title: 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.
authors.affiliation: Institut für Nuklearchemie, Forschungszentrum Jülich GmbH, Germany.
authors.forename: M H
authors.initials: MH
authors.lastname: Holschbach
authors.forename: T
authors.initials: T
authors.lastname: Fein
authors.forename: C
authors.initials: C
authors.lastname: Krummeich
authors.forename: R G
authors.initials: RG
authors.lastname: Lewis
authors.forename: W
authors.initials: W
authors.lastname: Wutz
authors.forename: U
authors.initials: U
authors.lastname: Schwabe
authors.forename: D
authors.initials: D
authors.lastname: Unterlugauer
authors.forename: R A
authors.initials: RA
authors.lastname: Olsson
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism*; D002417:Cattle; D002462:Cell Membrane / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism; D015195:Drug Design; D007202:Indicators and Reagents; D008024:Ligands; D058915:Purinergic P1 Receptor Antagonists; D011869:Radioligand Assay; D051381:Rats; D013329:Structure-Activity Relationship; D014055:Tomography, Emission-Computed; D015899:Tomography, Emission-Computed, Single-Photon; D014316:Tritium; D014970:Xanthines / Q000138:chemical synthesis* / Q000493:pharmacokinetics
chemical_list: D007202:Indicators and Reagents; D008024:Ligands; D058915:Purinergic P1 Receptor Antagonists; D014970:Xanthines; D014316:Tritium; C051360:1,3-dipropyl-8-cyclopentylxanthine