Mixed-affinity binding in humans with 18-kDa translocator protein ligands - PubMed (original) (raw)

Mixed-affinity binding in humans with 18-kDa translocator protein ligands

David R J Owen et al. J Nucl Med. 2011 Jan.

Abstract

11C-PBR28 PET can detect the 18-kDa translocator protein (TSPO) expressed within macrophages. However, quantitative evaluation of the signal in brain tissue from donors with multiple sclerosis (MS) shows that PBR28 binds the TSPO with high affinity (binding affinity [Ki], ∼4 nM), low affinity (Ki, ∼200 nM), or mixed affinity (2 sites with Ki, ∼4 nM and ∼300 nM). Our study tested whether similar binding behavior could be detected in brain tissue from donors with no history of neurologic disease, with TSPO-binding PET ligands other than 11C-PBR28, for TSPO present in peripheral blood, and with human brain PET data acquired in vivo with 11C-PBR28.

Methods: The affinity of TSPO ligands was measured in the human brain postmortem from donors with a history of MS (n=13), donors without any history of neurologic disease (n=20), and in platelets from healthy volunteers (n=13). Binding potential estimates from thirty-five 11C-PBR28 PET scans from an independent sample of healthy volunteers were analyzed using a gaussian mixture model.

Results: Three binding affinity patterns were found in brains from subjects without neurologic disease in similar proportions to those reported previously from studies of MS brains. TSPO ligands showed substantial differences in affinity between subjects classified as high-affinity binders (HABs) and low-affinity binders (LABs). Differences in affinity between HABs and LABs are approximately 50-fold with PBR28, approximately 17-fold with PBR06, and approximately 4-fold with DAA1106, DPA713, and PBR111. Where differences in affinity between HABs and LABs were low (∼4-fold), distinct affinities were not resolvable in binding curves for mixed-affinity binders (MABs), which appeared to express 1 class of sites with an affinity approximately equal to the mean of those for HABs and LABs. Mixed-affinity binding was detected in platelets from an independent sample (HAB, 69%; MAB, 31%), although LABs were not detected. Analysis of 11C-PBR28 PET data was not inconsistent with the existence of distinct subpopulations of HABs, MABs, and LABs.

Conclusion: With the exception of 11C-PK11195, all TSPO PET ligands in current clinical application recognize HABs, LABs, and MABs in brain tissue in vitro. Knowledge of subjects' binding patterns will be required to accurately quantify TSPO expression in vivo using PET.

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Figures

FIGURE 1

FIGURE 1

Competition assay with 3H-PK11195 and unlabeled PBR28, using tissue from donors with no history of neurologic disease. Each data point represents mean value of all subjects, and error bars represent SEM. Conc = concentration.

FIGURE 2

FIGURE 2

Competition assays with 3H-PK11195 and unlabeled TSPO ligand using brain tissue previously characterized as HAB, LAB, or MAB by PBR28 assays. Each data point represents mean value of at least 4 subjects, and error bars represent SEM. (A) Phenoxyphenyl acetamide derivatives. (B) Bicyclic linker derivatives. (C) Phenyl–isoquinolinecarboxamide derivatives. Conc = concentration; SB = specific binding.

FIGURE 3

FIGURE 3

Competition assays with 3H-PK11195 and unlabeled PBR111 in presence or absence of PBR28 (50 nM).

FIGURE 4

FIGURE 4

11C- PBR28 PET data from 32 healthy volunteers expressed as histogram with mixture model analysis showing 2 distributions for each measurement. (A) Volume of distribution. (B) Plasma free fraction. (C) Volume of distribution/plasma free fraction. Blue curves denote single-component solutions, and green and black curves denote 2-component solutions. For 2-component solutions, whereas different individuals are within each gaussian group (e.g., green) for 3 parameters, there was good agreement between A and B (74%) and A and C (66%).

FIGURE 5

FIGURE 5

TSPO ligands displayed in structural classes.

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