¹⁸F-Labeling of Arenes and Heteroarenes for Applications in Positron Emission Tomography

Abstract

Diverse radiochemistry is an essential component of nuclear medicine; this includes imaging techniques such as positron emission tomography (PET). As such, PET can track diseases at an early stage of development, help patient care planning through personalized medicine and support drug discovery programs. Fluorine-18 is the most frequently used radioisotope in PET radiopharmaceuticals for both clinical and preclinical research. Its physical and nuclear characteristics (97% β(+) decay, 109.8 min half-life, 635 keV positron energy) and high specific activity make it an attractive nuclide for labeling and molecular imaging. Arenes and heteroarenes are privileged candidates for (18)F-incorporation as they are metabolically robust and therefore widely used by medicinal chemists and radiochemists alike. For many years, the range of (hetero)arenes amenable to (18)F-fluorination was limited by the lack of chemically diverse precursors, and of radiochemical methods allowing (18)F-incorporation in high selectivity and efficiency (radiochemical yield and purity, specific activity, and radio-scalability). The appearance of late-stage fluorination reactions catalyzed by transition metal or small organic molecules (organocatalysis) has encouraged much research on the use of these activation manifolds for (18)F-fluorination. In this piece, we review all of the reactions known to date to install the (18)F substituent and other key (18)F-motifs (e.g., CF3, CHF2, OCF3, SCF3, OCHF2) of medicinal relevance onto (hetero)arenes. The field has changed significantly in the past five years, and the current trend suggests that the radiochemical space available for PET applications will expand rapidly in the near future.

18F-Labeling of Mannan for Inflammation Research with Positron Emission Tomography

“…Another favorable physical property of 18 F is its suitably long half-life (109.8 min), although 18 F is a shortlived radionuclide. This enables multistep radiosynthesis feasible 14,15 and distribution to hospitals distanced from production sites possible.…”

Pd-Catalyzed Mizoroki-Heck Reactions Using Fluorine-Containing Agents as the Cross-Coupling Partners

“…It is undoubted that the development of efficient methods to construct fluorine-containing molecules is of great importance [46][47][48][49][50][51]. In general, the fluorinated compounds can be synthesized by direct fluorination or fluoroalkylation, or through reactions with the fluorine-containing building blocks [39][40][41][42][43][44][45][46][47][48][49][50][51]. The incorporation of fluorinecontaining fragments into organic frameworks by Pd-catalyzed Mizoroki-Heck reactions has proved to be the simplest and most convenient pathway to build diverse alkenes bearing fluorinated functionalities.…”

“…There have been as many as 25% of pharmaceuticals and 30-40% of agrochemicals on the market containing at least a single fluorine atom [41]. Because only a few naturally-occurring organofluorides have been discovered, most of the fluorinated organic compounds have to be manually synthesized [36][37][38][39][40][41][42][43][44][45][46][47][48][49][50][51]. It is undoubted that the development of efficient methods to construct fluorine-containing molecules is of great importance [46][47][48][49][50][51].…”

“…Because only a few naturally-occurring organofluorides have been discovered, most of the fluorinated organic compounds have to be manually synthesized [36][37][38][39][40][41][42][43][44][45][46][47][48][49][50][51]. It is undoubted that the development of efficient methods to construct fluorine-containing molecules is of great importance [46][47][48][49][50][51]. In general, the fluorinated compounds can be synthesized by direct fluorination or fluoroalkylation, or through reactions with the fluorine-containing building blocks [39][40][41][42][43][44][45][46][47][48][49][50][51].…”

Iodonium ylides in organic synthesis

“…[118][119][120][121] Iodonium ylides have an advantage over diaryliodonium salts as the selective PET precursors. Due to the carbanionic character of the ylidic carbon, the attack of an external nucleophile in principle should be directed exclusively toward the aromatic ring of the Ar group of an aryliodonium ylide.…”