Development and Evaluation of Novel 18F-PET Tracers for Imaging of Cardiac Angiotensin II Type 1 Receptor
Final Report Abstract
The aim of the DFG grant was to develop 18F-labelled radiotracers targeting AT1R from clinically used antagonists, i.e. the sartan series of drugs. We have successfully accomplished the goal with two novel radiotracers: 18F-valsartan and 18F-irbesartan. They both show high radiolabelling yield and were evaluated in animal models. Distinct kidney uptake could be observed with high AT1R specificity - the uptake of which could be blocked by the pretreatment of corresponding drug valsartan or irbesartan. Alpha-fluorination instead of omega-fluorination has been applied to irbesartan due to the poor stability of the corresponding precursor. The strategy has been proved successful and further radiotracers targeting AT1R are under developing including 18F-labelled candesartan and SK1080. In addition, using the similar pattern and strategy derived from this project, we were able to initiate a parallel project to develop radiotracers targeting norepinephrine transporter. The results have also been proved successful, which could be used not only for cardiac sympathetic nervous system imaging on diagnosis of cardiac diseases, but also for the therapy of certain neuroendocrine tumours, especially for baby patients. With the support of this work we could also build up a pattern of novel radiotracer discovery by building up a collaborative and multidisciplinary team including medicinal chemist, radiopharmacist, biologist and medical doctor. In addition, we have been able to equip an organic synthesis lab in the new building of Comprehensive Heart Failure Center, University Hospital of Wurzburg.
Publications
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18F-labeled derivatives of irbesartan for angiotensin II receptor PET imaging. ChemMedChem. 2018;13:2546-57
Hoffmann M, Chen X, Hirano M, et al.
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Novel 18F-labeled PET imaging agent FV45 targeting the renin-angiotensin system. ACS Omega. 2018;3:10460-70
Chen X, Hirano M, Werner RA, et al.
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Subcellular storage and release mode of the novel 18F-labeled sympathetic nerve PET tracer LMI1195. EJNMMI Res. 2018;8:12
Chen X, Werner RA, Lapa C, et al.
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Initial evaluation of AF78: A rationally designed fluorine-18-labelled PET radiotracer targeting norepinephrine transporter. Mol Imaging Biol. 2019
Chen X, Fritz A, Werner RA, et al.
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Sartans analogues as novel PET tracers targeting angiotensin II type 1 receptor. 2019. WO 2019/134765
Chen X, Decker M, Higuchi T, Hoffmann M
