Recent Advances in the Design and Synthesis of Carbon-14 Labelled Pharmaceuticals from Small Molecule Precursors

Abstract

Over the past decade, the increased chemical complexity of new drug candidates has resulted in a parallel need to develop innovative syntheses of carbon-14 labelled pharmaceuticals. Faced with short time-lines and a limited number of labelled precursors, radiochemists have addressed this challenge by developing new reagents and adapting existing technology to labelled syntheses. Selected examples from the recent radiochemical literature illustrate some of the creative strategies used to rapidly solve these synthetic challenges. Examples describing the handling and use of common small molecule reagents, such as carbon-14 labelled carbon dioxide, methyl iodide, cyanide, acetic acids, sulfur and phosphorous stabilized ylides for the synthesis of labelled steroids, prostanoids, nucleosides, pyridines, quinolines, benzazepines and other heterocycles are presented. Several general strategies for radiolabelling are also discussed including the degradation strategy for accessing necessary intermediates and precursors, the radiolabelling of aromatic substrates, transition metal mediated cross-couplings, and the use of chiral auxiliaries for the enantioselective syntheses of radiolabelled pharmaceuticals.

Nickel-Mediated Alkoxycarbonylation for Complete Carbon Isotope Replacement

“…Generally, a de novo synthesis strategy must be adopted because of a limited number of commercially available labeled starting materials. Eventually, such labeled compounds can be attained by a “brute-force” approach, which in the case of carbon-14 and its long half-life ultimately leads to considerable issues of radioactive exposure and waste disposal. − …”

A C-14 labeled Py–Im polyamide localizes to a subcutaneous prostate cancer tumor

“…The approach enables the observation of in vivo compound uptake for a relatively prolonged period of time with a wider range of concentrations, as opposed to the more commonly used LC/MS/MS quantitation methods. Consequentially, this technique was put to advantage in investigating biodistribution and metabolism of diverse molecular classes, comprising small molecules, 12 proteins, 13 and antibody-drug conjugates. 14 The present account reports the synthesis and biodistribution of three C-14 labeled Py-Im polyamides in an in vivo tumor xenograft model.…”

Using a Tritiated Compound to Elucidate Its Preclinical Metabolic and Excretory Pathways in Vivo: Exploring Tritium Exchange Risk

“…The most common radionuclide used for these studies is 14 C because of its synthetic versatility, safety relative to other radioisotopes, and favorable nuclear properties dictating optimal half-life and specific activity (McCarthy, 2000). However, in certain instances, 3 H has been used instead of (or in addition to) 14 C to attain in vitro (Guroff et al, 1967;Kler et al, 1992;Linnet, 2004) and in vivo (Prakash et al, 1997;Ehlhardt et al, 1998;Koller-Lucae et al, 1999;Rosenborg et al, 1999;Gray et al, 2001) biotransformation data.…”