Rapid and Efficient Synthesis of ¹¹C‐Labeled Benzimidazolones Using [¹¹C]Carbon Dioxide

Abstract

[11C]Carbon dioxide is an attractive synthon for the labeling of positron emission tomography (PET) tracers for subsequent use in biomedical research and drug development. In this study, [11C]CO2 was used for direct 11C‐labeling of a set of cyclic aromatic ureas starting from their corresponding ortho‐phenylenediamines, BEMP (2‐tert‐butylimino‐2‐diethylamino‐1,3‐dimethylperhydro‐1,3,2‐diazaphosphorine) as fixation base, and Mitsunobu reagents (DBAD, nBu3P) for the intramolecular cyclization. The procedure is rapid (6 minutes total synthesis time), mild (proceeds at room temperature) and provided a set of 11C‐benzimidazolones in good to excellent radiochemical yields. As a final testament to the utility of this method, the beta‐adrenoceptor PET ligand [11C]CGP12177, was successfully prepared using the optimized conditions.

[11C]Carbonyl Difluoride—a New and Highly Efficient [11C]Carbonyl Group Transfer Agent

“…We observed that reductions in the amount of precursor from 4 mg to 1 mg and then to 0.25 mg did not change the yield of [ 11 C] 2 appreciably; high yields were maintained (that is, 88±5 % and 86±6 %, respectively; Figure ). Use of 0.25 mg of 1 is already a major decrease in the amount of precursor used by Horkka et al . and by Del Vecchio et al .…”

“…From a perspective of seeking short synthesis time, the direct use of cyclotron‐produced [ 11 C]CO 2 as a labeling synthon is attractive. Some newer methods for labeling cyclic ureas are now based on [ 11 C]CO 2 fixation (Scheme C) . These methods are nonetheless multistep with sequential reagent additions that require cooling and/or heating.…”

Synthesis and Pharmacokinetic Study of a 11C-Labeled Cholesterol 24-Hydroxylase Inhibitor Using ‘In-Loop’ [11C]CO2 Fixation Method

“…[21][22][23][24] With this technology, we and other groups have successfully synthesized a series of PET tracers, such as [ 11 C]SL25.1188, [ 11 C]JNJ1661010 and [ 11 C]MAGL-2-11. 23,[25][26][27] As our combined interest in the CYP46A1-targeted PET ligand development and application of 'in-loop' [ 11 C]CO2 fixation, we present herein the facile synthesis of 11 C-labeled compound 1, which was recently patented as a potent CYP46A1 inhibitor (Figure 1). 28,29 Pharmacological and physicochemical evaluation of compound 1, as well as pharmacokinetic profiling via in vivo PET imaging and whole-body biodistribution experiments of [ 11 C]1 are reported in this work.…”

Synthesis and pharmacokinetic study of a 11C-labeled cholesterol 24-hydroxylase inhibitor using ‘in-loop’ [11C]CO2 fixation method

“…[18][19][20] PET studies of CYP46A1 would allow to better understand in vivo biochemistry and physiology of cholesterol homeostasis, help to accelerate the translation of CYP46A1 modulators in clinical trials, as well as offer an in-depth insight into AD. Recently, we developed a facile "in loop" [ 11 23,[25][26][27] As our combined interest in the CYP46A1-targeted PET ligand development and application of 'in-loop' [ 11 C]CO2 fixation, we present herein the facile synthesis of 11 C-labeled compound 1, which was recently patented as a potent CYP46A1 inhibitor (Figure 1). 28,29 Pharmacological and physicochemical evaluation of compound 1, as well as pharmacokinetic profiling via in vivo PET imaging and whole-body biodistribution experiments of [ 11 C]1 are reported in this work.…”