Over the last two decades, immunoPET has become a staple of clinical imaging workflows. Indeed, antibodies are formidable targeting vectors, thanks to their high affinity and specificity for their antigen. However, the long circulation time of antibodies means that they must be labeled with radioisotopes with half-lives greater than 3 days, which can lead to high radiation doses to the patient. By decoupling radioactivity and targeting vector, pretargeting circumvents this drawback. Regardless of the details, different pretargeting strategies retain the same four steps:(1) a modified version of the IgG is administered;(2) the antibody slowly concentrates into the tumor and clears from blood;(3) the radiotracer – a small molecule designed to bind the antibody – is injected;(4) the radiotracer binds the antibody. The rapid clearance of the radiotracer allows to use shorter-lived isotopes than the ones regularly used for immunoPET. One of the main pretargeting strategies, pioneered by Rossin et al., relies on the inverse electron-demand Diels-Alder reaction between tetrazines and alkenes to perform the in vivo radiolabeling of the antibody. We have synthesized a tetrazine-bearing chelator for 68Ga, dubbed TRAP-Tz3. As 68Ga (t½ = 68 min) can be easily produced at low cost with 68Ge/68Ga generators, this isotope is highly suited for clinical application of pretargeted PET imaging. 68Ga-labeled TRAP-Tz3was efficiently obtained pure without purification with a radiochemical yield of 75% and a specific activity of 0.39 Ci/mol. In a murine colorectal cancer model injected with a trans-cyclooctene-modified antibody, 68Ga-TRAP-Tz3 allowed the delineation of the tumor as early as 60 min after injection, with an average tumor uptake of 5 %ID/g at 3 hours p.i. Encouraged by these promising results, we are currently modifying the tracer in order to tune its circulation time in the blood, as it has been demonstrated that this parameter strongly influences the in vivo radiolabeling efficiency.

68Ga-labeled tracer for pretargeted immunoPET imaging of colorectal cancer

255th National Meeting (2018)

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