Preclinical evaluation of a microtubule PET ligand [11C]MPC-6827 in tau and amyotrophic lateral sclerosis animal models.

Abstract

Microtubules are abundant in brain and their malfunctioning occurs in the early-to-advanced stages of neurodegenerative disorders. At present, there is no in vivo test available for a definitive diagnosis of most of the neurodegenerative disorders. Herein, we present the microPET imaging of microtubules using our recently reported Positron Emission Tomography (PET) tracer, [11C]MPC-6827, in transgenic mice models of tau pathology (rTg4510) and amyotrophic lateral sclerosis pathology (SOD1*G93A) and compared to corresponding age-matched controls. Automated synthesis of [11C]MPC-6827 was achieved in a GE-FX2MeI/FX2M radiochemistry module. In vivo PET imaging studies of [11C]MPC-6827 (3.7 ± 0.8MBq) were performed in rTg4510 and SOD1*G93A mice groups and their corresponding littermates (n = 5 per group). Dynamic PET images were acquired using a microPET Inveon system (Siemens, Germany) at 55min for rTg4510 and 30min for SOD1*G93A and corresponding controls. PET images were reconstructed using the 3D-OSEM algorithm and analyzed using VivoQuant version 4 (Invicro, MA). Tracer uptake in ROIs that included whole brain was measured as %ID/g over time to generate standardized uptake values (SUV) and time-activity curves (TACs). [11C]MPC-6827 exhibit a trend of lower tracer binding in mouse models of Alzheimer's disease (tau pathology, line rTg4510) and Amyotrophic Lateral Sclerosis (line SOD1*G93A) compared to wild-type littermates. Our finding indicates a trend of loss of microtubule binding of [11C]MPC-6827 in the whole brain of AD and ALS transgenic mice models compared to control mice. The pilot studies described herein show that [11C]MPC-6827 could be used as a PET ligand for preclinical and human brain imaging of Alzheimer's disease, ALS, and other neurodegenerative diseases. Preclinical Evaluation of a Microtubule PET Ligand [11C]MPC-6827 in Tau and Amyotrophic Lateral Sclerosis Animal Models. J. S. Dileep Kumar, Andrei Molotkov, Jongho Kim, Patrick Carberry, Sidney Idumonyi, John Castrillon, Karen Duff, Neil A. Shneider, Akiva Mintz.