Methodological advancements in microfluidic and carbonylation PET radiochemistry

Abstract

Along with the progress of PET as a powerful imaging tool in medicine, there has been increasing demand for new labeling methods. The main aim of this PhD dissertation was to develop novel labeling methodologies using the positron emitter carbon-11.

Advancements within the field of palladium-mediated carbonylation reaction are discussed in the first part of the thesis. Paper I describes the development of a Pd-ligand complex where [11C]carbon monoxide (11CO) is efficiently trapped and incorporated as a part of the CO- insertion procedure. The consequent carbonylation reaction proceeds smoothly in good and reproducible yields using aryl halides or triflates as substrates. As a proof of concept, the utility of the protocol was applied to the synthesis of a candidate radioligand for the histamine type-3 receptor. The same protocol was further improved using microwave heating in paper II. An improved yield was observed in the 11C-aminocarbonylation of electron deficient aryl halides and even allowing for the use of an aryl chloride as substrate. Moreover, high yields for hydroxy- and alkoxycarbonylation were obtained when efficient microwave-energy absorbent nucleophiles, such as water and alcohol, were utilized as co-solvents. In paper III, an efficient and convenient carbonylative approach for the direct synthesis of 11C-labeled aryl methyl ketones from aryl halides is presented, employing [11C]methyl iodide (11CH3I) as the radioactive precursor under Co2(CO)8-mediated conditions. A total of ten model (hetero)aryl methyl ketones were obtained in a 22-63% decay-corrected radiochemical yield, based on radioactivity in the solution at the end of synthesis.

The increasing demand of rapid labeling procedures has stimulated the development of emerging technologies such as microfluidics for more flexible and efficient radioligand supply. To this end, in the second part of the thesis, microfluidic-assisted radiochemistry was evaluated for the labeling with fluorine-18 and carbon-11. Firstly, in paper IV, a commercially available microfluidic (MF) platform was evaluated using the two-step preparation of 18F-fluorobenzyl amines via a reductive amination reaction. The microfluidic apparatus allowed for rapid parameter optimization and was also applied preparatively to produce adequate radioactivities for PET applications. Finally, in paper V, a novel gas-liquid segmented microfluidic platform was developed. The large gas-to-liquid interfacial area generated by the segmented approach facilitated the 11CO insertion even while less reactive Pd-ligand species were applied. The Pd- mediated 11C-carbonylation reaction proceeded smoothly on this platform and good to excellent radiochemical yields were observed. Twelve compounds were successfully radiolabeled in a RCY range of 41-99%, including the well establiched D2 receptor radioligands [11C]raclopride and [11C]FLB 457.