A carbon-11 labeled imidazo[1,2-]pyridine derivative as a new potential PET probe targeting PI3K/mTOR in cancer.

The PI3K/Akt/mTOR pathway is frequently dysregulated in cancer due to its central role in cell growth, survival, and proliferation. Overactivation of the PI3K/Akt/mTOR pathway may occur through varying mechanisms including mutations, gene amplification, and upstream signaling events, ultimately resulting in cancer. Therefore, PI3K/Akt/mTOR pathway has emerged as an attractive target for cancer therapy and imaging. A promising approach to inhibit this pathway involves a simultaneous inhibition of both PI3K and mTOR using a dual inhibitor. Recently, a potent dual PI3K/mTOR inhibitor, 2,4-difluoro--(2-methoxy-5-(3-(5-(2-(4-methylpiperazin-1-yl)ethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-]pyridin-6-yl)pyridin-3-yl)benzenesulfonamide (), was discovered and demonstrated excellent kinase selectivity IC (PI3K/mTOR) = 0.20/21 nM; good cellular growth inhibition IC (HCT-116 cell) = 10 nM, modest plasma clearance, and acceptable oral bioavailability. Expanding on this discovery, here we present the synthesis of the carbon-11 labeled imidazo[1,2-]pyridine derivative 2,4-difluoro--(2-methoxy-5-(3-(5-(2-(4-[C]methylpiperazin-1-yl)ethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-]pyridin-6-yl)pyridin-3-yl)benzenesulfonamide (-[C]) as a new potential radiotracer for the biomedical imaging technique positron emission tomography (PET) imaging of PI3K/mTOR in cancer. The reference standard and its -demethylated precursor, 2,4-difluoro--(2-methoxy-5-(3-(5-(2-(piperazin-1-yl)ethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-]pyridin-6-yl)pyridin-3-yl)benzenesulfonamide (), were synthesized in 7 and 8 steps with 10% and 7% overall chemical yield, respectively. -[C] was prepared from using [C]methyl triflate ([C]CHOTf) through -C-methylation and isolated by high-performance liquid chromatography (HPLC) and solid-phase extraction (SPE) formulation in 40-50% radiochemical yield decay corrected to end of bombardment (EOB) based on [C]CO. The radiochemical purity was > 99% and the molar activity (A) at EOB was in the range of 296-555 GBq/µmol (n = 5).