An 18-kDa translocator protein (TSPO) polymorphism explains differences in binding affinity of the PET radioligand PBR28.
[(11)C]PBR28 binds the 18-kDa Translocator Protein (TSPO) and is used in positron emission tomography (PET) to detect microglial activation. However, quantitative interpretations of signal are confounded by large interindividual variability in binding affinity, which displays a trimodal distribution compatible with a codominant genetic trait. Here, we tested directly for an underlying genetic mechanism to explain this. Binding affinity of PBR28 was measured in platelets isolated from 41 human subjects and tested for association with polymorphisms in TSPO and genes encoding other proteins in the TSPO complex. Complete agreement was observed between the TSPO Ala147Thr genotype and PBR28 binding affinity phenotype (P value=3.1 × 10(-13)). The TSPO Ala147Thr polymorphism predicts PBR28 binding affinity in human platelets. As all second-generation TSPO PET radioligands tested hitherto display a trimodal distribution in binding affinity analogous to PBR28, testing for this polymorphism may allow quantitative interpretation of TSPO PET studies with these radioligands.
Division of Experimental Medicine, Department of Medicine, Imperial College London, Hammersmith Hospital, London, UK. d.owen@imperial.ac.uk
David R
DR
Owen
Astrid J
AJ
Yeo
Roger N
RN
Gunn
Kijoung
K
Song
Graham
G
Wadsworth
Andrew
A
Lewis
Chris
C
Rhodes
David J
DJ
Pulford
Idriss
I
Bennacef
Christine A
CA
Parker
Pamela L
PL
StJean
Lon R
LR
Cardon
Vincent E
VE
Mooser
Paul M
PM
Matthews
Eugenii A
EA
Rabiner
Justin P
JP
Rubio
D000081:Acetamides / Q000378:metabolism*; D000328:Adult; D019943:Amino Acid Substitution / Q000235:genetics; D001667:Binding, Competitive / Q000235:genetics; D001792:Blood Platelets / Q000378:metabolism; D002462:Cell Membrane / Q000235:genetics / Q000378:metabolism; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D007546:Isoquinolines / Q000378:metabolism; D008297:Male; D020641:Polymorphism, Single Nucleotide; D049268:Positron-Emission Tomography; D011485:Protein Binding; D011725:Pyridines / Q000378:metabolism*; D011869:Radioligand Assay; D019275:Radiopharmaceuticals / Q000378:metabolism*; D018079:Receptors, GABA / Q000235:genetics* / Q000378:metabolism*; D014316:Tritium
D000081:Acetamides; D007546:Isoquinolines; C526798:N-(2-methoxybenzyl)-N-(4-phenoxypyridin-3-yl)acetamide; D011725:Pyridines; D019275:Radiopharmaceuticals; D018079:Receptors, GABA; C499229:TSPO protein, human; D014316:Tritium; C037850:PK 11195