Development of ^99mTc-Labeled Pyridyl Benzofuran Derivatives To Detect Pancreatic Amylin in Islet Amyloid Model Mice

Abstract

While islet amyloid deposition comprising amylin is one of pathological hallmarks of type 2 diabetes mellitus (T2DM), no useful amylin-imaging probe has been reported. In this study, we evaluated two (99m)Tc-labeled pyridyl benzofuran derivatives as novel amylin-imaging probes using the newly established islet amyloid model mouse. Binding experiments in vitro demonstrated that [(99m)Tc]1 displayed a higher affinity for amylin aggregates than [(99m)Tc]2. Autoradiographic studies using human pancreas sections with T2DM revealed that [(99m)Tc]1 clearly labeled islet amyloid in T2DM pancreatic sections, while [(99m)Tc]2 did not. Although the initial uptake of [(99m)Tc]1 by the normal mouse pancreas was low (0.74%ID/g at 2 min post-injection), [(99m)Tc]1 showed higher retention in the model mouse pancreas than that of the normal mouse, and exhibited strong binding to amylin aggregates in the living pancreas of the model mice. These results suggest that [(99m)Tc]1 is a potential imaging probe targeting islet amyloids in the T2DM pancreas.

Concentration‐Dependent Interactions of Amphiphilic PiB Derivative Metal Complexes with Amyloid Peptides Aβ and Amylin**

“…Yoshimura et al. reported 99m Tc complexes bearing a pyridyl‐benzofurane (PBF) attached via a triethylene glycol spacer [9] . The best affinity, determined by radiocompetition, was K i =146 n m , two orders of magnitude below the K i of the 125 I‐labelled PBF (2.66 n m ), indicating a strong affinity loss induced by the Tc complex.…”

“…[8] Another example concerns SPECT detection of amylin in the pancreas with a 99m Tc complex. [9] Amyloid deposits in pancreatic islets appear in >90% of type 2 diabetes mellitus (T2DM) patients and their quantity has been recognized as a direct indicator of disease severity. Amylin or islet amyloid polypeptide (IAPP) is a 37-amino-acid peptide co-secreted with insulin by β-cells.…”

Use of the PET ligand florbetapir for in vivo imaging of pancreatic islet amyloid deposits in hIAPP transgenic mice

“…Previous studies have provided histological and autoradiographic evidence for in vitro binding of A beta imaging probes to synthetic hIAPP aggregates [26], and when administered intravenously, these agents accumulated in implanted hIAPP aggregates in mice [27]. However, these studies did not determine whether amyloid-imaging probes bind to endogenous islet amyloid, or whether they allow identification of islet amyloid deposits in vivo using PET.…”

“…Amyloid imaging probes have been designed for PET detection of amyloid beta (A beta) deposits in the brain [22–24], and since brain and islet amyloid deposits share structural similarities [25], these probes have been proposed as tools to detect islet amyloid as well. Limited studies have found that some A beta amyloid imaging probes bind synthetic hIAPP in vitro and ex vivo [26,27]. To our knowledge, no studies to date have tested whether these probes can identify and quantify endogenous islet amyloid in vivo.…”

A pilot study of pancreatic islet amyloid PET imaging with [18F]FDDNP

“…Thus, there is an unmet need to develop a noninvasive imaging method to quantitatively measure the pancreatic islet amyloid burden in T2DM patients. So far, only one molecular probe, 99m Tc-labeled pyridyl benzofuran, has been evaluated in vivo on the islet amyloid mouse model with single-photon emission computed tomography 10 . It showed a 1.6-fold higher uptake in the pancreas of the model mice than the control mice at 1 h after injection.…”