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The deuterium labelling of pharmaceuticals is a useful strategy for altering pharmacokinetic properties, particularly for improving metabolic resistance. The pharmacological effects of such metabolites are often assumed to be negligible during standard drug discovery and are factored in later at the clinical phases of development, where the risks and benefits of the treatment and side-effects can be wholly assessed. This paradigm does not translate to the discovery of radiopharmaceuticals, however, as the confounding effects of radiometabolites can inevitably show in preliminary positron emission tomography (PET) scans and thus complicate interpretation. Consequently, the formation of radiometabolites is crucial to take into consideration, compared to non-radioactive metabolites, and the application of deuterium labelling is a particularly attractive approach to minimise radiometabolite formation. Herein, we provide a comprehensive overview of the deuterated carbon-11 and fluorine-18 radiopharmaceuticals employed in PET imaging experiments. Specifically, we explore six categories of deuterated radiopharmaceuticals used to investigate the activities of monoamine oxygenase (MAO), choline, translocator protein (TSPO), vesicular monoamine transporter 2 (VMAT2), neurotransmission and the diagnosis of Alzheimer's disease; from which we derive four prominent deuteration strategies giving rise to a kinetic isotope effect (KIE) for reducing the rate of metabolism. Synthetic approaches for over thirty of these deuterated radiopharmaceuticals are discussed from the perspective of deuterium and radioisotope incorporation, alongside an evaluation of the deuterium labelling and radiolabelling efficacies across these independent studies. Clinical and manufacturing implications are also discussed to provide a more comprehensive overview of how deuterated radiopharmaceuticals may be introduced to routine practice., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to declare., (Copyright © 2021. Published by Elsevier Inc.)

Purpose: The first biological evaluation of two potent fluorine-18 radiolabelled inhibitors of caspase-3/7 was achieved in a cerebral stroke rat model to visualize apoptosis., Procedures: In vivo characteristics of isatins [(18)F]-2 and [(18)F]-3 were studied and compared by μPET to previously described 1-[4-(2-[(18)F]fluoroethyl)benzyl]-5-(2-methoxymethylpyrrolidin-1-ylsulfonyl)isatin ([(18)F]-1) and to 2-(5-[(18)F]fluoropentyl)-2-methyl-malonic acid ([(18)F]ML-10) used as a reference radiotracer in a rat stroke model., Results: [(18)F]-2 and [(18)F]-3 were radiolabelled with high radiochemical purity and high specific radioactivity. Radioactivity uptakes in ischemic and contralateral brain regions were weak for the three radiolabelled isatins and lower for [(18)F]ML-10. In μPET, time activity curves showed significant uptake differences between both regions of interest for [(18)F]-1 after 45 min. No differences were observed for [(18)F]ML-10., Conclusions: Radiolabelled isatins are more promising radiotracers to image apoptosis than [(18)F]ML-10 in this stroke animal model without craniectomy. In particular, [(18)F]-1 presented significant uptake in apoptotic area 45 min after administration.

Reproducible methods for [(18)F]radiolabeling of biological vectors are essential for the development of new [(18)F]radiopharmaceuticals. Molecules such as carbohydrates, peptides and proteins are challenging substrates that often require multi-step indirect radiolabeling methods. With the goal of developing more robust, time saving, and less expensive procedures for indirect [(18)F]radiolabeling of such molecules, our group has synthesized ethynyl-4-[(18)F]fluorobenzene ([(18)F]2, [(18)F]EYFB) in a single step (14 ± 2% non-decay corrected radiochemical yield (ndc RCY)) from a readily synthesized, shelf stable, inexpensive precursor. The alkyne-functionalized synthon [(18)F]2 was then conjugated to two azido-functionalized vector molecules via CuAAC reactions. The first 'proof of principle' conjugation of [(18)F]2 to 1-azido-1-deoxy-β-D-glucopyranoside (3) gave the desired radiolabeled product [(18)F]4 in excellent radiochemical yield (76 ± 4% ndc RCY (11% overall)). As a second example, the conjugation of [(18)F]2 to matrix-metalloproteinase inhibitor (5), which has potential in tumor imaging, gave the radiolabeled product [(18)F]6 in very good radiochemical yield (56 ± 12% ndc RCY (8% overall)). Total preparation time for [(18)F]4 and [(18)F]6 including [(18)F]F(-) drying, two-step reaction (nucleophilic substitution and CuAAC conjugation), two HPLC purifications, and two solid phase extractions did not exceed 70 min. The radiochemical purity of synthon [(18)F]2 and the conjugated products, [(18)F]4 and [(18)F]6, were all greater than 98%. The specific activities of [(18)F]2 and [(18)F]6 were low, 5.97 and 0.17 MBq nmol(-1), respectively., (Copyright © 2015 John Wiley & Sons, Ltd.)

Microfluidic techniques are increasingly being used to synthesize positron-emitting radiopharmaceuticals. Several reports demonstrate higher incorporation yields, with shorter reaction times and reduced amounts of reagents compared with traditional vessel-based techniques. Microfluidic techniques, therefore, have tremendous potential for allowing rapid and cost-effective optimization of new radiotracers. This protocol describes the implementation of a suitable microfluidic process to optimize classical (18)F radiofluorination reactions by rationalizing the time and reagents used. Reaction optimization varies depending on the systems used, and it typically involves 5-10 experimental days of up to 4 h of sample collection and analysis. In particular, the protocol allows optimization of the key fluidic parameters in the first tier of experiments: reaction temperature, residence time and reagent ratio. Other parameters, such as solvent, activating agent and precursor concentration need to be stated before the experimental runs. Once the optimal set of parameters is found, repeatability and scalability are also tested in the second tier of experiments. This protocol allows the standardization of a microfluidic methodology that could be applied in any radiochemistry laboratory, in order to enable rapid and efficient radiosynthesis of new and existing [(18)F]-radiotracers. Here we show how this method can be applied to the radiofluorination optimization of [(18)F]-MEL050, a melanoma tumor imaging agent. This approach, if integrated into a good manufacturing practice (GMP) framework, could result in the reduction of materials and the time required to bring new radiotracers toward preclinical and clinical applications.