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Preclinical evaluation of (S)-[18F]GE387, a novel 18-kDa translocator protein (TSPO) PET radioligand with low binding sensitivity to human polymorphism rs6971.
Ramakrishnan, Nisha K; Hird, Matthew; Thompson, Stephen; Williamson, David J; Qiao, Luxi; Owen, David R; Brooks, Allen F; Scott, Peter J H; Bacallado, Sergio; O'Brien, John T; Aigbirhio, Franklin I.
Afiliação
  • Ramakrishnan NK; Molecular Imaging Chemistry Laboratory, Wolfson Brain Imaging Centre, Department of Clinical Neurosciences, University of Cambridge, Biomedical Campus, Cambridge, CB2 0SZ, UK. nk473@cam.ac.uk.
  • Hird M; Molecular Imaging Chemistry Laboratory, Wolfson Brain Imaging Centre, Department of Clinical Neurosciences, University of Cambridge, Biomedical Campus, Cambridge, CB2 0SZ, UK.
  • Thompson S; Molecular Imaging Chemistry Laboratory, Wolfson Brain Imaging Centre, Department of Clinical Neurosciences, University of Cambridge, Biomedical Campus, Cambridge, CB2 0SZ, UK.
  • Williamson DJ; Molecular Imaging Chemistry Laboratory, Wolfson Brain Imaging Centre, Department of Clinical Neurosciences, University of Cambridge, Biomedical Campus, Cambridge, CB2 0SZ, UK.
  • Qiao L; Molecular Imaging Chemistry Laboratory, Wolfson Brain Imaging Centre, Department of Clinical Neurosciences, University of Cambridge, Biomedical Campus, Cambridge, CB2 0SZ, UK.
  • Owen DR; Department of Brain Sciences, Imperial College London, Hammersmith Hospital, London, UK.
  • Brooks AF; Division of Nuclear Medicine, Department of Radiology, University of Michigan Medical School, 1301 Catherine Street, Ann Arbor, MI, 48109, USA.
  • Scott PJH; Division of Nuclear Medicine, Department of Radiology, University of Michigan Medical School, 1301 Catherine Street, Ann Arbor, MI, 48109, USA.
  • Bacallado S; Statistical Laboratory, Centre for the Mathematical Sciences, University of Cambridge, Wilberforce Rd., Cambridge, CB3 0WB, UK.
  • O'Brien JT; Department of Psychiatry, School of Clinical Medicine, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK.
  • Aigbirhio FI; Molecular Imaging Chemistry Laboratory, Wolfson Brain Imaging Centre, Department of Clinical Neurosciences, University of Cambridge, Biomedical Campus, Cambridge, CB2 0SZ, UK.
Eur J Nucl Med Mol Imaging ; 49(1): 125-136, 2021 12.
Article em En | MEDLINE | ID: mdl-34405276
ABSTRACT

PURPOSE:

Positron 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.

METHODS:

Dynamic 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.

CONCLUSION:

We 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.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Receptores de GABA / Compostos Radiofarmacêuticos Tipo de estudo: Diagnostic_studies / Prognostic_studies Limite: Animals / Female / Humans / Male Idioma: En Ano de publicação: 2021 Tipo de documento: Article
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Receptores de GABA / Compostos Radiofarmacêuticos Tipo de estudo: Diagnostic_studies / Prognostic_studies Limite: Animals / Female / Humans / Male Idioma: En Ano de publicação: 2021 Tipo de documento: Article