Dual‐Modal Magnetic Resonance/Fluorescent Zinc Probes for Pancreatic β‐Cell Mass Imaging |
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| Authors: | Dr Graeme J Stasiuk Dr Florencia Minuzzi Dr Myra Sae‐Heng Charlotte Rivas Dr Hans‐Paul Juretschke Dr Lorenzo Piemonti Dr Peter R Allegrini Dr Didier Laurent Andrew R Duckworth Prof Andrew Beeby Prof Guy A Rutter Prof Nicholas J Long |
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| Affiliation: | 1. Department of Chemistry, Imperial College London, South Kensington Campus, London SW7 2AZ (UK);2. Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Imperial College London, Hammersmith Hospital, London W12 0NN (UK);3. Sanofi‐Aventis Deutschland GmbH, R&D DSAR/Biomakers, Biom & Biol Ass, FF, Industriepark Hoechst, Building H825, 65926 Frankfurt (Germany);4. Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milano (Italy);5. Novartis Pharma AG, Fabrikstrasse, 28‐3.04, 4002 Basel (Switzerland);6. Novartis Institute for Biomedical Research, Fabrikstrasse, 10‐2.40.4, 4056, Basel (Switzerland);7. Department of Chemistry, Durham University, South Road, Durham, DH1 3LE (UK) |
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| Abstract: | Despite the contribution of changes in pancreatic β‐cell mass to the development of all forms of diabetes mellitus, few robust approaches currently exist to monitor these changes prospectively in vivo. Although magnetic‐resonance imaging (MRI) provides a potentially useful technique, targeting MRI‐active probes to the β cell has proved challenging. Zinc ions are highly concentrated in the secretory granule, but they are relatively less abundant in the exocrine pancreas and in other tissues. We have therefore developed functional dual‐modal probes based on transition‐metal chelates capable of binding zinc. The first of these, Gd ?1 , binds ZnII directly by means of an amidoquinoline moiety (AQA), thus causing a large ratiometric Stokes shift in the fluorescence from λem=410 to 500 nm with an increase in relaxivity from r1=4.2 up to 4.9 mM ?1 s?1. The probe is efficiently accumulated into secretory granules in β‐cell‐derived lines and isolated islets, but more poorly by non‐endocrine cells, and leads to a reduction in T1 in human islets. In vivo murine studies of Gd ?1 have shown accumulation of the probe in the pancreas with increased signal intensity over 140 minutes. |
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| Keywords: | diabetes fluorescence imaging agents lanthanides zinc |
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