Tritium-labelled 8-cyclopentyl-3-(3-fluoropropyl)-1-propylxanthine ([3H]CPFPX), a potent and selective antagonist for the A1 adenosine receptor

The reduction of 1-allyl-8-cyclopentyl-3-(3-fluoropropyl)xanthine, 7, with tritium gas catalyzed by 10% Pd-C gave 8-cyclopentyl-3-(3-fluoropropyl)-1[2,3-H-3]propylxanthine ([H-3]CPFPX), 8*, a potent and selective antagonist for the A, adenosine receptor (AIAR). The synthesis of 7 proceeded from 6-aminouracil, 1, which underwent silylation and alkylation with allyl bromide to form 6-amino-3-allyluracil, 2. Nitrosation led to the 5-nitroso compound, 3, which underwent reduction to the 4,5-diaminouracil, 4, and carbodiimide-mediated acylation with cyclopentanecarboxylic acid produced 3-allyl-6amino-5-cyclopentylcarboxamidouracil, 6. Alkylation at N-1 with 3-fluoro-1-bromopropane and cyclization with alkali completed the synthesis of 7. [H-3]CPFPX had a radiochemical purity of > 98% and a specific activity of > 2.1 TBq/mmol (57 Ci/mmol). [H-3]CPFPX bound to the rat, pig and human A(1)AR with a K-D of 0.63, 1.37 and 0.71 nM, respectively. The K-D at the rat and human A(2A)AR was 812 and 940 nM, respectively, thus giving selectivities of > 1200- and > 700-fold. Copyright (C) 2003 John Wiley Sons, Ltd.