Development of [18F]BMS-754807 as a potential PET tracer for the insulin-like growth factor-1 receptor (IGF-1R)

Objectives Insulin-like growth factor-1 receptor (IGF-1R) plays a central role in cellular growth, differentiation, survival, and cell cycle progression. Non-invasive imaging of this potential target for cancer treatment is of paramount clinical importance for development of new treatments targeting IGF-1R. BMS-754807 is an orally bioavailable, potent and reversible small molecule inhibitor of the IGF-1R, which is currently being evaluated in phase II clinical trials for the treatment of a variety of human cancers. This study describes the radiosynthesis of [18F]BMS-754807 as a potential PET radiotracer for imaging IGF-1R.

Methods Preferential displacement of the C-4 chloride in 2,4-dichloropyrrolo[1,2-f][1,2,4]triazine with 5-cyclopropyl-1H-pyrazol-3-amine followed by displacement at C-2 position with (S)-2-methylpyrrolidine-2-carboxylic acid gave the corresponding carboxylic acid in 2 steps. The carboxylic acid was then condensed with 6-bromopyridin-3-amine to yield the bromo analogue of BMS-754807, which on treatment with [18F]KF/K222 under microwave conditions gave [18F]BMS-754807.

Results The sequential displacement of C-4 and C-2 chlorides to yield the desired carboxylic acid produced a 65% overall yield in 2 steps. The condensation of carboxylic acid with 6-bromopyridin-3-amine to yield the bromo precursor for radiosynthesis produced a 60% yield. [18F]BMS-754807 was then synthesized in 10-20% yield by the aromatic [18F]fluorination of the corresponding bromo precursor.

Conclusions A high affinity IGF-1R selective PET ligand [18F]BMS-754807 has been identified and radiolabeled. The details of synthesis, radiosynthesis and in vitro evaluation of the radioligand will be presented