Synthesis and Pharmacological Evaluation of Identified and Putative Metabolites of the A₁ Adenosine Receptor Antagonist 8‐Cyclopentyl‐3‐(3‐fluoropropyl)‐1‐propylxanthine (CPFPX)

Abstract

The A adenosine receptor (A AR) antagonist [ F]8-cyclopentyl-3-(3-fluoropropyl)-1-propylxanthine ([ F]CPFPX), used in imaging human brain A ARs by positron emission tomography (PET), is stable in the brain, but rapidly undergoes transformation into one major (3-(3-fluoropropyl)-8-(3-oxocyclopenten-1-yl)-1-propylxanthine, M1) and several minor metabolites in blood. This report describes the synthesis of putative metabolites of CPFPX as standards for the identification of those metabolites. Analysis by (radio)HPLC revealed that extracts of human liver microsomes incubated with no-carrier-added (n.c.a.)[ F]CPFPX contain the major metabolite, M1, as well as radioactive metabolites corresponding to derivatives functionalized at the cyclopentyl moiety, but no N1-despropyl species or metabolites resulting from functionalization of the N3-fluoropropyl chain. The putative metabolites were found to displace the binding of [ H]CPFPX to the A AR in pig brain cortex at K values between 1.9 and 380 nm and the binding of [ H]ZM241385 to the A AR in pig striatum at K values >180 nm. One metabolite, a derivative functionalized at the ω-position of the N1-propyl chain, showed high affinity (K 2 nm) to and very good selectivity (>9000) for the A AR.

Species Differences in Microsomal Metabolism of Xanthine-Derived A1 Adenosine Receptor Ligands

“…All compounds listed in Table 1 were synthesized and characterized in our laboratories according to the procedures described in [4,10,[39][40][41].…”