METABOLISM OF THE A₁ ADENOSINE RECEPTOR POSITRON EMISSION TOMOGRAPHY LIGAND [¹⁸F]8-CYCLOPENTYL-3-(3-FLUOROPROPYL)-1-PROPYLXANTHINE ([¹⁸F]CPFPX) IN RODENTS AND HUMANS

Abstract

Positron emission tomography (PET) is a useful procedure for assessing the density (Phelps, 2000) and pharmacological properties of receptors in vivo (Merlet et al., 1993;Beugel et al., 1999). However, receptor-PET studies favor radioligands that are either stable in the body or that give rise to metabolites that do not interfere with the imaging of specifically bound ligand.The ligand (Holschbach et al., 2002) is used to image the A 1 adenosine receptor (A 1 AR) in human brain (Bauer et al., 2003). Because this ligand does not undergo degradation in the central nervous system, specifically bound ligand accounts for a very large fraction of brain radioactivity. However, such is not the case in peripheral tissues. The metabolism of [18 F]CPFPX in primates (Boy et al., 1998) and humans gives rise to at least three polar metabolites in blood, and studies illustrated the confounding effects of these metabolites. For example, the intravenous administration of [18 F]CPFPX to experimental animals caused intense labeling of the heart that was unaffected by the administration of unlabeled ligand, evidence for high unspecific binding of a metabolite (Holschbach et al., 1998).The physiological importance of the A 1 AR, its wide tissue distribution, and the success of PET-imaging A 1 ARs in the central nervous system urge extension of this technique to other organs. The design of more stable radioligands to achieve that end requires the kind of information about the metabolism of [18 F]CPFPX provided by this study.Measurements of receptor density by PET depend on compartmental analysis by mathematical models that are very sensitive to the concentration of native radioligand in blood perfusing the organ (the "input function"). Such measurements on the plasma of human subjects (Meyer et al., 2004) identified several [18 F]CPFPX metabolites in addition to unchanged ligand. Because the radiotracers for PET studies are prepared under no-carrier-added conditions, the amount of compound administered is in the low to subnanomolar range, making direct spectrometric identification of metabolites impossible. As this report describes, incubating CPFPX with human liver microsomes generated compounds that by HPLC had the same mobilities as the metabolites in plasma, and LC-MS tentatively identified them by measuring m/z of the [M ϩ H] ϩ ions. The literature contains little information about the metabolism of synthetic xanthines. The use of CPFPX in humans for diagnostic and research PET imaging necessitates the knowledge of its metabolism in vivo. To our knowledge, the present study of the biotransformation of CPFPX in humans is the first of its kind.Article, publication date, and citation information can be found at

PET radiotracers: crossing the blood–brain barrier and surviving metabolism

“…Oxidation of the cyclopentyl ring was established as the route of metabolism [63], and CYP1A2 was identified as the metabolizing enzyme. Inhibition of this enzyme with fluovoxamine greatly reduced radiotracer metabolism in human subjects [64]. …”

Collision‐induced dissociation studies of caffeine in positive electrospray ionisation mass spectrometry using six deuterated isotopomers and one N1‐ethylated homologue

“…Our previous work has demonstrated that spectra of simple collision‐induced dissociation (CID) fragmentation reactions principally allow to obtain reliable information about the identity of metabolites without using a collision chamber . The fragmentation scheme used to obtain structural information about the metabolites of CPFPX was derived from MS spectra of reference compounds CPFPX and DPCPX.…”

Effect of Animal Condition and Fluvoxamine on the Result of [18F]N-3-Fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl) Nortropane ([18F]FP-CIT) PET Study in Mice

“…Pretreatment with fluvoxamine induced a significant increase in the striatal uptake and striatal specific to cortical non-specific activity ratio, while causing a gradual decrease in bone uptake. This finding suggests that fluvoxamine may inhibit the defluorination of [ 18 [31]. Because CYP3A4, which is inhibited by fluvoxamine [32], is involved in the N-dealkylation step [33,34], fluvoxamine may decrease the defluorination of [ 18 F]FP-CIT.…”

“…Oxidation of the cyclopentyl ring was established as the route of metabolism, and CYP1A2 was identified as the metabolizing enzyme [17]. Inhibition of this enzyme with fluvoxamine greatly reduced metabolism of radiotracers in human subjects [18].…”