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| Home > Publications database > 8-Bicycloalkyl-CPFPX derivatives as potent and selective tools for PET imaging of the A1 adenosine receptor |
| Home > Publications database > 8-Bicycloalkyl-CPFPX derivatives as potent and selective tools for PET imaging of the A1 adenosine receptor |
| Conference Presentation (After Call) | FZJ-2024-04004 |
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2022
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Please use a persistent id in citations: doi:10.1016/S0969-8051(22)00096-8
Abstract: Objectives: The first successful in-house development [1] ofa radiofluorinated A 1 adenosine receptor (A1AR) antagonist withnanomolar affinity for the bovine A 1 AR for in vivo PET studies was8-cyclopentyl-3-(3-[ 18 F]Fluoropropyl)-1-propyl-xanthine, [ 18 F]CPFPX. Although this ligand proved to be useful in vivo in rodents,already first preclinical studies revealed possible limitations for PETimaging. At the beginning our efforts aimed at synthesizing metabol-ically stabilized CPFPX derivatives, but the recently published findingby Schneider et al. [2] that affinity is the key pharmacokinetic deter-minant of radiolabeled xanthines in the brain prompted us to focusour efforts on the synthesis of A1AR ligands with high affinity.Methods: In search of CPFPX-like A1AR ligands with higher targetaffinity, we decided to replace the cyclopentyl residue in the 8-posi-tion of the xanthine backbone with sterically more demanding nor-bornyl residues [3]. The target xanthines and the radiofluorinationprecursors (sulfonates) were synthesized through multistep syn-theses by a modified Traube protocol [4]. Binding experiments wereperformed with membranes from CHO K1 cells stably transfectedwith either the human A1 or A2AAR. Nucleophilic radiofluorinationon the n.c.a level used the classical Kryptofix™ 2.2.2/K 2 CO 3 method.For in vitro autoradiography, frozen horizontal sections (20 μm) of ratbrains were used.Results: From a series of newly synthesized compounds 1-NBXhas emerged as the most potent and selective candidate (Figure 1).The norbornyl group has two surfaces, one being essentially a cyclo-pentyl ring backed by a two-carbon bridge and the other being acyclohexyl ring backed by a one-carbon bridge. The greater potencyof 1-NBX relative to the 2- and 7-norbornyl isomers probably occursbecause 1-NBX binds to the receptor with its cyclopentyl surfacefacing the receptor, whereas the 2- and 7-isomers are forced to bindwith the less favorable cyclohexyl ring facing the receptor.Cyclopentane exists mainly in an “envelope” conformation, in whichfour of the carbons form the corners of a flat envelope, and the fifthcarbon represents the apex of a triangular flap, which projects at anangle of about 120° from the body of the envelope [5, 6]. Althoughany of the carbons can take the out-of-plane position in cyclopen-tane, in norbornane the bridging carbon is locked in this position.The greater affinity of 1-NBX compared to that of CPFPX is mostlikely due to the former being locked in the optimal conformation. Asexpected from earlier studies, 1-propyl and 3-fluoropropylsubstitution at both 1- and 3-positions of the xanthine scaffold wasoptimum to potent and selective A1AR antagonism.#Conclusions: [ 18 F]1-NBX seems to be a promising A1AR antagonisttracer suitable for PET. Future preclinical studies will reveal weather1 NBX will have the potential to serve as a substitute for [ 18 F]CPFPX.References:[1] Holschbach et al., J Med Chem. 2002, 45(23), 5150-5156.[2] Schneider et al., Nucl Med Biol. 2020, 82-83, 1-8.[3] Shimada et al., J Med Chem. 1992, 35, 924-930.[4] Holschbach et al., Org Lett. 2009, 11, 4266-4269.[5] Dragojlovic V., ChemTexts 2015, 1, 14.[6] Trivedi et al., J Med Chem 1989, 32, 8-11
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