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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,
Language English Country United States
Document type Journal Article, Research Support, N.I.H., Extramural
Grant support
P30 MH075673
NIMH NIH HHS - United States
P01MH075673
NIH HHS - United States
UL1 TR001079
CTSA - International
NLK
ProQuest Central
from 2006-03-01 to 1 year ago
Medline Complete (EBSCOhost)
from 2010-03-01 to 1 year ago
Health & Medicine (ProQuest)
from 2006-03-01 to 1 year ago
- 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
[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.
References provided by Crossref.org
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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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