Optimization of Direct Aromatic 18F-Labeling of Tetrazines

Abstract

Radiolabeling of tetrazines has gained increasing attention due to their important role in pretargeted imaging or therapy. The most commonly used radionuclide in PET imaging is fluorine-18. For this reason, we have recently developed a method which enables the direct aromatic 18F-fluorination of tetrazines using stannane precursors through copper-mediated fluorinations. Herein, we further optimized this labeling procedure. 3-(3-fluorophenyl)-1,2,4,5-tetrazine was chosen for this purpose because of its high reactivity and respective limited stability during the labeling process. By optimizing parameters such as elution conditions, precursor amount, catalyst, time or temperature, the radiochemical yield (RCY) could be increased by approximately 30%. These conditions were then applied to optimize the RCY of a recently successfully developed and promising pretargeting imaging agent. This agent could be isolated in a decay corrected RCY of 14 ± 3% and Am of 201 ± 30 GBq/µmol in a synthesis time of 70 min. Consequently, the RCY increased by 27%.

Recent Advances in Bioorthogonal Click Chemistry for Enhanced PET and SPECT Radiochemistry

“…In addition, Herth’s group revealed that a radiolabeled orthogonal tetrazine [ 18 F]­F-Tz with slow metabolism and high lipophilicity was chosen from a series of 18 F-labeled tetracyclines based on the basis of their structure–activity connection . The authors also examined the possibility of pretargeted imaging using 18 F-labeled tetrazine by optimizing labeling parameters, such as elution conditions, precursor and catalyst amounts, reaction time, and temperature …”

“…76 The authors also examined the possibility of pretargeted imaging using 18 Flabeled tetrazine by optimizing labeling parameters, such as elution conditions, precursor and catalyst amounts, reaction time, and temperature. 77 In conclusion, the selection of radiolabeled reactive scaffolds may facilitate the creation of peptide-or protein-based radiotracers. 78 Radiolabeled Peptides.…”

Rapid Construction of 18F-Triazolyl-tetrazines through the Click Reaction

“…Notably, the inverse electron demand Diels–Alder (IEDDA) reaction between 1,2,4,5-tetrazine and trans -cyclooctenes (TCO) has emerged as a valuable technique for PET imaging due to its exceptionally fast reaction rates (Figure a). − Consequently, numerous 18 F-labeled tetrazines have been designed and synthesized for PET tracer construction over the past decade. ,,,,− Despite significant progress, innovative methods for the synthesis of 18 F-fluorinated tetrazines remain attractive in terms of reaction rates, labeling efficiency, and selectivity for PET tracer synthesis and the modification of in vivo biological properties. ,,,− Generally, the direct 18 F labeling of a tetrazine-based precursor had proven challenging due to the decomposition of tetrazine under basic and heating conditions, ,, while the indirect synthesis approach from a readily available 18 F-labeled building block offers superior substrate compatibility and overall higher radiochemical yield, though a longer synthesis time is generally required (Figure b). ,,,− , …”

Development of 18F-Labeled hydrophilic trans-cyclooctene as a bioorthogonal tool for PET probe construction

“…13–16 Herth's group reported their recent studies of direct 18 F labeling of tetrazine derivatives and showed dramatically increased RCYs under less basic conditions or Cu-mediation. 17–20 Instead of direct fluorination of tetrazine, Keinänen et al reported an indirect tetrazine labeling method by conjugation with 5-deoxy-5-[ 18 F]fluoro- d -ribose ([ 18 F]FDR) in almost quantitative yields. 21 For 18 F-labeled TCO derivatives, the radiofluorination procedure is relatively straightforward and high-yielding.…”