Exploiting the Concept of Multivalency with 68 Ga- and 89 Zr-Labelled Fusarinine C-Minigastrin Bioconjugates for Targeting CCK2R Expression

Contrast Media & Molecular Imaging
Dominik SummerClemens Decristoforo

Abstract

Cholecystokinin-2 receptors (CCK2R) are overexpressed in a variety of malignant diseases and therefore have gained certain attention for peptide receptor radionuclide imaging. Among extensive approaches to improve pharmacokinetics and metabolic stability of minigastrin (MG) based radioligands, the concept of multivalency for enhanced tumour targeting has not been investigated extensively. We therefore utilized fusarinine C (FSC) as chelating scaffold for novel mono-, di-, and trimeric bioconjugates for targeting CCK2R expression. FSC-based imaging probes were radiolabelled with positron emitting radionuclides (gallium-68 and zirconium-89) and characterized in vitro (log⁡D, IC50, and cell uptake) and in vivo (metabolic stability in BALB/c mice, biodistribution profile, and microPET/CT imaging in A431-CCK2R/A431-mock tumour xenografted BALB/c nude mice). Improved targeting did not fully correlate with the grade of multimerization. The divalent probe showed higher receptor affinity and increased CCK2R mediated cell uptake while the trimer remained comparable to the monomer. In vivo biodistribution studies 1 h after administration of the 68Ga-labelled radioligands confirmed this trend, but imaging at late time point (24 h) with 89Z...Continue Reading

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May 4, 2017·Bioconjugate Chemistry·Dominik SummerClemens Decristoforo

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Citations

Aug 6, 2020·Pharmaceuticals·Benedikt JudmannCarmen Wängler
Jan 14, 2021·Trends in Molecular Medicine·Verena I BöhmerPhilip H Elsinga
Dec 12, 2018·Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine·Maximilian KlinglerElisabeth von Guggenberg
Jun 27, 2020·Current Medicinal Chemistry·Maximilian KlinglerElisabeth Von Guggenberg

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Methods Mentioned

BETA
size exclusion chromatography
Assay
xenografts
acetylation

Software Mentioned

Excel
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Flex Analysis

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