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

Abstract

[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.

• Authors: Camilo Rojas, Marigo Stathis, Jennifer M Coughlin, Martin Pomper, Barbara S Slusher
• Journal: Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology (J Neuroimmune Pharmacol) Vol. 13 Issue 1 Pg. 1-5 (03 2018) ISSN: 1557-1904 [Electronic] United States
• PMID: 28875261 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Radiopharmaceuticals
• Receptors, GABA
• TSPO protein, human

Topics

• Binding Sites
• Genotype
• Humans
• Neuroimaging (methods)
• Positron-Emission Tomography (methods)
• Radiopharmaceuticals (chemistry)
• Receptors, GABA (analysis, chemistry, genetics)