- Open Access
Current paradigm of the 18-kDa translocator protein (TSPO) as a molecular target for PET imaging in neuroinflammation and neurodegenerative diseases
© European Society of Radiology 2011
- Received: 4 May 2011
- Accepted: 9 September 2011
- Published: 16 October 2011
Neuroinflammation is a process characterised by drastic changes in microglial morphology and by marked upregulation of the 18-kDa translocator protein (TSPO) on the mitochondria. The continual increase in incidence of neuroinflammation and neurodegenerative diseases poses a major health issue in many countries, requiring more innovative diagnostic and monitoring tools. TSPO expression may constitute a biomarker for brain inflammation that could be monitored by using TSPO tracers as neuroimaging agents. From medical imaging perspectives, this review focuses on the current concepts related to the TSPO, and discusses briefly on the status of its PET imaging related to neuroinflammation and neurodegenerative diseases in humans.
- Translocator protein
- Neurodegenerative diseases
- Microglial activation
- PET ligands
Medical imaging—from morphome to molecules
The current trend of new medical imaging scanner design and development is based on multimodel and multiparametric approaches. Indeed PET and its hybrid imaging modalities PET/CT, and before long magnetic resonance imaging (MRI)/PET, are changing the way we practice medicine. To date, PET/CT is currently a diagnostic imaging technique used in many hospitals worldwide to provide services for patients, especially in the fields of oncology, neuroscience and cardiology . In spite of the recent advances of molecular and imaging techniques, there is still a gap between basic biomedical research and its clinical applications. Nowadays clinical PET tracer still mainly refers to the commercially available 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG). The impact of PET and its hybrid systems to medicine is limited by the worldwide shortage of radiochemistry facilities to produce novel PET tracers to detect various pathophysiological mechanisms or to specify diagnosis or even theranostics of neurodegenerative diseases.
With the launching of new hybrid imaging systems like MRI/PET, radiologists will expect to play an even more active role in directing development of the rapidly evolving field of medical imaging. Although not all practicing radiologists will engage in the field of research and sciences, it is worthwhile that they keep abreast of recent development of PET tracers in the areas as diverse as oncology, cardiology, metabolic diseases and neurology. In this tutorial article, we review the current concepts related to the pathophysiology of neuroinflammation and neurodegenerative diseases and give a glance on the status of PET imaging of 18-kDa translocator protein (TSPO) tracers in neuroinflammation of the living brain, with the aim of providing a basis for future discussions on the development of TSPO tracers for the diagnosis and therapy of neurodegenerative diseases.
Comparison of radionuclide imaging and MRI as molecular imaging systems 
Spatial resolution (mm)
Minimal amount of tracer (or contrast agent) used
μg to mg
Microglia are the critical convergence point for the many diverse triggers in orchestrating the activity of other immune cells in the brain . These cells are derived from the monocytic lineage display high sensitivity to different types of CNS injury . During neuroinflammation, microglia undergo drastic changes in their morphology, migrate towards the lesion site, proliferate, and produce neurotoxic factors such as proinflammatory cytokines and reactive oxygen species. Stroke, hypoxia, and trauma compromise neuronal survival and indirectly trigger neuroinflammation as microglia become activated in response to insult in an attempt to limit further injury. A mild autoimmune reaction with microglial activation can have neuroprotective function after CNS injury . An acute insult may trigger oxidative and nitrosative stress, it is typically short lived and unlikely to be detrimental to long-term neuronal survival. On the contrary, chronic neuroinflammation is a longstanding and often self-perpetuating response that persists long after an initial injury or insult. It includes not only longstanding activation of microglia but also subsequent release of inflammatory factors. In chronic inflammation, immune response can be full-blown, including the activation of microglia, and damage the brain tissues by autoimmunogens . That means activated microglia can be either friends or foes to neighbouring neurons. It is not yet clear how to manipulate them to minimise their damaging effects.
PK11195 [1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinoline carboxamide] is the first non-benzodiazepine and selective TSPO ligand labelled with carbon-11. It was discovered in 1984 and named by a French company, Pharmuka . It remains most widely used in TSPO PET imaging with nanomolar binding affinity and it is the prototypical reference . [11C]PK11195 has been used in many human CNS studies, including Rasmussen’s encephalitis, MS, AD, PD, amyotrophic lateral sclerosis, HD, HIV, herpes encephalitis, and neuropsychiatric disorders such as schizophrenia . Studies found increased binding of [11C]PK11195 in corresponding MR regions of focal gadolinium-enhanced lesions and normal-appearing white matter (NAWM) in MS patients . Brain atrophy, correlating with disease duration and disability of MS is directly related to [11C]PK11195 uptake, NAWM and inflammatory-related T2 hyperintense lesions [20, 21]. A study also showed an increase in brain uptake of [11C]PK11195 in MS patients during acute relapse . Taken together, these studies suggest that microglial activation is of central importance in the pathophysiology of MS and can be visualised with PET using TSPO tracers.
In cerebral infarction, [11C]PK11195 is a useful tool to investigate acute neuroinflammatory changes related to cerebral infarct and could be beneficial in the evaluation of neuroprotective regimens related to microglial deregulation . Aβ is known as a pathological substance in AD and is assumed to coexist with a degree of activated microglia in the brain. A few studies showed in vivo microglial activation in the brain of patients with mild to moderate AD using PET with [11C]PK11195, but the role is limited in severe AD [12, 23]. Increased microglial activation has been observed in patients with HD and presymptomatic carriers by [11C]PK11195 PET imaging . In HD, the degree of microglial activation in the striatum has been found to correlate with D2 receptor dysfunction using PET with [11C]raclopride . More recent studies suggest neuroinflammation might have a crucial role in neuropsychiatric disorders such as schizophrenia [26, 27]. Although there was large individual variation in humans, binding of [11C]PK11195 was increased in brain areas corresponding to different pathological processes in ongoing or recent clinical deficits. TSPO imaging with PET might provide insight into the process beyond the realm of traditional neuroimaging techniques.
Although it is well established that [11C]PK11195 shows increased uptake in a wide array of neurodegenerative disorders, it suffers from unresolved methodological and kinetic issues. There is low sensitivity and a limited capacity to quantify subtle TSPO expression in vivo. Relatively low receptor affinity could lead to low binding potential, which results from substantial binding of the tracer to other parts of the body. It suffers from high plasma protein binding and high non-specific binding likely related to high lipophilicity. The more lipophilic molecule is undesirable not only for slowing passive brain entry but also for increasing high non-specific binding to brain fats and protein. Relatively poor penetration of the blood brain barrier (BBB) and low brain uptake also lead to poor signal-to-noise ratio on PET imaging. Also, the lack of sensitivity and specificity and highly variable kinetic behaviour of [11C]PK11195 have precluded the development of a standard quantitative method of analysis [8, 14]. Without an on-site cyclotron facility, the short half-life of carbon-11 (t1/2 = 20.38 min) also limits PET imaging using [11C]PK11195 in routine clinical practice.
In the light of the limitations of [11C]PK11195, many groups worldwide are actively engaged in a search for new radiotracers with improved capacities to image and quantify TSPO expression. In the literature, a number of excellent comprehensive reviews have been published on TSPO imaging [8, 9, 14, 16, 28]. Schweitzer et al.  and Rupprecht et al.  offer more details on the updated trend of TSPO radiotracers development.
Examples of new potential PET tracers for TSPO imaging in clinical studies
AD, ALS, FTD, MS, CI
MS, healthy subjects
Match known patterns of TSPO distribution a
Good agreement of pattern in TSPO distribution a
Match known patterns of TSPO distribution a
Potentially higher binding affinity than PK11195 a
Potentially higher binding potential in brain 
There is accumulating evidence that neuroinflammation plays a crucial role in the development and progression of many neurodegenerative disorders such as MS, AD and HD. Collateral neuronal damage is clearly inherent to primary neuroinflammation, and neuroinflammation is a likely sequel of primary neurodegenerative diseases. It is important to understand the mechanisms that initiate neuroinflammation and neurodegeneration. Many questions remain regarding the use of TSPO tracers as diagnostic tools to assess activation of microglia. Overexpressed TSPO constitutes an important target for the detection or novel treatment of neuroinflammation and neurodegenerative disorders. The concept of multiple TSPO binding sites, variable conformational states of the protein and mixed binding affinity in living brain needs to be addressed when developing new PET TSPO radiotracers. Provided the broad spectrum of putative applications of TSPO ligands, further studies are eagerly awaited. With further development of potential tracers by better understanding of the protean nature of the receptor in healthy and diseased brain, PET imaging of the TSPO could offer a non-invasive modality for early diagnosis and theranostics of CNS diseases in ways beyond the scope of conventional imaging techniques.
This work was supported by the FP6 European Networks of Excellence EMIL (LSHC-CT-2004-503569) and DIMI (LSHB-CT2005-5121146), and the STREP RATstream, (LSHM-CT-2007-037846).
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