Translocator Protein (18 kDa) Polymorphism (rs6971) Explains in-vivo Brain Binding Affinity of the PET Radioligand [18F]-FEPPA

• Published in: Journal of cerebral blood flow and metabolism Vol. 32; no. 6; pp. 968 - 972
• Main Authors: Mizrahi, Romina, Rusjan, Pablo M, Kennedy, James, Pollock, Bruce, Mulsant, Benoit, Suridjan, Ivonne, De Luca, Vincenzo, Wilson, Alan A, Houle, Sylvain
• Format: Journal Article
• Language: English
• Published: London, England SAGE Publications 01.06.2012; Nature Publishing Group; Sage Publications Ltd
• Subjects: Adult; Aged; Alanine; Amino Acid Substitution; Anilides - pharmacokinetics; Anilides - pharmacology; Biological and medical sciences; Brain; Cerebral blood flow; Exons; Female; Gene polymorphism; Humans; Investigative techniques, diagnostic techniques (general aspects); Male; Medical sciences; Microglia - diagnostic imaging; Microglia - metabolism; Middle Aged; Monoclonal antibodies; Nervous system; Neurology; Polymorphism, Genetic; Positron emission tomography; Positron-Emission Tomography - methods; Protein Binding; Pyridines - pharmacokinetics; Pyridines - pharmacology; Radiography; Radioisotopes; Rapid Communication; Receptors, GABA - genetics; Receptors, GABA - metabolism; Threonine; tspO gene; Ultrasonic investigative techniques; Vascular diseases and vascular malformations of the nervous system; genetics; positron emission tomography; inflammation; microglia; mitochondria; Mitochondria; Nervous system diseases; Central nervous system disease; Inflammation; Positron emission tomography; Cerebrovascular disease; Cerebral disorder; Encephalon; Microglia; Polymorphism; Emission tomography
• ISSN: 0271-678X; 1559-7016
• DOI: 10.1038/jcbfm.2012.46

[18F]-FEPPA binds to the 18-kDa translocator protein (TSPO) and is used in positron emission tomography (PET) to detect microglial activation. However, quantitative interpretations of the PET signal with new generation TSPO PET radioligands are confounded by large interindividual variability in binding affinity. This presents as a trimodal distribution, reflecting high-affinity binders (HABs), low-affinity binder (LAB), and mixed-affinity binders (MABs). Here, we show that one polymorphism (rs6971) located in exon 4 of the TSPO gene, which results in a nonconservative amino-acid substitution from alanine to threonine (Ala147Thr) in the TSPO protein, predicts [18F]-FEPPA total distribution volume in human brains. In addition, [18F]-FEPPA exhibits clearly different features in the shape of the time activity curves between genetic groups. Testing for the rs6971 polymorphism may allow quantitative interpretation of TSPO PET studies with new generation of TSPO PET radioligands.