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Enhanced specific activity by multi-chelation of exendin-3 leads to improved image quality and in vivo beta cell imaging Lieke Joosten, Maarten Brom, Hanneke Peeters, Sandra Heskamp, Martin Behe, Otto C. Boerman, and Martin Gotthardt Mol. Pharmaceutics, Just Accepted Manuscript • DOI: 10.1021/acs.molpharmaceut.7b00853 • Publication Date (Web): 11 Dec 2017 Downloaded from http://pubs.acs.org on December 20, 2017
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Molecular Pharmaceutics
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Enhanced specific activity by multi-chelation of exendin-3 leads to improved image quality and in
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vivo beta cell imaging
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Lieke Joosten *, Maarten Brom , Hanneke Peeters
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Martin Gotthardt
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, Sandra Heskamp , Martin Béhé , Otto Boerman ,
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6500 HB Nijmegen, The Netherlands
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Department of Radiology and Nuclear Medicine, Radboud university medical center, PO Box 9101
Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Paul Scherrer Institut, 5232 Villigen,
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Switzerland
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Present address:
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Biology, Maastricht University Medical Center, Maastricht, The Netherlands
Maastricht Radiation Oncology (Maastro) Lab, GROW – School for Oncology and Developmental
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Lieke Joosten
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Department of Radiology and Nuclear Medicine, Radboud university medical Center, PO Box
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9101, 6500 HB Nijmegen, The Netherlands
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Telephone/fax: +31 24 36 67319 / +31 24 36 18942
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Email:
[email protected] ACS Paragon Plus Environment
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Table of Contents/Abstract graphic
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Molecular Pharmaceutics
Abstract
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Objective: Glucagon like peptide-1 receptor (GLP-1R) targeting using radiolabeled exendin is a promising
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approach to non-invasively visualize and determine beta cell mass (BCM), which could help to unravel the
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pathophysiology of diabetes. However, saturation of the GLP-1R on beta cells occurs at low peptide
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doses, since the number of receptors expressed under physiological conditions is low. Therefore, tracers
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with high specific activities are required to sensitively image small variations in BCM. Here, we describe a
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novel exendin-3-based radiotracer with multiple chelators and determined its potential for in vivo beta cell
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imaging.
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Methods: Exendin-3 was modified by adding six lysine residues C-terminally conjugated with one, two or
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six DTPA moieties. All compounds were labeled with
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vitro using GLP-1R expressing cells. The in vivo behavior of the
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BALB/c nude mice with a subcutaneous GLP-1R expressing tumor (INS-1). Brown Norway rats were used
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for SPECT visualization of the pancreatic BCM.
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Results: Addition of six lysine and six DTPA residues (hexendin(40-45)) resulted in a seven-fold increase
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in specific activity (from 0.73 GBq/nmol to 5.54 GBq/nmol). IC50 values varied between 5.2 and 69.5 nM.
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All compounds with two or six lysine and DTPA residues had a significantly lower receptor affinity than
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[Lys (DTPA)]exendin-3 (4.4 nM, p < 0.05). The biodistribution in mice revealed no significant decrease in
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pancreatic uptake after addition of six lysine and DTPA molecules. Hexendin(40-45) showed a six-fold
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increase
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[Lys (DTPA)]exendin-3 (182.7 ± 42.3 kBq vs. 28.8 ± 6.0 kBq, p
