PET Imaging of [11C]MPC-6827, a Microtubule-Based Radiotracer in Non-Human Primate Brains

Abstract

Dysregulation of microtubules is commonly associated with several psychiatric and neurological disorders, including addiction and Alzheimer’s disease. Imaging of microtubules in vivo using positron emission tomography (PET) could provide valuable information on their role in the development of disease pathogenesis and aid in improving therapeutic regimens. We developed [11C]MPC-6827, the first brain-penetrating PET radiotracer to image microtubules in vivo in the mouse brain. The aim of the present study was to assess the reproducibility of [11C]MPC-6827 PET imaging in non-human primate brains. Two dynamic 0–120 min PET/CT imaging scans were performed in each of four healthy male cynomolgus monkeys approximately one week apart. Time activity curves (TACs) and standard uptake values (SUVs) were determined for whole brains and specific regions of the brains and compared between the “test” and “retest” data. [11C]MPC-6827 showed excellent brain uptake with good pharmacokinetics in non-human primate brains, with significant correlation between the test and retest scan data (r = 0.77, p = 0.023). These initial evaluations demonstrate the high translational potential of [11C]MPC-6827 to image microtubules in the brain in vivo in monkey models of neurological and psychiatric diseases.

Preliminary Evaluations of [11C]Verubulin: Implications for Microtubule Imaging With PET

“…The lack of brain uptake in NHP by [ 11 C]colchicine was expected as colchicine is a known P-gp substrate in rodents, and was considered in the present work to explore a potential species difference as this radiotracer was previously labeled in a different position (C-ring vs. A-ring) and imaged only in rodents ( Levchenko et al, 2000 ). Both [ 11 C]verubulin and [ 11 C]HD-800 show initial uptake in brain with no signs of efflux issues that follows previously reported PET studies with MT imaging agents in NHP ( Kumar et al, 2019 ; Sai et al, 2019 ; Damuka et al, 2020 ). The PET summation images of [ 11 C]verubulin and [ 11 C]HD-800 show a heterogenous distribution between WM and GM in brain.…”

“…Since significant differences in radiotracer binding could only be quantified in hippocampus, and although indications of increased [ 11 C]verubulin uptake was seen in PFC as well, a better model of MT dynamics in AD pathology is needed in order to apply the colchicine binding site PET tracers for MT quantification in AD. (Damuka et al, 2020) was recently reported along with [ 11 C]HD-800 as a meeting abstract (Sai et al, 2019), concurrent with our ongoing study. Herein we report the first comparative in vivo PET imaging study of [ 11 C]colchicine, [ 11 C]verubulin, and [ 11 C]HD-800 in a NHP.…”

“…Preliminary PET imaging studies in NHP of [ 11 C]verubulin ( Damuka et al, 2020 ) was recently reported along with [ 11 C]HD-800 as a meeting abstract ( Sai et al, 2019 ), concurrent with our ongoing study. Herein we report the first comparative in vivo PET imaging study of [ 11 C]colchicine, [ 11 C]verubulin, and [ 11 C]HD-800 in a NHP.…”

“…Verubulin (Azixa, MCP-6827; IC 50 = 1.5 nM to MT) is a drug in clinical trials that inhibits MT polymerization in tumor development and has shown to bind β-tubulin and disrupt dimerization ( Chamberlain et al, 2014 ). [ 11 C]Verubulin and [ 11 C]HD-800 (IC 50 = 4.3 nM to MT) have shown promise as PET radiotracers for MT imaging in mice ( Kumar et al, 2018 ; Sai et al, 2018 ), and both have been used in baseline PET measurements in non-human primate (NHP) ( Sai et al, 2019 ; Damuka et al, 2020 ).…”

Effect of ethanol and cocaine on [11C]MPC-6827 uptake in SH-SY5Y cells

“…It exerts antitumor (glioblastoma) properties by binding to β-tubulin sites. We reported the automated radiochemical synthesis of [ 11 C]MPC-6827 as the first brain-penetrating, MT-tracking PET ligand and imaged it in vivo in normal rodents and non-human primates [ 22 , 23 ]. To establish the potential of [ 11 C]MPC-6827 as a PET imaging ligand for various neurological disorders, we need to investigate its mechanism of action.…”