Development of a novel [18F]fluorobenzyl derivative of the AT1 receptor antagonist Candesartan

Candesartan is a clinically approved angiotensin II type 1 receptor (AT1R)‐blocker that selectively binds AT1Rs in high affinity. We report here the radiosynthesis and automation of the novel [18F]fluorobenzyl derivative of Candesartan using the Sonogashira cross‐coupling reaction. [18F]Fluorobenzyl‐Candesartan ([18F]7) was developed from 4‐[18F]fluoroiodobenzene ([18F]FIB) that was conjugated with alkyne‐trityl‐candesartan with the assistance of a Pd (PPh3)4/CuI catalyst followed by acid deprotection. The three‐step two‐reactor 2‐HPLC purification process was automated resulting in >90% pure [18F]7 in a RCY of 4.6 ± 1.1% (decay corrected from EOB) and molar activities of 1,406‐5,513 GBq/mmol. [18F]FIB was reproducibly obtained by direct radiofluorination of the mono‐iodinated triphenylsulfonium salt in the presence of K222/K2CO3 in an ~30% yield (decay‐corrected). [18F]7 was stable (>97%) up to 4 h in solution and up to 1 h in rat plasma at 37°C. However, the use of Sonogashira cross‐coupling reaction to produce [18F]7 in high yields and molar activities was found to be challenging for routine use in radiochemistry labs. The optimized production of [18F]FIB ([18F]6) was achieved in ~30% radiochemical yield. [18F]Fluorobenzyl‐Candesartan ([18F]7) was successfully synthesized using the Sonogashira cross‐coupling followed by acid de‐protection. The whole process was automated in 3‐steps and 2‐HPLC purifications. [18F]7 displayed high stability in solution and rat plasma.