[¹¹C]Ro 31-7453 (MKC-1) as a new PET cancer imaging agent involving multiple targets

Objectives Ro 31-7453 (MKC-1) belongs to a novel class of antimitotic and apoptosis-inducing agents with in vitro efficacy against a wide range of human tumor cell lines including multidrug resistance cell lines. Ro 31-7453 has a novel mechanism involving multiple targets such as importin β, microtubule destabilizing activity and PI3K-mTOR pathway. This study was designed to develop [¹¹C]Ro 31-7453 (MKC-1) as a new PET cancer imaging agent.

Methods Ro 31-7453 {3-(1-methyl-1H-indol-3-yl)-4-(1-methyl-6-nitro-1H-indol-3-yl)-1H-pyrrole-2,5-dione} and its precursor 3-(1-1H-indol-3-yl)-4-(1-methyl-6-nitro-1H-indol-3-yl)furan-2,5-dione for radiolabeling were synthesized from 6-nitroindole and indole-3-acetic acid in 7 and 5 steps, respectively. The precursor was labeled with [¹¹C]CH₃I under basic conditions through N-[¹¹C]methylation to provide a radiolabeled intermediate 3-(1-[¹¹C]methyl-1H-indol-3-yl)-4-(1-methyl-6-nitro-1H-indol-3-yl)furan-2,5-dione, which was then quickly reacted with hexamethyldisilazane in DMF/MeOH to give target tracer [¹¹C]Ro 31-7453. The two-step radiolabeling reaction was performed in a home-built automated ¹¹C-radiosynthesis module, and the target tracer was purified by HPLC method.

Results The overall chemical yields for the target compound and the precursor in 7 and 5 steps were 0.4% and 2% respectively. The radiochemical yield for the target tracer was 20-30%, decay corrected to end of bombardment (EOB), based on [¹¹C]CO₂. The specific activity was 222-296 GBq/μmol at EOB.

Conclusions A new synthetic route to labeling precursor and Ro 31-7453 has been described, and a two-step radiosynthesis approach to [¹¹C]Ro 31-7453 has been well-developed for the first time.

Research Support The Breast Cancer Research Foundation