Synthesis and Evaluation of No-Carrier-Added 8-Cyclopentyl-3-(3-[18F]fluoropropyl)-1-propylxanthine ([18F]CPFPX):  A Potent and Selective A1-Adenosine Receptor Antagonist for in Vivo Imaging

This report describes the precursor synthesis and the no-carrier-added (nca) radiosynthesis of the new A1 adenosine receptor (A1AR) antagonist [18F]8-cyclopentyl-3-(3-fluoropropyl)-1-propylxanthine (CPFPX), 3*, with fluorine-18 (half-life = 109.6 min). Nucleophilic radiofluorination of the precursor tosylate 8-cyclopentyl-3-(3-tosyloxypropyl)-7-pivaloyloxymethyl-1-propylxanthine, 2, with nca [18F]KF under aminopolyether-mediated conditions (Kryptofix 2.2.2/K2CO3) followed by deprotection was straightforward and, after formulation, gave the radioligand ready for injection with a radiochemical yield of 45 ± 7%, a radiochemical purity of >98% and a specific radioactivity of >270 GBq/μmol (>7.2 Ci/μmol). Preparation time averaged 55 min. The synthesis proved reliable for high batch yields (∼7.5 GBq) in routine production (n = 120 runs). The radiotracer was pharmacologically evaluated in vitro and in vivo and its pharmacokinetics in rodents determined in detail. After iv injection a high accumulation of radioactivity occurred in several regions of mouse brain including thalamus, striatum, cortex, and cerebellum. Antagonism by the specific A1AR antagonists 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) and N 6-cyclopentyl-9-methyladenine (N-0840), but not with the A2AR antagonist 3,7-dimethyl-1-propargylxanthine (DMPX), indicated specific and reversible binding of the radioligand to A1AR in cortical and subcortical regions of interest. In mouse blood at least two polar metabolites formed rapidly (50% at 5 min after tracer application). However, chromatographic analyses of brain homogenate extracts taken 60 min pi showed that >98% of radioactivity was unchanged radioligand. Chromatographic isolation and reinjection of peripherally formed radioactive metabolites revealed no accumulation of radioactivity in mouse brain, probably due to the polarity of the metabolites. These preliminary results suggest that nca [18F]CPFPX is a useful radioligand for the noninvasive imaging of the brain A1AR.