Synthesis of the Main Metabolite in Human Blood of the A₁ Adenosine Receptor Ligand [¹⁸F]CPFPX

Abstract

In human blood, the PET radiotracer [(18)F]CPFPX (1) is metabolized to numerous metabolites, one (M1) being the most prominent in plasma 30 min p.i. Because the mass of injected tracer is < or = 5 nmol, concentrations in plasma are too low to analyze. Human liver microsomes generate main metabolites having HPLC retention times identical to those in plasma. HPLC-MS tentatively identified M1 as 2. Synthesis of 2 and identical HPLC-MS spectra of 2 and M1 confirmed that assignment.

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

“…The fragmentation scheme used to obtain structural information about the metabolites of CPFPX was derived from MS spectra of reference compounds CPFPX and DPCPX. An elaborated study could reveal that the chemical structure of the main metabolite of CPFPX in human blood, tentatively identified by HPLC/MS, is in full agreement with that of a reference compound obtained via a multistep organic synthesis …”

“…An elaborated study could reveal that the chemical structure of the main metabolite of CPFPX in human blood, tentatively identified by HPLC/MS, is in full agreement with that of a reference compound obtained via a multistep organic synthesis. [8] From a retrospective point of view the identification of metabolites originating from the synthetic xanthine CPFPX should theoretically have been possible with the knowledge extracted from existing publications which deal with various MS-fragmentation mechanisms of caffeine. [9][10][11][12][13] However, the published experiments were performed either by using advanced spectrometers in combination with additional ionisation modes like collision-activated dissociation (CAD) or by a priori using different ionisation methods like electron ionisation (EI).…”

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

“…Because the presence of double bonds in the cyclopentenyl moieties and an O ‐benzyl protecting group in the cyclopentyl building block used in the synthesis of compounds 24 a – c was incompatible with the hydrogenation conditions necessary to remove an amide benzyl protecting group, the acid‐labile 2,4‐dimethoxybenzyl (DMB) protecting group was alternatively installed . Thus, carbodiimide/DMAP induced condensation of the key intermediate 5,6‐diamino‐1‐(2,4‐dimethoxybenzyl)‐3‐propyluracil 18 with either cyclopent‐2‐enecarboxylic acid or the isomeric cyclopent‐3‐enecarboxylic acid followed by alkali‐induced ring closure of amides 19 a and 19 b , as described for the synthesis of 6 , furnished xanthines 20 a and 20 b . Xanthine 20 c was obtained by the reaction of diamine 18 with cis ‐2‐benzyloxycyclopentane‐1‐carboxylic acid using the mixed anhydride method followed by alkali‐induced cyclization of the intermediate amide 19 c .…”

“…N ‐(6‐Amino‐1‐(2,4‐dimethoxybenzyl)‐2,4‐dioxo‐3‐propyl‐1,2,3,4‐tetrahydro‐pyrimidin‐5‐yl)‐cyclopent‐1‐enecarboxamide (19 b) : At ambient temperature the DMB protected diamine 18 (3.34 g, 10 mmol) was suspended in a mixture of dioxane (100 mL) and water (40 mL) . Under efficient stirring 1‐(3‐dimethylaminopropyl)‐3‐ethylcarbodiimide hydrochloride (EDAC, 1.92 g, 10 mmol) and a catalytic amount (150 mg) of 4‐dimethylaminopyridine (DMAP) was added.…”

“…cis ‐8‐(2‐Benzyloxycyclopentyl)‐3‐(2,4‐dimethoxybenzyl)‐1‐propyl‐1 H ‐purine‐2,6(3 H ,7 H )‐dione (20 c) : Under an argon atmosphere neat isobutyl chloroformate (10 mmol, 1.3 mL) and 4‐methylmorpholine (10 mmol, 1.1 mL) were added to a well‐stirred ice‐cold solution of the DMB protected diamine 18 (3.34 g, 10 mmol) in dry DMF (30 mL) . At this temperature a solution of 2‐benzyloxycyclopentanecarboxylic acid (2.2 g, 10 mmol) in dry DMF (5 mL) was added dropwise.…”