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Synthesis and Pharmacological Evaluation of Identified and Putative Metabolites of the A 1 Adenosine Receptor Antagonist 8‐Cyclopentyl‐3‐(3‐fluoropropyl)‐1‐propylxanthine (CPFPX)
Author(s) -
Holschbach Marcus H.,
Bier Dirk,
Sihver Wiebke,
Schulze Annette,
Neumaier Bernd
Publication year - 2017
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201600592
Subject(s) - metabolite , chemistry , moiety , stereochemistry , antagonist , adenosine receptor , adenosine , adenosine receptor antagonist , striatum , receptor , microsome , biochemistry , enzyme , dopamine , biology , agonist , endocrinology
The A 1 adenosine receptor (A 1 AR) antagonist [ 18 F]8‐cyclopentyl‐3‐(3‐fluoropropyl)‐1‐propylxanthine ([ 18 F]CPFPX), used in imaging human brain A 1 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.)[ 18 F]CPFPX contain the major metabolite, M1 , as well as radioactive metabolites corresponding to derivatives functionalized at the cyclopentyl moiety, but no N 1‐despropyl species or metabolites resulting from functionalization of the N 3‐fluoropropyl chain. The putative metabolites were found to displace the binding of [ 3 H]CPFPX to the A 1 AR in pig brain cortex at K i values between 1.9 and 380 n m and the binding of [ 3 H]ZM241385 to the A 2A AR in pig striatum at K i values >180 n m . One metabolite, a derivative functionalized at the ω‐position of the N 1‐propyl chain, showed high affinity ( K i 2 n m ) to and very good selectivity (>9000) for the A 1 AR.