1-(3-[¹⁸F]fluoropropyl)piperazines as model compounds for the radiofluorination of pyrido[2,3-d]pyrimidines

Abstract

The visualization of cyclin-dependent kinases (CDKs), which are overexpressed in multiple tumor types, with radiolabeled CDK inhibitors by means of positron emission tomography in vivo is a promising approach for tumor imaging. Pyrido[2,3-d]pyrimidines belong to a class of inhibitors, which bind with high affinity to CDK4 and CDK6. 1-(3-[¹⁸F]Fluoropropyl)-4-(4-nitrophenyl)piperazine and 1-(3-[¹⁸F]fluoropropyl)-4-(6-nitropyridin-3-yl)piperazine represent structural elements of the appropriate CDK inhibitors and were therefore chosen as model compounds for the incorporation of fluorine-18 into pyrido[2,3-d]pyrimidines. Three methods are known for the preparation of tertiary 3-[¹⁸F]fluoropropyl-amines: 1) the direct substitution of a good leaving group, 2) the two-step reaction synthesizing a 3-[¹⁸F]fluoropropyl intermediate, and 3) the utilization of aziridinium or azetidinium salts. In general, radiofluorinations using azetidinium salts lead to excellent radiochemical yields in short periods of time. For these reasons, we developed a synthesis route to tosylated piperazine precursors and established a radiolabeling approach based on the incorporation of fluorine-18 into open-chained tosylates as well as the respective azetidinium spiro compounds to yield the desired radiofluorinated piperazines successfully.