Recent developments on PET radiotracers for TSPO and their applications in neuroimaging

• Type of Material: Article
• Authors: Lingling Zhang, First Affiliated Hospital of Jinan University; Kuan Hu, National Institute of Radiological Sciences Chiba; Tuo Shao, Harvard Medical School; Lu Hou, First Affiliated Hospital of Jinan University; Shaojuan Zhang, First Affiliated Hospital of Jinan University; Weijian Ye, First Affiliated Hospital of Jinan University; Lee Josephson, Harvard Medical School; Jeffrey H. Meyer, University of Toronto; Ming-Rong Zhang, National Institute of Radiological Sciences Chiba; Neil Vasdev, Harvard Medical School; Jinghao Wang, First Affiliated Hospital of Jinan University; Hao Xu, First Affiliated Hospital of Jinan University; Lu Wang, First Affiliated Hospital of Jinan University; Steven Huan Liang, Emory University
• Language: English
• Date: 2021-02-01
• Publisher: Elsevier
• Publication Version: Final Published Version
• Copyright Statement: © 2021 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.apsb.2020.08.006
• Title of Journal or Parent Work: Acta Pharmaceutica Sinica B
• Volume: 11
• Issue: 2
• Start Page: 373
• End Page: 393
• Grant/Funding Information: Wong Education Foundation (China), and the Project of Innovative Team for the Guangdong Universities (2018KCXTD001, China). This work was financially supported by the National Natural Science Foundation of China (Nos. 81701751 and 81871383) and Guangdong Basic and Applied Basic Research Foundation (2020A1515011192, China).
• Keywords: OMM, outer mitochondrial membrane; ROS, reactive oxygen species; Neuroinflammation; OCD, obsessive compulsive disorder; RRMS, relapsing remitting multiple sclerosis; PSP, progressive supranuclear palsy; MDD, major depressive disorder; Positron emission tomography (PET); EP, epilepsy; CNS, central nervous system; MAO-B, monoamine oxidase B; BMSC, bone marrow stromal cells; PCA, posterior cortical atrophy; VDAC, voltage-dependent anion channel; NAA/Cr, N-acetylaspartate/creatine; TBI, traumatic brain injury; Am, molar activities; CNS disorders; KA, kainic acid; TSPO, translocator protein; SUV, standard uptake volume; MAB, mixed-affinity binding; PRAX-1, PBR-associated protein 1; MRI, magnetic resonance imaging; BcTSPO, Bacillus cereus TSPO; MMSE, mini-mental state examination; TBAH, tetrabutyl ammonium hydroxide; p.i., post-injection; SCIDY, spirocyclic iodonium ylide; PET, positron emission tomography; P2X7R, purinergic receptor P2X7; FTD, frontotemporal dementia; d.c. RCYs, decay-corrected radiochemical yields; PpIX, protoporphyrin IX; MCI, mild cognitive impairment; HD, Huntington's disease; PDD, PD dementia; SNR, signal to noise ratio; SUVR, standard uptake volume ratio; DLB, Lewy body dementias; BP, binding potential; TLE, temporal lobe epilepsy; BPND, non-displaceable binding potential; dMCAO, distal middle cerebral artery occlusion; CRAC, cholesterol recognition amino acid consensus sequence; PD, Parkinson's disease; LPS, lipopolysaccharide; BBB, blood‒brain barrier; SAR, structure–activity relationship; fP, plasma free fraction; RCYs, radiochemical yields; PAP7, RIa-associated protein; AD, Alzheimer's disease; Microglial activation; PKA, protein kinase A; n.d.c. RCYs, non-decay-corrected radiochemical yields; HSE, herpes simplex encephalitis; SAH, subarachnoid hemorrhage; VT, distribution volume; AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid; QA, quinolinic acid; LAB, low-affinity binding; MSA, multiple system atrophy; IMM, inner mitochondrial membrane; SNL, selective neuronal loss; ANT, adenine nucleotide transporter; ALS, amyotrophic lateral sclerosis; CBD, corticobasal degeneration; SA, specific activity; TSPO; HAB, high-affinity binding; PBR, peripheral benzodiazepine receptor; MS, multiple sclerosis
• Research Categories: Biology, Cell; Biology, Neuroscience; Chemistry, Biochemistry

Abstract

The 18 kDa translocator protein (TSPO), previously known as the peripheral benzodiazepine receptor, is predominately localized to the outer mitochondrial membrane in steroidogenic cells. Brain TSPO expression is relatively low under physiological conditions, but is upregulated in response to glial cell activation. As the primary index of neuroinflammation, TSPO is implicated in the pathogenesis and progression of numerous neuropsychiatric disorders and neurodegenerative diseases, including Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), multiple sclerosis (MS), major depressive disorder (MDD) and obsessive compulsive disorder (OCD). In this context, numerous TSPO-targeted positron emission tomography (PET) tracers have been developed. Among them, several radioligands have advanced to clinical research studies. In this review, we will overview the recent development of TSPO PET tracers, focusing on the radioligand design, radioisotope labeling, pharmacokinetics, and PET imaging evaluation. Additionally, we will consider current limitations, as well as translational potential for future application of TSPO radiopharmaceuticals. This review aims to not only present the challenges in current TSPO PET imaging, but to also provide a new perspective on TSPO targeted PET tracer discovery efforts. Addressing these challenges will facilitate the translation of TSPO in clinical studies of neuroinflammation associated with central nervous system diseases.