Synthesis and Evaluation of an 18F Labeled SV2A Ligand as a Novel Biomarker for Alzheimers Disease

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ABSTRACT The goal of this award is to foster the transition of the applicant to an independent investigator in the field of PET neuroimaging focusing on the development and translation of novel PET neuroimaging probes for early detection of Alzheimer’s disease (AD) to clinics. The applicant is redirecting his research focus from oncological PET imaging to PET neuroimaging. And the new direction is significantly different from the applicant’s former training, not only in pathophysiology, but also in approaches to image acquisition, and especially data analysis (image processing, kinetic modeling), characteristics of the tracers (BBB penetration, pharmacokinetics, metabolism), and animal models for translational studies. The training plan includes focused coursework, seminars and conferences, interaction with mentors from fields of PET neuroimaging probe development, tracer kinetic modeling, anti-AD drug development, and clinical AD research. Through the proposed study, the applicant will acquire new techniques, i.e., ex vivo autoradiography, image processing, and kinetic modeling. The applicant will also acquire new skills such as preparation for IND application, which is required for translating the imaging agent to the clinic. The objective of the proposed research activities is to develop an 18F-labeled PET imaging probe for early detection of AD. The proposed research project is based on pilot data obtained using [11C]UCB-J, which demonstrated both the feasibility, and clinical potential, of imaging SV2A as a biomarker for preclinical or prodromal AD. To overcome the limitations of [11C]UCB-J, an 18F-labeled analog was proposed to be developed for the clinical translation. The specific aims of the proposal are: 1) To synthesize and evaluate enantiopure UCB-J analogs through in vitro homogenate binding assays; 2) To evaluate in nonhuman primates the in vivo pharmacokinetic and metabolism profiles of the [18F]UCB-J analogs advanced from Aim 1; 3) To use SV2A PET imaging to monitor the pre-dementia AD progression in a transgenic rodent model of AD through longitudinal multi-tracer PET imaging and ex vivo autoradiography. Successful completion of this project will yield a PET tracer ready to be translated to clinics for testing as a biomarker for early detection of AD.