Radiosynthesis of [¹⁸F]Trifluoroalkyl Groups: Scope and Limitations

Abstract

The present paper is concerned with radiochemical methodology to furnish the trifluoromethyl motif labelled with 18F. Literature spanning the last four decades is comprehensively reviewed and radiochemical yields and specific activities are discussed.

Synthesis of [18F]Fluoroform with High Molar Activity

“…Hence, some successes have been achieved in the synthesis of [ 18 F]trifluoromethylated compounds for PET imaging. However, most of the strategies suffer from a fundamental issue: as the trifluoromethyl group is polyfluorinated, there is a high risk for isotopic dilution with fluorine‐19 caused by exchange processes between fluorine‐18 and fluorine‐19 . This results in low molar activities, defined as the amount of radioactivity per mol of compound .…”

“…The molar activity should be as high as possible when targeting receptors with low density in order to guarantee preservation of the tracer principle i.e. negligible receptor occupation by the injected tracer , . Most likely, [ 19 F]fluoride from the precursor is released in the presence of trace amounts of water and excess of base originating from the drying of [ 18 F]fluoride.…”

“…However, most of the strategies suffer from a fundamental issue: as the trifluoromethyl group is polyfluorinated, there is a high risk for isotopic dilution with fluorine-19 caused by exchange processes between fluorine-18 and fluorine-19. [8] This results in low molar activities, defined as the amount of radioactivity per mol of compound. [12] The molar activity should be as high as possible when targeting receptors with low density in order to guarantee preservation of the tracer principle i.e.…”

A catalytic fluoride-rebound mechanism for C(sp 3 )-CF 3 bond formation

“…These compounds can be used for high-resolution real-time imaging of tissue-level phenomena, enabling direct interrogation of disease states and mechanisms of bioactivity. However, nucleophilic substitution (i.e., S N 2 or S N Ar) chemistry, which is used for the majority of organic fluoride radiosynthesis, is generally incompatible with the stereo-electronic demands of the CF 3 unit (10). Rather, in the most successful technology, a “CF 2 ” precursor is reacted with radiofluoride to generate the relevant CF 3 unit prior to incorporation into the tracer via an organocopper intermediate (Fig.…”

N′-3-(Trifluoromethyl)phenyl Derivatives of N-Aryl-N′-methylguanidines as Prospective PET Radioligands for the Open Channel of the N-Methyl-d-aspartate (NMDA) Receptor: Synthesis and Structure–Affinity Relationships

“…Second, ligands bearing aryl trifluoromethyl groups are now plausible targets for labeling with fluorine-18 by recently developed no-carrier-added methods. 25–29 Moreover, we aimed to retain a N ′-methyl group, as this provides a site that is readily labeled with carbon-11. 14,17,24 …”