Total Radiosynthesis: Thinking Outside ‘the Box’

Steven H. Liang; Neil Vasdev

doi:10.1071/CH15406

RESEARCH FRONT

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Total Radiosynthesis: Thinking Outside ‘the Box’

Steven H. Liang ^A and Neil Vasdev ^A ^B

+ Author Affiliations

- Author Affiliations

^A Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital, and Department of Radiology, Harvard Medical School, 55 Fruit Street, Boston, MA 02114, USA.

^B Corresponding author. Email: vasdev.neil@mgh.harvard.edu

Australian Journal of Chemistry 68(9) 1319-1328 https://doi.org/10.1071/CH15406
Submitted: 7 July 2015 Accepted: 24 July 2015 Published: 28 August 2015

Abstract

The logic of total synthesis transformed a stagnant state of chemistry when there was a paucity of methods and reagents to synthesize pharmaceuticals. Molecular imaging by positron emission tomography (PET) is now experiencing a renaissance in the way radiopharmaceuticals are synthesized; however, a paradigm shift is desperately needed in the radiotracer discovery pipeline to accelerate drug development. As with most drugs, most radiotracers also fail, therefore expeditious evaluation of tracers in preclinical models before optimization or derivatization of the lead molecules is necessary. Furthermore the exact position of the ¹¹C and ¹⁸F radionuclide in tracers is often critical for metabolic considerations, and flexible methodologies to introduce radionuclides are needed. A challenge in PET radiochemistry is the limited choice of labelled building blocks available with carbon-11 (¹¹C; half-life ~20 min) and fluorine-18 (¹⁸F; half-life ~2 h). In fact, most drugs cannot be labelled with ¹¹C or ¹⁸F owing to a lack of efficient and diverse radiosynthetic methods. Routine radiopharmaceutical production generally relies on the incorporation of the isotope at the last or penultimate step of synthesis. Such reactions are conducted within the constraints of an automated synthesis unit (‘box’), which has further stifled the exploration of multistep reactions with short-lived radionuclides. Radiopharmaceutical synthesis can be transformed by considering logic of total synthesis to develop novel approaches for ¹¹C- and ¹⁸F-radiolabelling complex molecules via retrosynthetic analysis and multistep reactions. As a result of such exploration, new methods, reagents, and radiopharmaceuticals for in vivo imaging studies are discovered and are critical to work towards our ultimate, albeit impossible goal – a concept we term as total radiosynthesis – to radiolabel virtually any molecule. In this account, we show how multistep radiochemical reactions have impacted our radiochemistry program, with prominent examples from others, focusing on impact towards human imaging studies. As the goal of total synthesis is to be concise, we strive to simplify the syntheses of radiopharmaceuticals. New clinically useful strategies, including [¹¹C]CO₂ fixation, which has enabled library radiosynthesis, as well as radiofluorination of non-activated arenes via iodonium ylides are highlighted. We also showcase state-of-the-art automation technologies, including microfluidic flow chemistry for radiopharmaceutical production.

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Total Radiosynthesis: Thinking Outside ‘the Box’

Abstract

References

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