TY - JOUR

T1 - Direct Cu-mediated aromatic18F-labeling of highly reactive tetrazines for pretargeted bioorthogonal PET imaging

AU - García-Vázquez, Rocío

AU - Battisti, Umberto M.

AU - Jørgensen, Jesper T.

AU - Shalgunov, Vladimir

AU - Hvass, Lars

AU - Stares, Daniel L.

AU - Petersen, Ida N.

AU - Crestey, François

AU - Löffler, Andreas

AU - Svatunek, Dennis

AU - Kristensen, Jesper L.

AU - Mikula, Hannes

AU - Kjaer, Andreas

AU - Herth, Matthias M.

PY - 2021

Y1 - 2021

N2 - Pretargeted imaging can be used to visualize and quantify slow-accumulating targeting vectors with short-lived radionuclides such as fluorine-18 - the most popular 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 direct18F-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 direct18F-labeling procedure has been developed. We initially studied the applicability of different leaving groups and labeling methods to develop this procedure. The copper-mediated18F-labeling exploiting stannane precursors showed the most promising results. This approach was then successfully applied to a set of tetrazines, including highly reactive H-tetrazines, suitable for pretargeted PET imaging. The labeling succeeded in radiochemical yields (RCYs) of up to approx. 25%. The new procedure was then applied to develop a pretargeting tetrazine-based imaging agent. The tracer was synthesized in a satisfactory RCY ofca.10%, with a molar activity of 134 ± 22 GBq μmol−1and a radiochemical purity of >99%. Further evaluation showed that the tracer displayed favorable characteristics (target-to-background ratios and clearance) that may qualify it for future clinical translation.

AB - Pretargeted imaging can be used to visualize and quantify slow-accumulating targeting vectors with short-lived radionuclides such as fluorine-18 - the most popular 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 direct18F-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 direct18F-labeling procedure has been developed. We initially studied the applicability of different leaving groups and labeling methods to develop this procedure. The copper-mediated18F-labeling exploiting stannane precursors showed the most promising results. This approach was then successfully applied to a set of tetrazines, including highly reactive H-tetrazines, suitable for pretargeted PET imaging. The labeling succeeded in radiochemical yields (RCYs) of up to approx. 25%. The new procedure was then applied to develop a pretargeting tetrazine-based imaging agent. The tracer was synthesized in a satisfactory RCY ofca.10%, with a molar activity of 134 ± 22 GBq μmol−1and a radiochemical purity of >99%. Further evaluation showed that the tracer displayed favorable characteristics (target-to-background ratios and clearance) that may qualify it for future clinical translation.

UR - http://europepmc.org/abstract/med/34659701

U2 - 10.1039/d1sc02789a

DO - 10.1039/d1sc02789a

M3 - Journal article

C2 - 34659701

AN - SCOPUS:85115162973

VL - 12

SP - 11668

EP - 11675

JO - Chemical Science

JF - Chemical Science

SN - 2041-6520

IS - 35

ER -