Synthesis and in vivo behaviour of an exendin-4-based MRI probe capable of ß-cell-dependent contrast enhancement in the pancreas.

Global rates of diabetes mellitus are increasing, and treatment of the disease consumes a growing proportion of healthcare spending across the world. Pancreatic ß-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 ß-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 ß-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 ß-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 ß-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.

Ligand design strategies to increase stability of gadolinium-based magnetic resonance imaging contrast agents.

Gadolinium(III) complexes have been widely utilised as magnetic resonance imaging (MRI) contrast agents for decades. In recent years however, concerns have developed about their toxicity, believed to derive from demetallation of the complexes in vivo, and the relatively large quantities of compound required for a successful scan. Recent efforts have sought to enhance the relaxivity of trivalent gadolinium complexes without sacrificing their stability. This review aims to examine the strategic design of ligands synthesised for this purpose, provide an overview of recent successes in gadolinium-based contrast agent development and assess the requirements for clinical translation.

H4octapa: synthesis, solution equilibria and complexes with useful radiopharmaceutical metal ions.

H4octapa is an extremely versatile acyclic chelator for a wide variety of medicinally relevant metal ions, forming complexes of both high thermodynamic and kinetic stability. This work reports a significantly simplified 3 step high yield straightforward synthesis of H4octapa directly from EDDA. Crystals of the octa-protonated form of the ligand [H8octapa]4+ as its tetrachloride salt, and of the mixed lanthanum-sodium salt of [La(octapa)]- were isolated and characterized by X-ray diffraction. All eight protonation constants for the ligand were determined through combined potentiometric-spectrophotometric titrations and in batch experiments using UV spectrophotometry and 1H NMR spectroscopy. Synthesis, characterisation and solution equilibria studies are presented for complexes [Ln(octapa)]- (Ln = lanthanide element) with Sm(iii), Dy(iii), and Yb(iii) (each of which have radiopharmaceutical applications). Complex formation equilibria studies provided evidence of Ln(Hoctapa), [Ln(octapa)]- and [Ln(octapa)(OH)]2- species in solution, and their stability constants were evaluated by pH-potentiometric competition titrations using [ttha]6- as a competing ligand, and by UV-vis spectrophotometric measurements. The high stability constants of the [Ln(octapa)]- complexes with Sm(iii), Dy(iii), and Yb(iii) (log KSmL = 20.10(2), log KDyL = 20.14(3) and log KYbL = 19.90(1)) are similar to the published values for other lanthanides and consequently these initial investigations confirm H4octapa as a valuable ligand for Sm(iii), Dy(iii), Yb(iii) and other Ln for application in diagnostic and therapeutic nuclear medicine.