18F-labelling innovations and their potential for clinical application

Abstract

An impressive variety of new methodologies for the preparation of 18 F-labelled tracers and ligands has appeared over the last decade. Most strategies of the newly developed radiofluorination methods predominantly aim at products of high molar activity by 'late-stage' labelling of small (hetero)aromatic molecules and the use of transition metals. This is accompanied by the improvement of technical procedures, like preparation of reactive [ 18 F]fluoride and automated syntheses. The newly introduced procedures reflect a high innovative level and creativity in radio(pharmaceutical) chemistry at present, which are based on modern chemical methods and deep mechanistic insights. Taking also automation and quality control into consideration, major recently developed radiofluorination methods, most of those still under development, are compiled here in view of their potential for clinical PET imaging and thus the ability to advance molecular imaging.

Radical C–H 18F-Difluoromethylation of Heteroarenes with [18F]Difluoromethyl Heteroaryl-Sulfones by Visible Light Photoredox Catalysis

“…The suitability of the 18 F radioisotope in anatomical alterations of a certain disease are detected [5][6][7][8]. The suitability of the 18 F radioisotope in PET has encouraged radiochemists to invest much effort in the development of efficient 18 Ffluorination and 18 F-fluoroalkylation strategies [9][10][11][12][13][14][15][16][17][18][19].…”

Baeyer‐Villiger oxidation tuned to chemoselective conversion of non‐activated [18F]fluorobenzaldehydes to [18F]fluorophenols

“…In contrast, in‐target produced [ 18 F]F 2 is practically only available in carrier‐added (c.a.) form, which leads to radiotracers with low molar activity …”

“…These methods were applied for the late‐stage 18 F‐fluorination of the [ 18 F]fluorophenol derivatives 6‐[ 18 F]fluoro‐ l ‐DOPA and [ 18 F]DAA1106 . However, since toxic metal compounds are employed, attention must be paid to the additional complexity in fulfilling the requirements of pharmaceutical drug safety (GMP) …”

Site‐Selective Late‐Stage Aromatic [18F]Fluorination via Aryl Sulfonium Salts

“…Over the past ten years,several promising new methods for the introduction of the 18 Fnucleus into small molecules have been disclosed, with the aim of improving clinical care and drug discovery through 18 Fp ositron-emission tomography (PET). [1,2] However,i mplementation and translation to hospital settings is challenging if the fluorination reactions are operationally complex. [3,4] Unfortunately,the introduction of conventional leaving groups that can directly provide aryl fluorides upon reaction with fluoride cannot currently be accomplished at al ate stage,s ot he requirement for de novo syntheses slows down the development of PET tracers (Scheme 1a).…”

“…The site-selective CÀHf unctionalization reaction developed herein exhibits broad substrate scope (Table 1). Both electron-poor (2, 21-23)a nd electron-rich (16, 24, 27)a renes proceed efficiently with high regioselectivity.V arious functional groups are well tolerated, including halides (2,(21)(22)(23)(24), nitriles (3), ethers (4)(5)20), esters (4, 10,15), ketones (5), aldehydes (7), amides (5,8,25), and sulfonamides (9,14). Heterocycles such as quinolines (12), imidazoles (19), and pyridines (20)a re also compatible.A renes that are more electron-deficient than 1,2-dichlorobenzene are too electronpoor to react.…”