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Challenges of quantification of TSPO in the human brain

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Abstract

The first positron emission tomography (PET) imaging studies in humans of the translocator protein 18 kDa (TSPO) were conducted in the 1980s with a primary interest in quantifying the binding in peripheral organs such as the heart, spleen and kidneys to what was then known as the peripheral benzodiazepine receptor. However, the number of studies rapidly increased when the focus of the research shifted to the brain, and [11C](R)-PK11195 became de facto the reference radiotracer for all in vivo TSPO binding assays. For the quantitative analysis of the data which initially was performed with compartmental models and plasma input functions, this led to the adoption of the reference tissue kinetic models which were developed at the same time in the mid 1990s. In contrast to many neuro-receptor studies of the dopaminergic or serotonergic system, it was not possible to anatomically define a brain region devoid of TSPO that could serve as a reference region. Instead, data-driven techniques were adopted that extracted at the voxel level reference tissue kinetics without incorporating anatomical information. In this review, an overview of the development, use and challenges of the various quantitative analysis methods for TSPO brain PET data is given. The different approaches to (automatically) extract reference tissue input curves from the dynamic images are discussed. Descriptions of key PET imaging studies exploring TSPO binding quantitatively in disease populations are included.

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Abbreviations

AD:

Alzheimer’s disease

B avail :

Density of sites available to bind radioligand in vivo

BBB:

Blood–brain barrier

BF:

Blood flow

BP:

Binding potential

BPF :

Binding potential relative to the free ligand concentration in plasma

BPND :

Binding potential relative to the non-displaceable binding in tissue

CBF:

Cerebral blood flow

CNS:

Central nervous system

CT:

Computed tomography

HAB:

High-affinity binder

HD:

Huntington’s disease

HPLC:

High-performance liquid chromatography

HHRT:

High Resolution Research Tomograph

INMiND:

Imaging of neuroinflammation in neurodegenerative diseases

K D :

Dissociation constant

LAB:

Low-affinity binder

MAB:

Mixed affinity binder

MCI:

Mild cognitive impairment

MRI:

Magnetic resonance imaging

PET:

Positron emission tomography

PK11195:

1-(2-Chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinolinecarboxamide

PVE:

Partial volume effect

ROI:

Region of interest

SD:

Standard deviation

SPE:

Solid-phase extraction

SRTM:

Simplified reference tissue model

SRTMV:

Simplified reference tissue model with vascular component

SUV:

Standard uptake value

SVCA4:

Supervised cluster analysis with four kinetic classes

SVCA6:

Supervised cluster analysis with six kinetic classes

TAC:

Time–activity curve

TLC:

Thin-layer chromatography

TSPO:

Translocator protein 18 kDa

V ND :

Non-displaceable volume of distribution

V T :

Total volume of distribution

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Acknowledgments

We gratefully acknowledge Christian Prenant and Gavin D. Brown for their explanations provided on the radiochemistry, David J. Brooks for the invitation to Århus and the stimulating discussions on [11C](R)-PK11195 data analysis there, Federico Roncaroli for his advice on neuropathological data and the European Union’s Seventh Framework Programme (FP7/2007-2013) for financial support under the Grant agreement HEALTH-F2-2011-278850 (Imaging of Neuroinflammation in Neurodegenerative Diseases) bringing the INMiND consortium together.

Authors’ contributions

R Hinz: Design and content planning of the article; literature search and review; manuscript writing, formatting and editing; correspondence with the editorial office. R Boellaard: Design and content planning of the article; literature search and review; manuscript writing and editing; data processing for the preparation of the figures.

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  1. Wolfson Molecular Imaging Centre, University of Manchester, Manchester, UK

    Rainer Hinz

  2. Department of Radiology and Nuclear Medicine, VU University Medical Center, Amsterdam, The Netherlands

    Ronald Boellaard

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  1. Rainer Hinz
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Correspondence to Rainer Hinz.

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All procedures performed in studies, with human participants, in which the authors were involved, were conducted in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants included in those studies.

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This review article does not contain studies with animals performed by any of the authors.

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Hinz, R., Boellaard, R. Challenges of quantification of TSPO in the human brain. Clin Transl Imaging 3, 403–416 (2015). https://doi.org/10.1007/s40336-015-0138-7

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