Chemistry Considerations for the Clinical Translation of Oncology PET Radiopharmaceuticals

Abstract

Positron emission tomography (PET) has proven to be an invaluable tool in the staging and management of disease in oncology; however, [18F]­fluorodeoxyglucose ([18F]­FDG) remains the most widely used PET radiopharmaceutical despite the large financial investment in novel radiotracer development. We report our perspective and experience of translating radiopharmaceuticals into clinical studies, discussing the PET development pipeline from a chemistry perspective. We hope that, by identifying potential points of attrition along the pipeline and suggesting solutions to these problems, we may help others take their preclinical radiotracers into human studies. This review focuses primarily on the development of fluorine-18 radiopharmaceuticals, although the broader field of radiometal chemistry is considered where the translation journey is similar.

The aluminium-[18F]fluoride revolution: simple radiochemistry with a big impact for radiolabelled biomolecules

“…Conventional fluorine-18 radiopharmaceuticals require automated radiosynthesis procedures for their GMP production, which adds additional complexity to the translational pathway (Allott and Aboagye 2020 ). However, automated procedures are convenient for [ 18 F]AlF-based radiopharmaceuticals and will be necessary where a centralized production model produces multi-patient doses for transportation to hospitals from a remote facility (Fig.…”

Synthesis and evaluation of 3′-[18F]fluorothymidine-5′-squaryl as a bioisostere of 3′-[18F]fluorothymidine-5′-monophosphate

“…The resulting precipitate was washed with acetone to give the product (585 mg, 80%) as a white solid. 1H NMR (400 MHz, DMSO) 5 0 -amino-5 0 ,3 0 -deoxy-3 0 -uoro-thymidine (9). Synthesised by adapting a literature procedure.…”

“…Positron emission tomography (PET) is a powerful and highly sensitive molecular imaging technique for probing living systems using sub-pharmacological doses of radiolabelled compounds for minimal biological perturbation. 9 Phosphate groups play an important role in the uptake and retention of some PET radiopharmaceuticals inside the cell, including 3 0 -[ 18 F]uorothymidine ([ 18 F]FLT), used to image rapidly proliferating cancer cells (Fig. 1).…”

A kit-based aluminium-[18F]fluoride approach to radiolabelled microbubbles

“…Expertise in organic 18 F-fluorination chemistry and specialist production facilities are also required to produce these MBs, presenting a potential obstacle to their clinical and routine use. 15 To ameliorate these concerns, our group recently reported a convenient radiometal chelation approach, in combination with inverse electron demand Diels Alder (IEDDA) chemistry, to radiolabel MBs using gallium-68 ( 68 Ga, t 1/2 = 68 min, E b+, max = 1.9 MeV). 16 Although the microbubbles can be produced within 50 minutes from 68 Ge/ 68 Ga generator elution, the relatively short half-life of 68 Ga, and somewhat onerous manual radiosynthesis process, reduce opportunities for further functionalisation (i.e.…”

“…Expertise in organic 18 F-fluorination chemistry and specialist production facilities are also required to produce these MBs, presenting a potential obstacle to their clinical and routine use. 15 …”