Preclinical evaluation of selective microtubule and amyloid PET tracers and in amyloid beta overexpression mice

1631 Objectives: The clinical diagnosis of Alzheimer’s Disease (AD) is frequently not well correlated to imaging findings with existing PET tracers including Aβ and tau tracers.Therefore, identifying novel biomarkers for neurodegeneration through PET imaging is a top priority in biomedical research. Loss of microtubules (MTs), a major component of cytoskeleton, have been identified as a validated biomarker for neurodegenerative disorders including AD. [11C]MPC-6827 is the validated blood brain barrier-penetrating PET tracer, available for in vivo imaging of MTs in brain.1,2 Herein, we present the in vivo comparison [11C]MPC-6827 and amyloid PET tracer [11C]Pittsburgh compound B ([11C]PIB) in Aβ over expressing APP mutated transgenic (Tg) J20 mice and controls (NTg). Methods: [11C]MPC-6827 and [11C]PIB were synthesized by reacting corresponding desmethyl-precursors with [11C]CH3I and [11C]CH3OTf respectively using GE Tracerlabs FXMEI and FX2 N modules. microPET studies were performed in 6-month-old J20 mice and littermates (n=4) using a Siemens Focus PET Scanner. Results: Automated synthesis of [11C]MPC-6827 and [11C]PIB were achieved in 35±10% decay corrected yield (DCY) at the end of synthesis (EOS) with >96% purity. [11C]MPC-6827 shows higher standardized uptake value (SUV) than [11C]PIB in all the imaged animals. SUV shows ~25% of reduced whole brain uptake of [11C]MPC-6827 in J20 mice than control. Whereas, [11C]PIB exhibited ~10% higher binding in J20 mice than control. In addition to whole brain, [11C]MPC-6827 shows higher extend of binding difference than [11C]PIB in prefrontal cortex and hippocampus in Tg and NTg mice. Conclusion: Our preliminary studies show that in J20 transgenic mice, binding of the MT PET ligand [11C]MPC-6827 exhibit higher effect size and SUV than the Aβ PET tracer [11C]PIB. Therefore, [11C]MPC-6827 could be used as a potential PET tracer for human brain imaging of AD and related neurodegenerative diseases. Acknowledgement: The research work was funded by Center for Biomedical Neuroscience (CBN) 2020-21, UT Health San Antonio, Texas, USA. References: 1. Kumar JSD et al. J. Med. Chem. 2018, 61(5), 2118. 2. Kumar JSD et al. Bioorg. Med. Chem. Lett. 2020, 29(10), 126785.