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by Wilbs, Jonas, René Raavé, Milou Boswinkel, Tine Glendorf, David Rodríguez, Eduardo Felipe Alves Fernandes, Sandra Heskamp, Inga Bjørnsdottir, und Magnus B. F. Gustafsson on behalf of the TRISTAN Consortium

Journal of Medicinal Chemistry 66, Nr. 12 (22. Juni 2023): 7772–84. doi: 10.1021/acs.jmedchem.2c02073

Abstract

Positron emission tomography (PET) imaging is used in drug development to noninvasively measure biodistribution and receptor occupancy. Ideally, PET tracers retain target binding and biodistribution properties of the investigated drug. Previously, we developed a zirconium-89 PET tracer based on a long-circulating glucagon-like peptide 1 receptor agonist (GLP-1RA) using desferrioxamine (DFO) as a chelator. Here, we aimed to develop an improved zirconium-89-labeled GLP-1RA with increased molar activity to increase the uptake in low receptor density tissues, such as brain. Furthermore, we aimed at reducing tracer accumulation in the kidneys. Introducing up to four additional Zr-DFOs resulted in higher molar activity and stability, while retaining potency. Branched placement of DFOs was especially beneficial. Tracers with either two or four DFOs had similar biodistribution as the tracer with one DFO in vivo, albeit increased kidney and liver uptake. Reduced kidney accumulation was achieved by introducing an enzymatically cleavable Met-Val-Lys (MVK) linker motif between the chelator and the peptide.