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The Low-Affinity Binding of Second Generation Radiotracers Targeting TSPO is Associated with a Unique Allosteric Binding Site
C. Rojas, M. Stathis, JM. Coughlin, M. Pomper, BS. Slusher,
Jazyk angličtina Země Spojené státy americké
Typ dokumentu časopisecké články, Research Support, N.I.H., Extramural
Grantová podpora
P30 MH075673
NIMH NIH HHS - United States
P01MH075673
NIH HHS - United States
UL1 TR001079
CTSA - International
NLK
ProQuest Central
od 2006-03-01 do Před 1 rokem
Medline Complete (EBSCOhost)
od 2010-03-01 do Před 1 rokem
Health & Medicine (ProQuest)
od 2006-03-01 do Před 1 rokem
- MeSH
- genotyp MeSH
- lidé MeSH
- neurozobrazování metody MeSH
- pozitronová emisní tomografie metody MeSH
- radiofarmaka chemie MeSH
- receptory GABA analýza chemie genetika MeSH
- vazebná místa MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Research Support, N.I.H., Extramural MeSH
[11C]-PK11195 (PK11195) has been widely used with positron emission tomography (PET) to assess levels of the translocator protein 18 kDa (TSPO) as a marker of neuroinflammation. Recent ligands, such as [11C]-PBR28 and [11C]-DPA713, have improved signal-to-noise ratio and specificity for TSPO over PK11195. However, these second generation radiotracers exhibit binding differences due to a single polymorphism (rs6971) that leads to three genotypes: C/C, C/T and T/T associated with high, mixed and low binding affinities, respectively. Here we report that [3H]-DPA-713 in the presence of cholesterol or PK11195 has an accelerated dissociation rate from TSPO in platelets isolated from individuals with the T/T genotype. This allosteric interaction was not observed in platelets isolated from individuals with the C/C or C/T genotype. The results provide a molecular rationale for low binding affinity of T/T TSPO and further support the exclusion of these subjects from PET imaging studies using second generation TSPO ligands.
Citace poskytuje Crossref.org
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- $a Rojas, Camilo $u Johns Hopkins Drug Discovery, Johns Hopkins University School of Medicine, 855 North Wolfe Street, Office 230, Baltimore, MD, 21205, USA. crojas2@jhmi.edu. Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. crojas2@jhmi.edu.
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- $a [11C]-PK11195 (PK11195) has been widely used with positron emission tomography (PET) to assess levels of the translocator protein 18 kDa (TSPO) as a marker of neuroinflammation. Recent ligands, such as [11C]-PBR28 and [11C]-DPA713, have improved signal-to-noise ratio and specificity for TSPO over PK11195. However, these second generation radiotracers exhibit binding differences due to a single polymorphism (rs6971) that leads to three genotypes: C/C, C/T and T/T associated with high, mixed and low binding affinities, respectively. Here we report that [3H]-DPA-713 in the presence of cholesterol or PK11195 has an accelerated dissociation rate from TSPO in platelets isolated from individuals with the T/T genotype. This allosteric interaction was not observed in platelets isolated from individuals with the C/C or C/T genotype. The results provide a molecular rationale for low binding affinity of T/T TSPO and further support the exclusion of these subjects from PET imaging studies using second generation TSPO ligands.
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