Pd0-Mediated Cross-Coupling of [11C]Methyl Iodide with Carboxysilane for Synthesis of [11C]Acetic Acid and its Active Esters: 11C-Acetylation of Small, Medium, and Large Molecules

A rapid Pd-0-mediated cross-coupling of [C-11]CH3I with carboxytriphenylsilane (1) to synthesize [2-C-11]acetic acid ([C-11]2) and its corresponding imidyl esters as radiolabeling reagents for C-11-acetylation is reported. The reaction of [C-11]CH3I with 1 using a Pd-2(dibenzylideneacetone)(3)/P(o-tolyl)(3) (1 : 4) catalyst in tetrahydrofuran/H2O (9 : 1) at 90 degrees C for 4 min afforded [C-11]2 having satisfactory radioactivity and a good yield. The coupling of the cationic carbon atom of methyl iodide and the carboxyl group in 1 is an ionicity-driven reversed-polarity reaction. An injectable radiopharmaceutical formulation of [C-11]2 prepared using 33 GBq of [C-11]CH3I had a radioactivity of 7.4-7.8 GBq, and the decay-corrected radiochemical yield of [C-11]CH3I into [C-11]2 was 63-73 %. [C-11]2 was converted to [2-C-11]acetic acid phthalimidyl ester ([C-11]3) or its succinimidyl ester ([C-11]10), which were used for the C-11-acetylation of 4-aminophenol, oxytocin, and albumin. Injectable solutions of these products (0.25-2.0 GBq) are suitable for in vivo positron emission tomography studies.

Automated summary

A rapid Pd-0-mediated cross-coupling reaction was reported for synthesizing C-11-acetic acid and its corresponding imidyl esters as radiolabeling reagents. The reaction yielded [C-11]2 with satisfactory radioactivity and good yield, suitable for in vivo imaging studies. The injectable radiopharmaceutical formulation of [C-11]2 prepared using 33 GBq of [C-11]CH3I showed a decay-corrected radiochemical yield of 63-73%, providing potential applications in positron emission tomography studies.