The methodology of TSPO imaging with positron emission tomography
Open accessAbstract
The 18-kDA translocator protein (TSPO) is consistently elevated in activated microglia of the central nervous system (CNS) in response to a variety of insults as well as neurodegenerative and psychiatric conditions. It is therefore a target of interest for molecular strategies aimed at imaging neuroinflammation in vivo. For more than 20 years, positron emission tomography (PET) has allowed the imaging of TSPO density in brain using [11C]-(R)-PK11195, a radiolabelled-specific antagonist of the TSPO that has demonstrated microglial activation in a large number pathological cohorts. The significant clinical interest in brain immunity as a primary or comorbid factor in illness has sparked great interest in the TSPO as a biomarker and a surprising number of second generation TSPO radiotracers have been developed aimed at improving the quality of TSPO imaging through novel radioligands with higher affinity. However, such major investment has not yet resulted in the expected improvement in image quality. We here review the main methodological aspects of TSPO PET imaging with particular attention to TSPO genetics, cellular heterogeneity of TSPO in brain tissue and TSPO distribution in blood and plasma that need to be considered in the quantification of PET data to avoid spurious results as well as ineffective development and use of these radiotracers.
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[11C]PK11195 is a TSPO PET tracer still routinely used in clinical imaging but has a poor signal-to-noise ratio due to low binding affinity.
“One of the earliest TSPO PET tracers is [11C]PK11195, still routinely used in clinical imaging but hampered by the poor signal-to-noise ratio arising from its low binding affinity [16, 17].”
From Pharmacological modulation of TSPO in microglia/macrophages and neurons in a chronic neurodegenerative model of prion disease (2023) · cites this paper as [16]
The section on [11C]-(R)-PK11195 calls it the radiotracer of choice for imaging neuroinflammation in vivo. The second-generation radioligands section says newer tracers were developed to improve its signal-to-noise properties, but does not establish that low binding affinity causes the poorer signal-to-noise ratio; it describes PK11195 as having nanomolar affinity. (LLM, conf=0.86)
Experimental — accuracy not yet measuredDiscrepancies in TSPO PET findings have been attributed to difference in ligand types, off-target binding, uneven distribution of the radioactive ligand in the brain parenchyma, and tissue-dependent differences in ligand affinity.
“These discrepancies have been attributed to the difference in ligand types, off-target binding (such as the vascular endothelial cells), uneven distribution of the radioactive ligand in the brain parenchyma, and tissue-dependent differences in ligand affinity (Suridjan et al, 2014;Turkheimer et al, 2015).”
From Microglia Priming with Aging and Stress (2017) · cites this paper as Turkheimer et al, 2015
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- Authors
- Turkheimer, F. E., Rizzo, G., Bloomfield, P. S., Howes, O., Zanotti-Fregonara, P., Bertoldo, A., & Veronese, M.
- Affiliations
- King's College London (GB)
- University of Padua (IT)
- Imperial College London (GB)
- University of Bordeaux, CNRS, INCIA, UMR 5287, France
- Corresponding author
- Howes, Oliver
- Veronese, Mattia
- ORCID
- Venue
- Biochemical Society Transactions
- Publisher
- Portland Press Ltd.
- Published
- 2015-08-01
- Volume
- 43
- Issue
- 4
- Pages
- 586-592
- ISSN
- 0300-5127 (ISSN-L)
- 1470-8752
- PMC
- PMC4613512
- OpenAlex
- W2121010289
- Cited by
- 238
- References
- 44
- Citations by year
- 2026: 12 · 2025: 15 · 2024: 17 · 2023: 13 · 2022: 14 · 2021: 32 · 2020: 21 · 2019: 31 · 2018: 27 · 2017: 37 · 2016: 16 · 2015: 3
- FWCI
- 2.17
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Biochemical Society Transactions (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Research Portal (King's College London) (submittedVersion)
- Padua Research Archive (University of Padova) (submittedVersion)
- Funders
- Wellcome Trust
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Medical Imaging Techniques and Applications
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Radiopharmaceutical Chemistry and Applications
- Keywords
- translocator protein (TSPO), TSPO PET imaging, microglial activation, neuroinflammation, [11C]PK11195, PET quantification, brain immunity, neurodegenerative diseases, mental illness
- MeSH terms
- Humans, Isoquinolines, Microglia, Receptors, GABA, Positron-Emission Tomography
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