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

Neil Vasdev,Arturo Aliaga,Peter J H Scott,Gassan Massarweh,Robert Hopewell,Andrew V Mossine,Anton Lindberg,Xia Shao,Pedro Rosa-Neto,Vadim Bernard-Gauthier

doi:10.3389/fnins.2021.725873

Abstract

[11C]Verubulin (a.k.a.[11C]MCP-6827), [11C]HD-800 and [11C]colchicine have been developed for imaging microtubules (MTs) with positron emission tomography (PET). The objective of this work was to conduct an in vivo comparison of [11C]verubulin for MT imaging in mouse and rat brain, as well as an in vitro study with this radiotracer in rodent and human Alzheimer’s Disease tissue. Our preliminary PET imaging studies of [11C]verubulin in rodents revealed contradictory results between mouse and rat brain uptake under pretreatment conditions. In vitro autoradiography with [11C]verubulin showed an unexpected higher uptake in AD patient tissue compared with healthy controls. We also conducted the first comparative in vivo PET imaging study with [11C]verubulin, [11C]HD-800 and [11C]colchicine in a non-human primate. [11C]Verubulin and [11C]HD-800 require pharmacokinetic modeling and quantification studies to understand the role of how these radiotracers bind to MTs before translation to human use.

Highlights

Microtubules (MTs) consist of α- and β- tubulin dimers that polymerize to form the backbone of the neural cell structure and represent one of the most densely expressed proteins in the central nervous system (CNS) (Verhey and Gaertig, 2007; Janke, 2014; Goodson and Jonasson, 2018; Xia et al, 2020)
Baseline measurements using [11C]verubulin showed significantly higher radioactivity in all regions compared to blocking measurements using verubulin (500 μM) (posterior cortex, p < 0.0001; medial cortex, p < 0.0001; anterior cortex, p = 0.0328; caudate putamen (Cpu), p < 0.0001; thalamus, p < 0.0001; hippocampus, p < 0.0001; midbrain, p < 0.0001; superior colliculus p < 0.0001; inferior colliculus, p < 0.0001; pons p < 0.0001; cerebellum (Cbl) gray matter (GM), p = 0.0003; Cbl white matter (WM), p < 0.0001) (Figure 3)
The ability to block tubulin binding in mouse has been shown previously using [11C]WX-132-18B and [11C]HD-800 (Sai et al, 2018, 2020), the decreased radiotracer uptake of [11C]verubulin in mouse is consistent with our expectations

Summary

Introduction

Microtubules (MTs) consist of α- and β- tubulin dimers that polymerize to form the backbone of the neural cell structure and represent one of the most densely expressed proteins in the central nervous system (CNS) (Verhey and Gaertig, 2007; Janke, 2014; Goodson and Jonasson, 2018; Xia et al, 2020). The polymerization-depolymerization of tubulin is a dynamic process that allows the MT scaffold to change over time (Zhu et al, 2021). This process allows tubulin to exist as free and dimeric protein as well as polymerized MTs in a continuous cycle (Honore et al, 2005). Loss of native functionality of MTs are a hallmark of several neurogenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease

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