Abstract
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 direct 18F-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 18F-labeling procedure has been developed. We initially studied the applicability of different leaving groups and labeling methods to develop this procedure. The copper-mediated 18F-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 of ca. 10%, with a molar activity of 134 ± 22 GBq μmol−1 and 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.
Highlights
Positron Emission Tomography (PET) is a powerful, noninvasive and routinely used imaging tool in precision medicine or drug development.[1,2,3] Its high sensitivity, isotropism and quantitativity are in combination unmatched compared to any other in vivo molecular imaging technique.[4,5] Fluorine-18 (18F) is considered as the best suited PET radionuclide for clinical applications as it provides almost ideal physical characteristics for molecular imaging
Bioorthogonal chemistry has emerged as a versatile tool for pretargeted nuclear imaging of slow-accumulating targeting vectors such as monoclonal antibodies or other nanomedicines.[9,10,11,12,13]
Improved imaging contrast and lower radiation burden to healthy tissue can be achieved using pretargeting compared to conventional imaging strategies.[14]
Summary
Positron Emission Tomography (PET) is a powerful, noninvasive and routinely used imaging tool in precision medicine or drug development.[1,2,3] Its high sensitivity (the level of detection approaches 10À12 M of tracer), isotropism and quantitativity are in combination unmatched compared to any other in vivo molecular imaging technique.[4,5] Fluorine-18 (18F) is considered as the best suited PET radionuclide for clinical applications as it provides almost ideal physical characteristics for molecular imaging. These include a relatively short positron range The exceptional target speci city of nanomedicines as well as the optimal pharmacokinetics of small molecules for molecular imaging, e.g. selective target accumulation and rapid clearance from blood, can be exploited using pretargeted imaging.[15,16] So far, the most prominent reaction for pretargeted imaging is the tetrazine (Tz) ligation.[11,17] Excellent chemoselectivity, metabolic stability and high reactivity make the Tz ligation as exceptional as the biotin– (strept)avidin interaction for pretargeting strategies.[18,19,20,21] The Tz
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