Preclinical evaluation of (S)-[18F]GE387, a novel 18-kDa translocator protein (TSPO) PET radioligand with low binding sensitivity to human polymorphism rs6971

Peter J H Scott,John T O’Brien,Nisha K Ramakrishnan,Sergio Bacallado,Luxi Qiao,Matthew Hird,David J Williamson,Franklin I Aigbirhio,Stephen Thompson,David R Owen,Allen F Brooks

doi:10.1007/s00259-021-05495-w

Abstract

PurposePositron emission tomography (PET) studies with radioligands for 18-kDa translocator protein (TSPO) have been instrumental in increasing our understanding of the complex role neuroinflammation plays in disorders affecting the brain. However, (R)-[11C]PK11195, the first and most widely used TSPO radioligand has limitations, while the next-generation TSPO radioligands have suffered from high interindividual variability in binding due to a genetic polymorphism in the TSPO gene (rs6971). Herein, we present the biological evaluation of the two enantiomers of [18F]GE387, which we have previously shown to have low sensitivity to this polymorphism.MethodsDynamic PET scans were conducted in male Wistar rats and female rhesus macaques to investigate the in vivo behaviour of (S)-[18F]GE387 and (R)-[18F]GE387. The specific binding of (S)-[18F]GE387 to TSPO was investigated by pre-treatment with (R)-PK11195. (S)-[18F]GE387 was further evaluated in a rat model of lipopolysaccharide (LPS)-induced neuroinflammation. Sensitivity to polymorphism of (S)-GE387 was evaluated in genotyped human brain tissue.Results(S)-[18F]GE387 and (R)-[18F]GE387 entered the brain in both rats and rhesus macaques. (R)-PK11195 blocked the uptake of (S)-[18F]GE387 in healthy olfactory bulb and peripheral tissues constitutively expressing TSPO. A 2.7-fold higher uptake of (S)-[18F]GE387 was found in the inflamed striatum of LPS-treated rodents. In genotyped human brain tissue, (S)-GE387 was shown to bind similarly in low affinity binders (LABs) and high affinity binders (HABs) with a LAB to HAB ratio of 1.8.ConclusionWe established that (S)-[18F]GE387 has favourable kinetics in healthy rats and non-human primates and that it can distinguish inflamed from normal brain regions in the LPS model of neuroinflammation. Crucially, we have reconfirmed its low sensitivity to the TSPO polymorphism on genotyped human brain tissue. Based on these factors, we conclude that (S)-[18F]GE387 warrants further evaluation with studies on human subjects to assess its suitability as a TSPO PET radioligand for assessing neuroinflammation.

Highlights

Neuroinflammation is a potential contributing factor to several disorders affecting the brain
We explored the in vivo behaviour of (S)-[18F]GE387 and (R)-[18F]GE387 in healthy male rats and healthy female rhesus macaques and assessed the (S)-[18F]GE387 in a rat model of neuroinflammation induced by unilateral injection of LPS into the striatum and further evaluated its Low affinity binder (LAB) to High affinity binder (HAB) binding ratio in genotyped human brain tissue
Positron emission tomography (PET) scan images of the brains of the healthy rats showed that the uptake of both (R)-[18F]GE387 and (S)-[18F]GE387 was low as expected in healthy naïve rats, with the olfactory bulb showing the highest uptake

Summary

Introduction

Neuroinflammation is a potential contributing factor to several disorders affecting the brain Whether it is sudden in onset like traumatic brain injury, intermittent like multiple sclerosis or progressive as with neurodegenerative disorders, post-mortem studies have shown the presence of markers of inflammation [1,2,3]. This polymorphism results in high affinity binders (HABs), low affinity binders (LABs) and mixed affinity binders (MABs) towards these radioligands in the general human population, with LAB to HAB binding ratios that vary from 55.3 to 4.0 (see Table 1), while the first-generation radioligand [11C]PK11195 has a low binding ratio of approximately 1 [9] This variation of binding affinities can complicate quantification of the acquired PET data, requiring all study participants to be genotyped and LABs (and potentially even MABs) to be excluded from clinical imaging studies. As well as complicating study design and logistics, this both limits the wider generalisability of findings generated from imaging studies, which only include HABs, and hinders potential future translation to clinical practice

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Discussion

Conclusion