New metabolically enhanced PET radioligands for the adenosine A(1) receptor

Objectives 8-Cyclopentyl-3-(3-[18F]fluoropropyl)-1-propylxanthine ([18F]CPFPX) is an established receptor ligand to examine cerebral adenosine A1 receptors in humans by positron-emission-tomography (PET) [1]. A large drawback of this compound is its short biological half-life of about only ten minutes in human blood plasma [2]. Therefore alternative, slower metabolizing 18F-labelled adenosine A1 receptor ligands for in vivo imaging were developed, while maintaining a high affinity. Methods The binding affinity of various xanthine derivatives to the adenosine A1 receptor was examined. Based on these studies as well as the results of in-house studies on metabolites, the xanthine derivatives 8-cyclobutyl-1-cyclopropymethyl-3-(3-fluoropropyl)xanthine (1) and 1-cyclopropylmethyl-3-(3-fluoropropyl)-8-(1-methylcyclobutyl)xanthine (2) were designed as alternatives of CPFPX. After synthesis of these compounds, their affinity to the adenosine A1 receptor was investigated by competitive assays. The mesylate derivatives were synthesized as precursors for nucleophilic 18F-labelling and the radiofluorinated ligands were used for autoradiographic studies. Furthermore, the metabolism of 1 and 2 was examined in vitro using human liver microsomes. Results The new xanthine derivatives were synthesized in 13 steps with total yields of 1.8 % (1) and 1.5 % (2). In binding studies both compounds showed nanomolar affinities to the adenosine A1 receptor. [18F]CBCPM was obtained by radiofluorination with a radiochemical yield of 21.3 ± 3.8 % and a molar activity of 12.3 ± 0.2 GBq/µmol. In case of [18F]CPMMCB, a radiochemical yield of 14.4 ± 2.5 % and a molar activity of 36.5 ± 1.1 GBq/µmol could be achieved. In vitro autoradiography with brain slices of rat showed for both compounds the expected enrichment in regions known to have a high adenosine A1 receptor expression, while exhibiting the necessary low unspecific binding. Further studies proved a significantly slower metabolism in vitro of both new xanthine derivatives than CPFPX. Conclusions Two new radiofluorinated affine and specific xanthine derivatives were developed as possible radioligands for the adenosine A1 receptor with a distinct higher stability than CPFPX. Acknowledgements References [1] Holschbach M. H. et al. (2002) J. Med. Chem., 45, 5150-5156. [2] Bier D. et al. (2006) Drug Metab. Dispos., 34, 570-576