Synthesis of structurally identical fluorine-18 and iodine isotope labeling compounds for comparative imaging.

Abstract

The synthesis of a benzophenone-based labeling compound designed for comparative imaging studies with both in vivo positron emission tomograph (PET) and single-photon computed tomography (SPECT) and ex vivo autoradiography is described. The new compound can be labeled with either F-18 or iodine radioisotopes to give two different radioisotopmers: N-[2-fluoro-5-(3-[I-131]iodobenzoyl)benzyl]-2-bromoacetamide (1) and N-[2-[F-18]fluoro-5-(3-iodobenzoyl)benzyl]-2-bromoacetamide (2). Compound 1 and 2 have a 2-bromoacetyl group, which can be used to conjugate with biomolecules through a nucleophilic substitution reaction. Compound 1 was synthesized from the corresponding tributyltin derivatives via an oxidative destannylation reaction, and compound 2 was prepared via a four-step radiosynthesis (nucleophilic aromatic substitution, reduction, oxidation, and alkylation) starting from 4-(N,N,N-trimethylammonio)-3-cyano-3'-iodobenzophenone triflate. A remarkably high radiochemical yield (>90%) was achieved for the F-18 nucleophilic aromatic substitution under mild conditions (room temperature in less than 10 min), indicating the structural advantage of the designed molecule to facilitate the F-18 for trimethylammonium substitution in the presence of two electron-withdrawing groups (nitrile and carbonyl). The overall radiosynthesis time for compound 2 is less than 3 h after end of bombardment (EOB) with an unoptimized radiochemical yield of about 2% (not decay corrected) and specific activity of 0.8 Ci/micromol at EOB. The radiolabeling precursors for compound 1 and 2 were synthesized via a carbon-carbon bond-forming reaction between 2-substituted-5-lithiobenzonitrile and 3-substituted benzaldehyde derivatives. Compounds 1 and 2 should allow us to label biomolecules with F-18 or iodine isotopes and gives structurally identical products, which are expected to have identical biological properties and should be useful for comparative imaging studies.