Method Development for [11C]carbon monoxide radiochemistry

Abstract: Positron emission tomography (PET) is a non-invasive molecular imaging technique that has found extensive utility in biomedical research and in drug development. A fundamental pre-requisite for PET is the tracer, which is a biologically relevant molecule, labeled with a short-lived radionuclide. One of the most attractive radionuclides for PET is carbon-11 (11C) that has a half-life of only 20 minutes (11C, t1/2=20.3 min). This radionuclide can be introduced via transition-metal mediated carbonylation with [11C]carbon monoxide ([11C]CO), a reaction that has found utility in the production of a wide range of drug-like molecules and radioligands. Transition-metal mediated 11C-carbonylation is typically performed at high pressure and high temperature due to the poor solubility of [11C]CO in organic solvents and its high dilution in inert gas. Because of its radioactive nature, chemical processes with 11C not only need to be fast, but also need to be automated inside a lead-shielded fume cupboard to ensure operator safety. The current PhD thesis aimed to develop novel and simplified methods for the introduction of 11C into one of the most abundant functional groups in bioactive molecules, namely the carbonyl group. Paper I describes the development of a new stainless-steel loop method for 11C-carbonylation reactions, in which a thin film of reagents is created on the interior surface of the loop. This operation creates a large surface area, which facilitates exchange between the liquid and gas phase and thus enhances trapping and incorporation of [11C]CO into target compounds via reactive palladium complexes. The method was applied to a set of test compounds and proved to be useful to provide 11C-labeled amides, esters and carboxylic acids with good to excellent yields. As a proof of concept, the histamine‐3 receptor radioligand [11C]AZ13198083, the oncology drug [11C]olaparib, the dopamine D2 receptor radioligands [11C]raclopride and [11C]FLB457 were produced using the same method. To allow tracers labeled by 11C-carbonylation to be used in studies of human physiology and pathophysiology, Paper II described the development of a new automated system for [11C]CO radiochemistry that complies with all regulations associated with such studies (e.g. good manufacturing practice (GMP)). The aim was to develop the first commercially available [11C]CO system with the purpose of making [11C]CO radiochemistry accessible to the wider PET community. Following development and optimization of each part of the GMP system, the [11C]CO synthesizer was successfully used to produce the histamine type-3 radioligand, [11C]AZ13198083. In Paper III, a novel and simple method for the synthesis of 11C-labeled primary amides was developed. This process consists on the Pd-mediated 11C-aminocarbonylation of aryl halides via intermediate electrophilic aroyl-DMAP-salts (DMAP – 4-dimethylaminopyridine). The method provided a range of substrates with good to excellent yields and was finally successfully applied to the radiolabeling of the two cancer drugs [11C]niraparib and [11C]veliparib for preclinical studies. To conclude, a variety of new methodologies have been described for 11C-labeling carbonyl groups that have the potential to be widely implemented in the development of new tracer molecules for PET imaging.

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