The Low-Affinity Binding of Second Generation Radiotracers Targeting TSPO is Associated with a Unique Allosteric Binding Site
Language English Country United States Media print-electronic
Document type Journal Article, Research Support, N.I.H., Extramural
Grant support
P30 MH075673
NIMH NIH HHS - United States
R25 MH080661
NIMH NIH HHS - United States
UL1 TR001079
NCATS NIH HHS - United States
P01MH075673
NIH HHS - United States
PubMed
28875261
PubMed Central
PMC5790609
DOI
10.1007/s11481-017-9765-2
PII: 10.1007/s11481-017-9765-2
Knihovny.cz E-resources
- Keywords
- Allosteric modulation, Residence time, Translocator protein 18 KDa (TSPO),
- MeSH
- Genotype MeSH
- Humans MeSH
- Neuroimaging methods MeSH
- Positron-Emission Tomography methods MeSH
- Radiopharmaceuticals chemistry MeSH
- Receptors, GABA analysis chemistry genetics MeSH
- Binding Sites MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, N.I.H., Extramural MeSH
- Names of Substances
- Radiopharmaceuticals MeSH
- Receptors, GABA MeSH
- TSPO protein, human MeSH Browser
[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.
See more in PubMed
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