Direct Aromatic 18F-Labeling of Highly Reactive Tetrazines for Pretargeted Bioorthogonal PET Imaging

Abstract

Pretargeted bioorthogonal imaging can be used to visualize and quantify slow accumulating targeting vectors with short-lived radionuclides such as fluorine-18 - the most clinically applied Positron Emission Tomography (PET) radionuclide. Pretargeting results in higher target-to-background ratios compared to conventional imaging approaches using long-lived radionuclides. Currently, the tetrazine ligation is the most popular bioorthogonal reaction for pretargeted imaging, but a direct18 F-labeling strategy for highly reactive tetrazines, which would be highly beneficial if not essential for clinical translation, has thus far not been reported. In this work, a simple, scalable and reliable direct 18 F-labeling procedure has been developed and applied to obtain a pretargeting tetrazine-based imaging agent with favorable characteristics (target-to-background ratios and clearance) that may qualify it for future clinical translation.

[11C]Carboxylated Tetrazines for Facile Labeling of Trans‐Cyclooctene‐Functionalized PeptoBrushes

“…Recently, we reported several new methodologies to radiolabel Tzs with fluorine-18. [37][38][39][40] In particular, aryl stannane Tz derivatives were employed as precursors allowing for the first-time direct aromatic 18 F-fluorination of this scaffold. [38] At the same time, the preparation of 11 C-labeled carboxylic acids from aryl stannane precursors and [ 11 C]CO 2 via a copper-mediated carboxylation was reported by other authors.…”

Uncovering the key role of distortion in tetrazine ligations guides the design of bioorthogonal tools that defy the reactivity/stability tradeoff

“…[2][3] Very recently, bioorthogonal chemistry has entered Phase 1 clinical trials, with Tz/TCO-reactions currently being tested in humans, aiming for locally restricted prodrug activation to improve the selectivity of chemotherapeutics. [9][10] In recent years, a variety of differently substituted tetrazines has been used for bioorthogonal reactions and in vivo chemistry, including bis-alkyl-substituted Tz, [11][12][13][14][15] alkyl-aryl-Tz, [16][17][18][19] mono-alkyl-Tz [20] (alkyl-H-Tz) as well as highly reactive bisheteroaryl [21][22] and mono-aryl [23][24][25][26] derivatives (aryl-H-Tz). These applications have motivated and fueled the development of advanced procedures for the synthesis of tetrazine scaffolds.…”

Uncovering the key role of distortion in tetrazine ligations guides the design of bioorthogonal tools that defy the reactivity/stability tradeoff

“…[2][3] Very recently, bioorthogonal chemistry has entered Phase 1 clinical trials, with Tz/TCO-reactions currently being tested in humans, aiming for locally restricted prodrug activation to improve the selectivity of chemotherapeutics. [9][10] In recent years, a variety of differently substituted tetrazines has been used for bioorthogonal reactions and in vivo chemistry, including bis-alkyl-substituted Tz, [11][12][13][14][15] alkyl-aryl-Tz, [16][17][18][19] mono-alkyl-Tz [20] (alkyl-H-Tz) as well as highly reactive bisheteroaryl [21][22] and mono-aryl [23][24][25][26] derivatives (aryl-H-Tz). These applications have motivated and fueled the development of advanced procedures for the synthesis of tetrazine scaffolds.…”