Abstract
The emission tomographic imaging of activated microglia in the brain moves into the focus of neuroscientific research with increasing recognition of contributions of early inflammatory processes to neurodegenerative, traumatic, cancerous and infectious diseases of the brain. Whereas the mitochondrial isoform of the 18 kDa translocator protein (TSPO1) has been the main cellular target for positron emission tomography (PET) of this type of cells for decades, alternative marker proteins in the plasma membrane of microglia challenge efforts in ligand development, recently. The present report includes PET approaches using the chemokine receptor CX3CR1 and the FR2 folate receptor in parallel to small molecule PET tracers available for in vivo visualization of the “classical” target TSPO1. It compares first and second generation of TSPO1 ligands as well as new compounds like the tetrahydrocarbazole [18F]GE-180 and the quinazoline [11C]ER176 presumed to reduce polymorphism-related inter-subject variations, with allosteric ligands for the chemokine receptor CX3CR1 and with radio labelled folate conjugates targeting the folate “cargo” receptor FR1 and the FR2 receptor characteristic for anti-inflammatory M2 microglia.
Highlights
One of the main targets investigated with positron emission tomography (PET) or SPECT in microglial cells has been for many years mitochondrial TSPO1, the former peripheral benzodiazepine binding sites (PBR) [27], overexpressed in activated microglia
The target preferred in clinical investigations remains, currently, the well-known mitochondrial TSPO1
Overexpression of translocator protein (TSPO) in brain tissue subjected to inflammatory diseases has been confirmed by postmortem studies [93] as well as in animal experiments
Summary
The imaging of microglia as a marker of inflammation in traumatic, degenerative, neuropsychiatric and infectious brain diseases has been already for years a. One of the main targets investigated with PET or SPECT in microglial cells has been for many years mitochondrial TSPO1 (translocator protein 18 kDa), the former peripheral benzodiazepine binding sites (PBR) [27], overexpressed in activated microglia. Potency as biomarkers of microglia and imaging targets promise the integrins CD18 and CD68 [37] [44], the chemokine receptor CX3CR1 [45] [46] [47], and the folate receptor subtype FR2 [48] The latter two membrane receptors and their expression in the brain gained rising attention by the PET community during the last decade. The present study regards the current availability of small-molecule TSPO1 ligands, their clinical advantages and disadvantages as well as the present experiences with CX3CR1 ligands and FR2 substrates as potential PET tracers for brain imaging
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