamine Agonists / Q000378:metabolism*; D008297:Male; D010078:Oxazines / Q000378:metabolism / Q000493:pharmacokinetics*; D049268:Positron-Emission Tomography / Q000379:methods*; D011485:Protein Binding; D020891:Raclopride / Q000378:metabolism / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000819:agonists*; D015203:Reproducibility of Results; D014018:Tissue Distribution
D002250:Carbon Radioisotopes; D018491:Dopamine Agonists; D010078:Oxazines; D017448:Receptors, Dopamine D2; C042631:naxagolide; D020891:Raclopride