Translocator protein (TSPO) ligands for the diagnosis or treatment of neurodegenerative diseases: a patent review (2010 – 2015; part 2)

ABSTRACT

Introduction: The 18-kDa translocator protein (TSPO) has been highlighted as a potential drug target in diverse neurodegenerative diseases because the up-regulation of TSPO in the CNS is related to neuroinflammation. Diverse TSPO ligands are currently in clinical trials or are under development at the preclinical stage for the treatment and/or diagnosis of neurodegenerative processes. These TSPO ligands may shed light on novel therapeutics for neurodegenerative diseases in the near future.

Areas covered: This review describes TSPO ligands that have been patented from 2010 to 2015. Numerous indole-derived TSPO ligands will be analyzed on the basis of their TSPO affinities. Furthermore, cholesterol-like compounds and miscellaneous TSPO ligands will be summarized along with their pharmaceutical uses.

Expert opinion: Diverse TSPO ligands have demonstrated their biological efficacies in experimental models of neurodegenerative diseases, and some of them are now in clinical trials. The indole-derived TSPO ligands can be highlighted as efficient diagnostic agents because they have high selectivity and affinity for TSPO. Moreover, one potent cholesterol-like TSPO ligand has been described as a neuroprotective compound. Therefore, additional preclinical and clinical studies for highly potent TSPO ligands are recommended for the successful pharmacological application of TSPO ligands.

KEYWORDS:

• TSPO
• PBR
• neurodegenerative disease
• neuroinflammation
• FGIN-1-27
• SSR180575
• TRO19622
• GE-180

Article highlights

• An indole-based core structure could be a promising feature for neuroprotective TSPO ligands.

• Structural modifications to indole-based TSPO ligands may represent a method to overcome the issue of mixed binding affinity.

• Based on their remarkable neuroprotective effects, several TSPO ligands are now in clinical trials for the treatment of neurodegenerative diseases in elderly populations.

• Radioactive isotope-labeled TSPO ligands efficiently quantify up-regulated TSPO in neuro-inflammatory regions; therefore, several radioactive TSPO ligands are in clinical trials as PET imaging agents.

• Compounds targeting the CRAC domain of TSPO have therapeutic potential for neurodegenerative diseases.

This box summarizes the key points contained in the article.

Declaration of interest

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

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Funding

This work was supported by the National Research Council of Science & Technology (NST) grant by the Korea government (MSIP) (No. CRC-15-04-KIST, 2N41660). This work was also supported by Korea Institute of Science and Technology (Grant: 2E26650).