Development of novel 67/68Ga-labeled pyridyl benzofuran derivatives as islet amyloid imaging probes.

INTRODUCTION

Type 2 diabetes mellitus (T2DM) accounts for the majority of diabetes mellitus cases, and β-cell function and mass may be involved in its pathophysiology. The deposition of islet amyloid in pancreas islets is one of the mechanisms of progression of T2DM. Therefore, the development of imaging techniques for islet amyloid deposition contributes to the early-phase diagnosis and elucidation of the pathogenic mechanism of T2DM. We have reported that pyridyl benzofuran (PBF) is a promising scaffold for islet amyloid imaging probes. In this study, we designed [67/68Ga]Ga-dedpa-(PBF)2, which contains two PBF scaffolds in one molecule for enhancing binding affinity for islet amyloid by multivalent interaction, and evaluated its utility as an islet amyloid imaging probe.

METHODS

We synthesized dedpa-PBF and dedpa-(PBF)2 as mono and bivalent compounds, respectively. We conducted an in vitro saturation binding assay for calculation of the dissociation constants (Kd) against islet amyloid aggregates. An in vitro autoradiographic study was performed using pancreatic tissue sections of T2DM patients. A biodistribution experiment was performed using normal mice. Finally, we carried out an ex vivo autoradiographic study using islet amyloid-transplanted model mice.

RESULTS

In the in vitro saturation binding assay, the affinity of [67Ga]Ga-dedpa-(PBF)2 (Kd = 2.46 ± 0.49 μM) for islet amyloid aggregates was higher than that of [67Ga]Ga-dedpa-PBF (Kd = 3.73 ± 1.75 μM). The in vitro autoradiographic study revealed that both compounds clearly labeled islet amyloid depositions in T2DM sections. In the biodistribution experiment using normal mice, both compounds had initial uptake in the pancreas, but retention of radioactivity was observed in the pancreas and surrounding organs. In ex vivo autoradiography, both compounds exhibited intensive accumulation of radioactivity, which corresponded to Thioflavin S staining in amylin-transplanted mouse pancreas.

CONCLUSION

[67/68Ga]Ga-dedpa-(PBF)2 demonstrated the fundamental characteristics of an islet amyloid imaging probe, although it is necessary to improve the clearance from organs.