A New Highly Reactive and Low Lipophilicity Fluorine-18 Labeled Tetrazine Derivative for Pretargeted PET Imaging

Abstract

A new 18 F-labeled tetrazine derivative was developed aiming at optimal radiochemistry, fast reaction kinetics in inverse electron-demand Diels−Alder cycloaddition (IEDDA), and favorable pharmacokinetics for in vivo bioorthogonal chemistry. The radiolabeling of the tetrazine was achieved in high yield, purity, and specific activity under mild reaction conditions via conjugation with 5-[ 18 F]fluoro-5-deoxyribose, providing a glycosylated tetrazine derivative with low lipophilicity. The 18 F-tetrazine showed fast reaction kinetics toward the most commonly used dienophiles in IEDDA reactions. It exhibited excellent chemical and enzymatic stability in mouse plasma and in phosphate-buffered saline (pH 7.41). Biodistribution in mice revealed favorable pharmacokinetics with major elimination via urinary excretion. The results indicate that the glycosylated 18 F-labeled tetrazine is an excellent candidate for in vivo bioorthogonal chemistry applications in pretargeted PET imaging approaches.

Improving Tumor‐to‐Background Contrast through Hydrophilic Tetrazines: The Construction of 18F‐Labeled PET Agents Targeting Nonsmall Cell Lung Carcinoma

“…Thereafter, Kuntner and Mikula and co‐workers designed an 18 F‐labeled tetrazine that rapidly combined with sTCO and other trans ‐cyclooctene and could be applied to conjugations in live animals . For applications in pretargeted imaging, Airaksinen and co‐workers described a method for radiolabeling of tetrazines via 5‐[ 18 F]fluoro‐5‐deoxyribose, and an Al[ 18 F]NOTA‐labeled tetrazine radioligand was described by Lewis and co‐workers . To retain the advantages associated with initially attaching the tetrazine component to the biomolecule, an 18 F‐labeled analog of sTCO was developed and shown to display rapid kinetics towards a PEGylated diphenyl‐s‐tetrazine analog (DiPhTz), which could be successfully used in PET probe construction (Scheme A) .…”

18F‐Labeling of Sensitive Biomolecules for Positron Emission Tomography

“…The labeled tetrazine showed excellent enzymatic stability in mouse serum and minimal radiodefluorination. [146] Another interesting report was summarized by Meyer et. al.…”

Tetrazine‐Responsive Self‐immolative Linkers

“…Tetrazines have recently been exploited in a variety of inverse electron‐demand Diels–Alder reactions (DA INV ) as a means of conjugating reporters, such as fluorophores and PET isotopes, to a variety of biological entities, such as DNA, targeting peptides and antibodies . Typically, these bioconjugations are performed between a tetrazine and a strained dienophile, such as trans ‐cyclooctene (TCO), thereby resulting in a fast DA INV reaction .…”