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

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 [68Ga]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 [68Ga]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. [68Ga]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: [68Ga]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.