Scalable cGMP production of SV2A PET tracers using photoredox chemistry for applications in clinical trials and early AD diagnosis

ABSTRACT The overarching goal of this project is to develop innovative and scalable synthetic methods for producing 18F- labeled synaptic density imaging agents, specifically 18F-SynVesT-1 and 18F-SynVesT-2, to facilitate early detection of Alzheimer’s disease (AD). AD is a progressive neurodegenerative disorder that affects over 35 million individuals worldwide, including 5.5 million in the United States, imposing significant emotional and economic burdens on patients, caregivers, and society. While recent advancements in anti-β-amyloid (aβ) therapies have shown promise in slowing AD progression, particularly in patients with mild disease, early detection remains critical for effective intervention. Regional synaptic loss, a hallmark of AD that precedes cognitive decline, is directly correlated with memory dysfunction and can serve as an early biomarker of disease progression. Synaptic vesicle glycoprotein 2A (SV2A), a biomarker for synaptic density, has been successfully imaged using PET radioligands such as 11C- UCB-J. However, the short half-life of 11C (~20 minutes) limits its scalability and utility for broader clinical application. To overcome these limitations, 18F-labeled SV2A PET agents, including 18F-SynVesT-1 and 18F- SynVesT-2, have been developed, demonstrating comparable imaging performance to 11C-UCB-J in initial clinical studies. Despite their promise, the current synthesis process for 18F-labeled agents relies on toxic tin precursors and achieves suboptimal yields, hindering commercialization. This STTR application seeks to address these challenges by developing and optimizing a novel photoredox radiolabeling method that improves the safety, efficiency, and scalability of 18F-SynVesT-1/2 synthesis. This project aims to identify the most suitable precursor and optimize the radiochemistry of 18F-SynVesT-1/2; and to perform large-scale radiolabeling, validate imaging results in nonhuman primates, and finalize the CMC section for IND submission. This work is expected to establish a robust and scalable method for producing 18F-SynVesT-1/2, enabling commercialization and widespread clinical use of these agents. These efforts will significantly enhance the accessibility of synapse imaging, facilitating early diagnosis and intervention for AD and related neurodegenerative disorders.