Bioorthogonal Diagnostic Tools for Pretargeted PET Imaging
a Institute of Applied Synthetic Chemistry, Vienna University of Technology (TU Wien), Getreidemarkt 9, 1060 Vienna, Austria
Pretargeting strategies circumvent slow accumulation of imaging agents and poor pharmacokinetics of molecular PET probes. Bioorthogonal ligations are capable of covalently linking a pre-administered marker compound to a radiolabeled imaging agent applying in vivo click chemistry. The fastest bioorthogonal ligation reported so far is the inverse electron demand Diels-Alder (IEDDA)-initiated conjugation between 1,2,4,5-tetrazines (Tz) and strained cycloalkenes . Until recently, only a few radiolabeled tetrazines have been developed using metal radionuclides such as 64Cu or 89Zr together with chelating ligands leading to relatively large and complex imaging agents. 18F-Tz have been inaccessible due to the previously observed instability of tetrazines during direct fluorination . Due to the favorable decay properties and the high specific activity of 18F (allowing administration of low mass dosages and shorter radiation exposures), readily accessible 18F-labeled tetrazines are of high significance for applications in bioorthogonal imaging and diagnostic tool development, especially in the field of cancer immunotherapy.
In this contribution, an overview will be presented showing the development of various 18F-labeled tetrazines as highly versatile tools for bioorthogonal PET imaging. Starting from the development of the first 18F-Tz  we have been successful in designing different synthetic strategies, for instance using orthogonal click reactions for rapid radiolabeling of precursor compounds, to gain access to highly reactive 18F-labeled tetrazines. In vitro investigations of selected probes identified cell-permeable click imaging agents with high stability, and PET/MR imaging in mice showed fast homogeneous biodistribution. Furthermore, we have been able to design a 11C-labeled tetrazine that was used within the first successful pretargeting experiment in the field of 11C-PET imaging .
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