A DPP6 ‐Targeted PET Tracer for Non‐Invasive Imaging of Transplanted Human Islets

Abstract

ABSTRACT Introduction Dipeptidyl peptidase‐like protein 6 (DPP6) is a potential molecular imaging biomarker for pancreatic and transplanted islets of Langerhans. 4hD29 is a single‐domain antibody with nanomolar affinity for DPP6. Here, we demonstrate the generation and validation of [ 68 Ga]Ga‐NOTA‐4hD29 for Positron Emission Tomography (PET) imaging of human stem cell‐derived islets (SC‐islets) and human islets. Methods The binding of fluorescently labelled 4hD29 to human islets, human beta cell models and pancreatic tissues from various species over time was characterised. NOTA‐4hD29 was radiolabelled with Gallium‐68, and the resulting tracer [ 68 Ga]Ga‐NOTA‐4hD29 was evaluated for in vitro DPP6 binding as well as in vivo biodistribution. In vivo PET imaging was performed in immunodeficient mice transplanted with 400 to 800 SC‐islets or human islets, and the uptake signal was compared to non‐transplanted control mice. Results Fluorescently labelled 4hD29 demonstrated specific binding and internalisation in human islets. Fluorescence signal remained detectable for up to 2 h following incubation, indicating sustained intracellular retention. [ 68 Ga]Ga‐NOTA‐4hD29 bound to human islets with high specificity, and binding intensity correlated to islet purity. The binding of fluorescent and radiolabelled 4hD29 was negligible in extra‐pancreatic tissues. In vivo PET imaging enabled reliable detection of grafts comprised of 400 to 800 SC‐islets or human islets in immunodeficient mice. Conclusion [ 68 Ga]Ga‐NOTA‐4hD29 is a promising PET tracer for in vivo imaging of DPP6 in human islets. The tracer enabled non‐invasive detection of transplanted human islet grafts in the 400–800 IEQ range and demonstrated favourable biodistribution and dosimetry profiles, supporting its further development for islet imaging applications.