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The Low-Affinity Binding of Second Generation Radiotracers Targeting TSPO is Associated with a Unique Allosteric Binding Site

. 2018 Mar ; 13 (1) : 1-5. [epub] 20170905

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

Links

PubMed 28875261
PubMed Central PMC5790609
DOI 10.1007/s11481-017-9765-2
PII: 10.1007/s11481-017-9765-2
Knihovny.cz E-resources

[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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