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

Abstract

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-N-(2-methoxy-5-(3-(5-(2-(4-methylpiperazin-1-yl)ethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-6-yl)pyridin-3-yl)benzenesulfonamide (7), was discovered and demonstrated excellent kinase selectivity IC₅₀ (PI3K/mTOR) = 0.20/21 nM; good cellular growth inhibition IC₅₀ (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-a]pyridine derivative 2,4-difluoro-N-(2-methoxy-5-(3-(5-(2-(4-[¹¹C]methylpiperazin-1-yl)ethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-6-yl)pyridin-3-yl)benzenesulfonamide (N-[¹¹C]7) as a new potential radiotracer for the biomedical imaging technique positron emission tomography (PET) imaging of PI3K/mTOR in cancer. The reference standard 7 and its N-demethylated precursor, 2,4-difluoro-N-(2-methoxy-5-(3-(5-(2-(piperazin-1-yl)ethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-6-yl)pyridin-3-yl)benzenesulfonamide (11), were synthesized in 7 and 8 steps with 10% and 7% overall chemical yield, respectively. N-[¹¹C]7 was prepared from 11 using [¹¹C]methyl triflate ([¹¹C]CH₃OTf) through N-¹¹C-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 [¹¹C]CO₂. The radiochemical purity was > 99% and the molar activity (A_m) at EOB was in the range of 296-555 GBq/µmol (n = 5).