Targeting GLP-1 receptors for repeated magnetic resonance imaging differentiates graded losses of pancreatic beta cells in mice

Abstract

Aims/hypothesisNon-invasive imaging of beta cells is a much-needed development but is one that faces significant biological and technological hurdles. A relevant imaging method should at least allow for an evaluation over time of the mass of beta cells under physiological and pathological conditions, and for an assessment of novel therapies. We, therefore, investigated the ability of a new MRI probe to repeatedly measure the loss of beta cells in a rodent model.MethodsWe developed an innovative nanoparticle probe that targets the glucagon-like peptide 1 receptor, and can be used for both fluorescence imaging and MRI. Using fluorescence, we characterised the specificity and biodistribution of the probe. Using 1.5T MRI, we longitudinally imaged the changes in insulin content in male and female mice of the RIP-DTr strain, which mimic the changes expected in type 1 and type 2 diabetes, respectively.ResultsWe showed that this probe selectively labelled beta cells in situ, imaged in vivo native pancreatic islets and evaluated their loss after diphtheria toxin administration, in a model of graded beta cell deletion. Thus, using clinical MRI, the probe quantitatively differentiates, in the same mouse strain, between female animals featuring a 50% loss of beta cells and the males featuring an almost complete loss of beta cells.Conclusions/interpretationThe approach addresses several of the hurdles that have so far limited the non-invasive imaging of beta cells, including the potential to repeatedly monitor the very same animals using clinically available equipment, and to differentiate graded losses of beta cells.Electronic supplementary materialThe online version of this article (doi:10.1007/s00125-014-3442-2) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

Beta cell specific probing with fluorescent exendin-4 is progressively reduced in type 2 diabetic mouse models

“…This demonstrates that exendin-4 probes are b cell specific in the rodent pancreas, which is in line with recent findings. 13,25,26 Besides b cells, the exact pancreatic expression sites of the GLP-1R have been a subject of debate due to conflicting data reported in earlier studies. [27][28][29][30][31][32] Recent studies have demonstrated that many commercially available GLP-1R antibodies are unspecific, and that there exists interspecies variation in pancreatic GLP-1R expression.…”

Approaches to Improve the Pharmacokinetics of Radiolabeled Glucagon-Like Peptide-1 Receptor Ligands Using Antagonistic Tracers

“…The following structures of the peptides [Nle 14 2 ]Ex(9-39) were designed by Svetlana N. Rylova and Helmut R. Maecke and custom-synthesized by Peptide Specialty Laboratories. The purity was analyzed using analytic reversed-phase high-performance liquid chromatography on an analytic 120-5 C18 Nucleosil column, with a linear gradient of 15%-90% solvent B in 25 min at a flow rate of 1 mL/min (solvent A, 0.1% trifluoroacetic acid/H2O; solvent B, 0.1% trifluoroacetic acid/acetonitrile).…”

“…Naturally occurring GLP-1 receptor agonist GLP-1(7-36)NH 2 was used as an internal reference, and agonist [Nle 14 ,Lys 40 (Ahx-DOTA-68 Ga)NH 2 ]Ex-4, validated for insulinoma imaging in patients (15), was used as a reference for biodistribution studies ( Table 1). The lowest IC 50 values were found for the 2 agonists [Nle 14 ,Lys 40 (Ahx-DOTA)NH 2 ]Ex-4 (0.9 6 0.3 nmol/L) and GLP-1(7-36)NH 2 (1.1 6 0.3 nmol/L).…”

“…Naturally occurring GLP-1 receptor agonist GLP-1(7-36)NH 2 was used as an internal reference, and agonist [Nle 14 ,Lys 40 (Ahx-DOTA-68 Ga)NH 2 ]Ex-4, validated for insulinoma imaging in patients (15), was used as a reference for biodistribution studies ( Table 1). The lowest IC 50 values were found for the 2 agonists [Nle 14 ,Lys 40 (Ahx-DOTA)NH 2 ]Ex-4 (0.9 6 0.3 nmol/L) and GLP-1(7-36)NH 2 (1.1 6 0.3 nmol/L). The unmodified antagonist Ex(9-39)NH 2 showed relatively high affinity for hGLP-1 receptor (10.9 6 1.1 nmol/L), but on conjugation of a DOTA chelator at positions Lys 27 Table 1 indicate that all tested GLP-1 antagonistic ligands had somewhat better affinity toward rat GLP-1, confirming the feasibility of using the rat insulinoma model for in vivo evaluation of tracer pharmacokinetics.…”

“…Preoperative imaging of insulinomas is critical, because it helps to precisely localize these often very small lesions in the pancreas. Therefore, imaging probes for optical (2), bimodal (3), SPECT (4-7), and PET (8-13) imaging as well as MRI (14) were developed to localize GLP-1 receptors preoperatively and in addition to determine b-cell mass in diabetic animal models and potentially in patients. In particular, SPECT (4,5,7) and PET (8,13,15) agents were successfully translated into the clinic, and several promising clinical studies were reported.…”