11C-Labeling of Aryl Ketones as Candidate Histamine Subtype-3 Receptor PET Radioligands through Pd(0)-Mediated 11C-Carbonylative Coupling

Abstract

Pd(0)-mediated coupling between iodoarenes, [11C]carbon monoxide and aryltributylstannanes has been used to prepare simple model [11C]aryl ketones. Here, we aimed to label four 2-aminoethylbenzofuran chemotype based molecules ([11C]1–4) in the carbonyl position, as prospective positron emission tomography (PET) radioligands for the histamine subtype 3 receptor (H3R) by adapting this methodology with use of aryltrimethylstannanes. Radiosynthesis was successfully performed on a platform equipped with a mini-autoclave and a liquid handling robotic arm, within a lead-shielded hot-cell. Candidate radioligands were readily formulated in saline containing ethanol (10%, v/v) and ascorbic acid (0.5 mg/10 mL). Yields for preclinical use were in the range of 5–9%, decay-corrected from cyclotron-produced [11C]CO2 and molar activities were >115 GBq/μmol at end of synthesis. Radiochemical purities exceeded >97%.

Development of [Carbonyl-11C]AZ13198083, a Novel Histamine Type-3 Receptor Radioligand with Favorable Kinetics

“…Positron emission tomography (PET) is a sensitive noninvasive imaging technique. The PET technology relies upon the intravenous administration of a radiolabeled imaging agent (radioligand) that serves as a molecular probe to investigate biological processes in vivo. − A number of H 3 R PET radioligands have been reported, − but only a few have shown promise in vivo. Of these, three have so far been translated for human use, namely, [ 11 C]­MK8278 ([ 11 C] 1 ), [ 11 C]­GSK189254 ([ 11 C] 2 ), , and [ 11 C]­TASP457 ([ 11 C] 3 ) (Figure , top).…”