Synthesis and in vivo behaviour of an exendin-4-based MRI probe capable of beta-cell-dependent contrast enhancement in the pancreas
File(s)
Author(s)
Type
Journal Article
Abstract
Global rates of diabetes mellitus are increasing, and treatment of the disease consumes a growing proportion of healthcare spending across the world. Pancreatic β-cells, responsible for insulin production, decline in mass in type 1 and, to a more limited degree, in type 2 diabetes. However, the extent and rate of loss in both diseases differs between patients resulting in the need for the development of novel diagnostic tools, which could quantitatively assess changes in mass of β-cells over time and potentially lead to earlier diagnosis and improved treatments. Exendin-4, a potent analogue of glucagon-like-peptide 1 (GLP-1), binds to the receptor GLP-1R, whose expression is enriched in β-cells. GLP-1R has thus been used in the past as a means of targeting probes for a wide variety of imaging modalities to the endocrine pancreas. However, exendin-4 conjugates designed specifically for MRI contrast agents are an under-explored area. In the present work, the synthesis and characterization of an exendin-4-dota(ga)-Gd(III) complex, GdEx, is reported, along with its in vivo behaviour in healthy and in β-cell-depleted C57BL/6J mice. Compared to the ubiquitous probe, [Gd(dota)]−, GdEx shows selective uptake by the pancreas with a marked decrease in accumulation observed after the loss of β-cells elicited by deleting the microRNA processing enzyme, DICER. These results open up pathways towards the development of other targeted MRI contrast agents based on similar chemistry methodology.
Date Issued
2020-04-21
Date Acceptance
2020-03-07
Citation
Dalton Transactions: an international journal of inorganic chemistry, 2020, 49 (15), pp.4732-4740
ISSN
1477-9226
Publisher
Royal Society of Chemistry
Start Page
4732
End Page
4740
Journal / Book Title
Dalton Transactions: an international journal of inorganic chemistry
Volume
49
Issue
15
Copyright Statement
© The Royal Society of Chemistry 2020.
Sponsor
Medical Research Council (MRC)
Medical Research Council (MRC)
Diabetes UK
Diabetes UK
Diabetes UK
Diabetes UK
Medical Research Council (MRC)
The Leverhulme Trust
Juvenile Diabetes Research Foundation International
Medical Research Council
Rosetrees Trust
Institut De Recherches Servier
Identifier
http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000527540400011&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
Grant Number
MR/P023223/1
R15019
12/0004535
18/0005934
16/0005485
16/0005485
MR/J013293/2
RF/4/RFG/2009/0493
3-2009-665
MR/R022259/1 (2018 – 2023)
M529
115881
Subjects
Science & Technology
Physical Sciences
Chemistry, Inorganic & Nuclear
Chemistry
PEPTIDE-1 RECEPTOR PET/CT
GADOLINIUM DEPOSITION
AGENTS
GLP-1
MASS
INSULIN
SENSITIVITY
APOPTOSIS
ANALOGS
GLUCOSE
Publication Status
Published
Date Publish Online
2020-03-19