Palladium-Mediated Synthesis of [Carbonyl-11C]acyl Amidines from Aryl Iodides and Aryl Bromides and Their One-Pot Cyclization to 11C-Labeled Oxadiazoles

Positron emission tomography (PET) is a highly valuable imaging technique with many clinical applications. The possibility to study physiological and biochemical processes in vivo also makes PET an important tool in drug discovery. Of importance is the possibility of labelling the compound of interest with a positron-emitting radionuclide, such as carbon-11. Carbonylation reactions with [11C]carbon monoxide ([11C]CO) has been used to label a number of molecules containing a carbonyl derivative, such as amides and esters, with carbon-11. Presented herein is the palladium-mediated carbonylative synthesis of [carbonyl-11C]acyl amidines and their subsequent cyclization to 11C labeled 1,2,4-oxadiazoles. Starting from amidines, [11C]CO, and either aryl iodides or aryl bromides, [carbonyl-11C]acyl amidines were synthesized and isolated in good to very good radiochemical yields (RCY). The 11C-labeled 1,2,4-oxadiazoles were synthesized without the isolation of the intermediate [carbonyl-11C]acyl amidines and isolated in useful RCYs, including the NF-E2-related factor 2 activator DDO-7263. 3-Phenyl-5-(4-tolyl)-1,2,4-(5-11C)oxadiazole was synthesized and isolated with a clinically relevant molar activity. The broadened substrate scope, together with the good RCY and high Am, demonstrates the utility of this method for the incorporation of carbon-11 into acyl amidines and 1,2,4-oxadiazoles, structural motifs of pharmacological interest.

Automated summary

Positron emission tomography (PET) is an important imaging technique with various clinical applications. This study presents a method for labeling acyl amidines and 1,2,4-oxadiazoles with carbon-11 using palladium-mediated carbonylation synthesis. The method demonstrated good radiochemical yields and high molar activity, indicating its utility for incorporating carbon-11 into pharmacologically relevant structural motifs.