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, [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.

Methods: 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 ± 0.8 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 min for rTg4510 and 30 min 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: [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.

Conclusions: 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.

Keywords: Alzheimer’s disease; Amyotrophic lateral sclerosis; Microtubule; PET.