Multivalent GLP‐1/Yhb for targeted therapy and imaging of pancreatic β‐cells

Abstract

Glucagon like peptide‐1 (GLP‐1) has potential for treating diabetes due to its effects on β‐cell proliferation and function. Described is a GLP‐1 analog that targets β‐cells specifically, which may increase its therapeutic efficacy and make it useful for monitoring β‐cell mass. GLP‐1 was coupled with a flexible linker to Yohimbine (Yhb) (α2 Adrenergic Receptor antagonist). GLP‐1/Yhb binds to cells expressing both receptors at low nM concentrations and is rapidly internalized. In cells where either GLP‐1R or α2AR were knocked down, binding of GLP‐1/Yhb was severely impaired (≤ half of control cells) indicating both receptors are required for high affinity binding. Intravenous injection of 250nM GLP‐1/Yhb‐Cy5 showed a high β‐cell:acinar ratio of ~1.8:1 in pancreatic sections while binding of 111In‐labeled GLP‐1/Yhb in isolated rat islets was significantly higher than acinar cells. Only islet binding was blocked by unlabeled GLP‐1/Yhb indicating specific binding. Following tail vein injection of 111In‐GLP‐1/Yhb, >; 90% of ligand was cleared from circulation within 30 mins. At this time, specific binding in pancreas relative to a range of other tissues was observed because pretreatment with cold GLP‐1/Yhb blocked only islet binding. In all, these data show that GLP‐1/Yhb binds selectively to β‐cells, demonstrating its potential for targeted β‐cell imaging and therapy.Support: Juvenile Diabetes Research Fnd