A₁ Adenosine Receptor Antagonists as Ligands for Positron Emission Tomography (PET) and Single-Photon Emission Tomography (SPET)

Abstract

The high affinity of 8-cyclopentyl-1,3-dipropylxanthine (CPX) for the A1 adenosine receptor (A1AR) provides a good lead for developing radioligands suitable for positron emission tomography (PET) and single-photon emission tomography (SPET). This study tested the hypothesis that the kinds of chemical modifications made in the synthesis of CPX analogues containing carbon-11, fluorine-18, or radioiodine will not alter affinity for the A1AR. This report describes the synthesis and radioligand binding assays of unlabeled CPX analogues having methyl, 2-methoxyethyl, 2-fluoropropyl, or 3-fluoropropyl substituents, respectively, at either N-1 (13a-d) or N-3 (8a-d) or an (E)-3-iodoprop-2-en-1-yl substituent at N-3 (8f). Compounds 8d,f and 13b,d antagonized the binding of [3H]CPX to the A1AR of rat brain with affinities similar to those of CPX; compound 8c was twice as potent as CPX. Analogues 8a,b and 13a were less potent than CPX, but for each the Ki of antagonism was > or = 0.5 nM. Attempts to iodinate the 8-(4-hydroxyphenyl) analogue of CPX failed, probably because the xanthine substituent strongly deactivated the phenol toward electrophilic iodination. In summary, several of the modifications of the propyl groups of CPX needed to produce ligands for imaging by PET and SPET preserve or enhance affinity for the A1AR.

Selective Human Adenosine A3 Antagonists based on Pyrido[2,1‐f]purine‐2,4‐diones: Novel Features of hA3 Antagonist Binding

“…Different debenzylation alternatives, using similar described methods for 1,3-disubstituted uracils [23] or xanthines, [24,25] did not lead us to the desired NH-free compound in a sufficient yield for our purposes. These difficulties to remove certain N-benzyl groups have already been described by other authors.…”

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

“…Alkylation with chloroacetone followed by reduction with sodium borohydride and deprotection without isolation of intermediates yielded the 1‐(2‐hydroxypropyl)‐7 H ‐xanthine 15 d , as a mixture of R and S enantiomers. Alkylation of 1‐propyl‐8‐cyclopentyl‐7‐pivaloylmethylxanthine 16 with epifluorohydrin in the presence of a catalytic amount of base, gave, after deprotection, racemic 3‐(3‐fluoro‐2‐hydroxypropyl)‐1‐propylxanthine 17 …”

“…1‐Benzyl‐5,6‐diaminouracil (4) : Compound 3 (7.4 g 30 mmol) was dissolved in NH 4 OH (10 %, ∼70 mL) at 50–60 °C to give a brownish solution. The addition of solid Na 2 S 2 O 4 (10 g, 90 mmol) in small portions over 0.3 h discharged the color.…”

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

“…Under efficient stirring and external cooling with ice the solid was transferred portionwise into a solution of saturated aqueous NaHCO 3 ($800 ml). The suspension was stirred overnight at ambient temperature, filtered by suction, washed with water, toluene and ether and dried in a dessicator in vacuo over P 4 …”