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by Eduardo Felipe Alves Fernandes, Jonas Wilbs, Rene Raavé, Christian Borch Jacobsen, Hanne Toftelund, Hans Helleberg, Milou Boswinkel, Sandra Heskamp, Magnus Bernt Frederik Gustafsson, and Inga Bjørnsdottir

ACS Pharmacol. Transl. Sci. 2022, 5, 8, 616–624. doi: 10.1021/acsptsci.2c00075

Abstract

Positron emission tomography (PET) is a molecular imaging modality that enables non-invasive visualization of tracer distribution and pharmacology. Recently, peptides with long half-lives allowed once-a-week dosing of glucagon-like peptide-1 receptor (GLP-1R) agonists with therapeutic applications in diabetes and obesity. PET imaging for such long-lived peptides is hindered by the typically used short-lived radionuclides. Zirconium-89 (⁸⁹Zr) emerged as a promising PET radionuclide with a sufficiently long half-life to be applied for biodistribution studies of long-circulating biomolecules. A comparison between the biodistribution profiles obtained via ⁸⁹Zr-PET and the current standard, quantitative whole-body autoradiography (QWBA), will be valuable for the development of novel peptide drugs. We determined the PET biodistribution of a ⁸⁹Zr-labeled acylated peptide agonist of GLP-1R and compared it to the profile obtained by QWBA using analogous tritiated tracers for up to 1 week after administration. The plasma metabolic profile was obtained and identification was done for the tritiated tracers. We found that, at early time points, the biodistribution profiles agreed between PET and QWBA. At the latertime points, the ⁸⁹Zr tracer remained primarily trapped in the kidneys. The introduction of desferrioxamine (DFO) chelator reduced the peptide stability, and UPLC-MS analysis identified a circulating metabolite arising from DFO hydrolysis. Kidney accumulation of radiolabeled peptides and DFO metabolic instability may compromise biodistribution studies using ⁸⁹Zr-PET to support the development of new biopharmaceuticals. PET and QWBA biodistribution data correlated well during the absorption phase, but new and more stable 89Zr chelators are needed for a more accurate description of the elimination phase.