title: Translocator protein (18 kDa) polymorphism (rs6971) explains in-vivo brain binding affinity of the PET radioligand [(18)F]-FEPPA.
abstract: [(18)F]-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 [(18)F]-FEPPA total distribution volume in human brains. In addition, [(18)F]-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.
authors.affiliation: PET Centre, Centre for Addiction and Mental Health, Toronto, Ontario, Canada. romina.mizrahi@camhpet.ca
authors.forename: Romina
authors.initials: R
authors.lastname: Mizrahi
authors.forename: Pablo M
authors.initials: PM
authors.lastname: Rusjan
authors.forename: James
authors.initials: J
authors.lastname: Kennedy
authors.forename: Bruce
authors.initials: B
authors.lastname: Pollock
authors.forename: Benoit
authors.initials: B
authors.lastname: Mulsant
authors.forename: Ivonne
authors.initials: I
authors.lastname: Suridjan
authors.forename: Vincenzo
authors.initials: V
authors.lastname: De Luca
authors.forename: Alan A
authors.initials: AA
authors.lastname: Wilson
authors.forename: Sylvain
authors.initials: S
authors.lastname: Houle
mesh_terms: D000328:Adult; D000368:Aged; D019943:Amino Acid Substitution; D000813:Anilides / Q000493:pharmacokinetics* / Q000494:pharmacology; D005091:Exons; D005260:Female; D006801:Humans; D008297:Male; D017628:Microglia / Q000000981:diagnostic imaging / Q000378:metabolism; D008875:Middle Aged; D011110:Polymorphism, Genetic; D049268:Positron-Emission Tomography / Q000379:methods*; D011485:Protein Binding; D011725:Pyridines / Q000493:pharmacokinetics* / Q000494:pharmacology; D011859:Radiography; D018079:Receptors, GABA / Q000235:genetics / Q000378:metabolism
chemical_list: D000813:Anilides; C530438:N-(2-((N-(4-phenoxypyridin-3-yl)acetamido)methyl)phenoxy)ethyl fluoride; D011725:Pyridines; D018079:Receptors, GABA; C499229:TSPO protein, human