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

Abstract

Background: 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, [ 11 C]MPC-6827, in transgenic mice models of tau pathology (rTg4510) and amyotrophic lateral sclerosis pathology (SOD1*G93A) and compared to corresponding age matched controls. Methods: Automated synthesis of [ 11 C]MPC-6827 was achieved in a GE-FX2MeI/FX2M radiochemistry module. In vivo PET imaging studies of [ 11 C]MPC-6827 (3.7+0.8 MBq)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 55 minutes for rTg4510 and 30 minutes 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).Results: [ 11 C]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. Conclusions:Our finding indicates a trend of loss of microtubule binding of [ 11 C]MPC-6827 in the whole brain of AD and ALS transgenic mice models compared to control mice.The pilot studies described herein show that [ 11 C]MPC-6827 could be used as a PET ligand for preclinical and human brain imaging of Alzheimer's disease, ALS and other neurodegenerative diseases.

Imaging of Tauopathies with PET Ligands: State of the Art and Future Outlook

“…Another tubular PET study is that of Kumar et al [51]. They tested 11 C-MPC-6827 in transgenic mice bearing tau pathology (rTg4510) and amyotrophic lateral sclerosis pathology (SOD1*G93A).…”