Solid phase radiosynthesis of an olaparib derivative using 4-[F] fluorobenzoic acid and in vivo evaluation in breast and prostate cancer xenograft models for PARP-1 expression.

Introduction: Solid-phase synthesis and conjugation reactions of acids and amines using coupling reagents are common in organic synthesis, but rare in F radiochemistry. 4-[F]Fluorobenzoic acid (FBA) is a useful building block, but is seldom used directly with coupling reagents for the preparation of F radiopharmaceuticals. To overcome the inconveniences associated with using [F]FBA in conjugation reactions, we have developed a non-covalent solid-phase synthesis (SPS) strategy for the radiosynthesis of [F]PARPi, a derivative of olaparib as a Poly (ADP-ribose) polymerase-1 (PARP-1) radioligand.

Methods: Fluoro-, bromo- and iodo-benzoic derivatives of olaparib were synthesized, and their PARP-1 affinities were measured using a recently developed cell culture-based competitive assay. To produce [F]PARPi, [F]FBA was radiosynthesized and purified using a cation-exchange cartridge, and then trapped by an anion-exchange resin cartridge, on which the solid-phase radiosynthesis was carried out to produce the desired product. [F]PARPi was evaluated in vivo in breast and prostate xenograft tumor models by microPET imaging, biodistribution and autoradiography.

Results: The best derivatives of olaparib were identified as compound 4, 7 and 8. [F]4 ([F]PARPi) was radiosynthesized in high radiochemical yield, high molar activity and high radiochemical purity using this SPS strategy. The in vivo evaluation of [F]PARPi demonstrates the PARP-1 specific uptake of [F]PARPi in the animal models.

Conclusions: This method is simple and efficient, having great potential for the synthesis of radiopharmaceuticals starting from [F]FBA or other radiolabeled aromatic acids. Using [F]PARPi prepared by this method, we demonstrated the promise of [F]PARPi in the nuclear imaging of PARP-1 expression.