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      The 18-kDa Translocator Protein PET Tracers as a Diagnostic Marker for Neuroinflammation: Development and Current Standing

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          Abstract

          Translocator protein (TSPO, 18 kDa) is an evolutionary, well-preserved, and tryptophan-rich 169-amino-acid protein which localizes on the contact sites between the outer and inner mitochondrial membranes of steroid-synthesizing cells. This mitochondrial protein is implicated in an extensive range of cellular activities, including steroid synthesis, cholesterol transport, apoptosis, mitochondrial respiration, and cell proliferation. The upregulation of TSPO is well documented in diverse disease conditions including neuroinflammation, cancer, brain injury, and inflammation in peripheral organs. On the basis of these outcomes, TSPO has been assumed to be a fascinating subcellular target for early stage imaging of the diseased state and for therapeutic purposes. The main outline of this Review is to give an update on dealing with the advances made in TSPO PET tracers for neuroinflammation, synchronously emphasizing the approaches applied for the design and advancement of new tracers with reference to their structure–activity relationship (SAR).

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          Translocator protein (18 kDa) (TSPO) as a therapeutic target for neurological and psychiatric disorders.

          Jinjiang Fan, Ghislaine Groyer, Michael Schumacher … (2010)
          The translocator protein (18 kDa) (TSPO) is localized primarily in the outer mitochondrial membrane of steroid-synthesizing cells, including those in the central and peripheral nervous system. One of its main functions is the transport of the substrate cholesterol into mitochondria, a prerequisite for steroid synthesis. TSPO expression may constitute a biomarker of brain inflammation and reactive gliosis that could be monitored by using TSPO ligands as neuroimaging agents. Moreover, initial clinical trials have indicated that TSPO ligands might be valuable in the treatment of neurological and psychiatric disorders. This Review focuses on the biology and pathophysiology of TSPO and the potential of currently available TSPO ligands for the diagnosis and treatment of neurological and psychiatric disorders.
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            Mixed-affinity binding in humans with 18-kDa translocator protein ligands.

            David R J Owen, Leanna P. Matthews, Masahiro Fujita … (2010)
            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. 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. 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. 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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              An 18-kDa Translocator Protein (TSPO) polymorphism explains differences in binding affinity of the PET radioligand PBR28

              David R J Owen, Astrid Yeo, Roger Gunn … (2011)
              [11C]PBR28 binds the 18-kDa Translocator Protein (TSPO) and is used in positron emission tomography (PET) to detect microglial activation. However, quantitative interpretations of signal are confounded by large interindividual variability in binding affinity, which displays a trimodal distribution compatible with a codominant genetic trait. Here, we tested directly for an underlying genetic mechanism to explain this. Binding affinity of PBR28 was measured in platelets isolated from 41 human subjects and tested for association with polymorphisms in TSPO and genes encoding other proteins in the TSPO complex. Complete agreement was observed between the TSPO Ala147Thr genotype and PBR28 binding affinity phenotype (P value=3.1 × 10−13). The TSPO Ala147Thr polymorphism predicts PBR28 binding affinity in human platelets. As all second-generation TSPO PET radioligands tested hitherto display a trimodal distribution in binding affinity analogous to PBR28, testing for this polymorphism may allow quantitative interpretation of TSPO PET studies with these radioligands.
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                Author and article information

                Journal
                Journal ID (nlm-ta): ACS Omega
                Journal ID (iso-abbrev): ACS Omega
                Journal ID (publisher-id): ao
                Journal ID (coden): acsodf
                Title: ACS Omega
                Publisher: American Chemical Society
                ISSN (Electronic): 2470-1343
                Publication date (Electronic): 18 April 2022
                Publication date Collection: 03 May 2022
                Volume: 7
                Issue: 17
                Pages: 14412-14429
                Affiliations
                [† ]Department of Chemistry, Babasaheb Bhimrao Ambedkar University (A Central University) , Lucknow, 226025, Uttar Pradesh, India
                Author notes
                [* ]Address: Department of Chemistry, Babasaheb Bhimrao Ambedkar University, Lucknow, Uttar Pradesh. Tel.: +91-7503381343. Fax: +91-522-2440821. E-mail: anjanik2003@ 123456gmail.com .
                Author information
                https://orcid.org/0000-0001-6271-3055
                Article
                DOI: 10.1021/acsomega.2c00588
                PMC ID: 9089361
                PubMed ID: 35557664
                SO-VID: 36acac1a-bd27-4931-a09d-5acbba89a171
                Copyright © © 2022 The Authors. Published by American Chemical Society
                License:

                Permits non-commercial access and re-use, provided that author attribution and integrity are maintained; but does not permit creation of adaptations or other derivative works ( https://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                Date received : 28 January 2022
                Date accepted : 05 April 2022
                Funding
                Funded by: Department of Biotechnology , Ministry of Science and Technology, doi 10.13039/501100001407;
                Award ID: BT/PR29449/NNT/28/1572/2018
                Categories
                Subject: Review
                Custom metadata
                document-id-old-9 ao2c00588
                document-id-new-14 ao2c00588
                ccc-price

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