Development of a fully automated low‐pressure [¹¹C]CO carbonylation apparatus

Abstract

carbon monoxide ([ 11 C]CO) is a versatile synthon for radiolabeling of drug-like molecules for imaging studies with positron emission tomography (PET). We here report the development of a novel, user-friendly, fully automated, and good manufacturing practice (GMP) compliant low-pressure synthesis module for 11 C-carbonylation reactions using [ 11 C]CO. In this synthesis module, [ 11 C]CO was reliably prepared from cyclotron-produced [ 11 C]carbon dioxide ([ 11 C]CO 2) by reduction over heated molybdenum and delivered to the reaction vessel within 7 min after end of bombardment, with an overall radiochemical yield (RCY) of 71%. [ 11 C]AZ13198083, a histamine type-3 receptor ligand, was used as a model compound to assess the functionality of the radiochemistry module. At full batch production conditions (55 μA, 30 min), our newly developed low-pressure 11 C-carbonylation apparatus enabled us to prepare [ 11 C]AZ13198083 in an isolated radioactivity of 8540 ± 1400 MBq (n = 3). The radiochemical purity of each of the final formulated batches exceeded 99%, and all other quality control tests results conformed with specifications typically set for carbon-11 labeled radiopharmaceuticals. In conclusion, this novel radiochemistry system offers a convenient GMP compliant production drugs and radioligands for imaging studies in human subjects.

Synthesis of Radiopharmaceuticals via “In-Loop” 11C-Carbonylation as Exemplified by the Radiolabeling of Inhibitors of Bruton's Tyrosine Kinase

“…We hypothesized that these challenges could be alleviated by leveraging the more ready availability of [ 11 C]CO from modern cyclotrons (e.g., utilizing the Process Cabinet of a GE PETtrace) and developing methods that are compatible with the automated synthesis modules used for cGMP manufacture of PET radiotracers today. Thus, we and others are motivated to develop more user-friendly approaches for 11 C-carbonylation (28,(39)(40)(41). Notably, concurrent with our efforts, Lindberg et al demonstrated that [ 11 C]ibrutinib can be prepared via 11 C-carbonylation in a reactor method (40), and reported preliminary pre-clinical imaging results comparable to our earlier findings (29).…”

One‐Pot Synthesis of 11C‐Labelled Primary Benzamides via Intermediate [11C]Aroyl Dimethylaminopyridinium Salts

“…It is worth noting that the aqueous hydrolysis step could be eliminated in this setting, possibly due to the use of non‐anhydrous TFA for the deprotection. The radiosynthesis of these drug molecules was performed according to good manufacturing practice (GMP) on a recently developed fully automated and commercially available radiochemistry system for low pressure radiocarbonylation [19] . Gratifyingly, both compounds were radiolabeled in sufficient quantity and quality to enable preclinical studies in non‐human primates.…”

Validation of a good manufacturing practice procedure for the production of [11C]AZD4747, a CNS penetrant KRASG12c inhibitor

“…The radioactivity was transferred from the target to a TracerMaker synthesizer (ScanSys Laboratorieteknik ApS). The fully automated production of [ 11 C]CO was performed according to previously reported methods 4–6 . The produced [ 11 C]CO 2 was concentrated in a cryogenic trap and reduced to [ 11 C]CO by passing it through a molybdenum column (preheated at ~850°C).…”

“…The fully automated production of [ 11 C]CO was performed according to previously reported methods. [4][5][6] The produced [ 11 C]CO 2 was concentrated in a cryogenic trap and reduced to [ 11 C]CO by passing it through a molybdenum column (preheated at $850 C). The produced [ 11 C]CO was then concentrated in a cryogenic silica trap.…”