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

• Published in: Acta pharmaceutica Sinica. B Vol. 11; no. 2; pp. 373 - 393
• Main Authors: Zhang, Lingling, Hu, Kuan, Shao, Tuo, Hou, Lu, Zhang, Shaojuan, Ye, Weijian, Josephson, Lee, Meyer, Jeffrey H., Zhang, Ming-Rong, Vasdev, Neil, Wang, Jinghao, Xu, Hao, Wang, Lu, Liang, Steven H.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01-02-2021; Elsevier
• Subjects: CNS disorders; Microglial activation; Neuroinflammation; Positron emission tomography (PET); Review; TSPO; AMPA; BBB; ALS; MDD; dMCAO; RCYs; QA; TSPO; TBI; BPND; HSE; NAA/Cr; PBR; AD; BcTSPO; MS; PKA; IMM; fP; EP; PSP; OMM; MAB; PCA; TBAH; SUV; FTD; ROS; SUVR; CNS disorders; DLB; PRAX-1; SAH; PAP7; VT; RRMS; BMSC; CBD; MRI; SAR; ANT; CNS; Am; TLE; BP; CRAC; LPS; P2X7R; SA; SNL; PDD; d.c. RCYs; KA; MMSE; SNR; MSA; Microglial activation; Positron emission tomography (PET); HAB; Neuroinflammation; PpIX; p.i; MAO-B; LAB; n.d.c. RCYs; OCD; MCI; PD; VDAC; HD; PET; SCIDY; Am, molar activities; DLB, Lewy body dementias; RCYs, radiochemical yields; fP, plasma free fraction; MCI, mild cognitive impairment; SA, specific activity; PDD, PD dementia; SCIDY, spirocyclic iodonium ylide; SAR, structure–activity relationship; CRAC, cholesterol recognition amino acid consensus sequence; HSE, herpes simplex encephalitis; MAB, mixed-affinity binding; NAA/Cr, N-acetylaspartate/creatine; MMSE, mini-mental state examination; PAP7, RIa-associated protein; PBR, peripheral benzodiazepine receptor; SNL, selective neuronal loss; p.i., post-injection; HAB, high-affinity binding; OMM, outer mitochondrial membrane; PET, positron emission tomography; IMM, inner mitochondrial membrane; FTD, frontotemporal dementia; d.c. RCYs, decay-corrected radiochemical yields; MSA, multiple system atrophy; PD, Parkinson's disease; LAB, low-affinity binding; AD, Alzheimer's disease; TBI, traumatic brain injury; LPS, lipopolysaccharide; BPND, non-displaceable binding potential; BcTSPO, Bacillus cereus TSPO; PKA, protein kinase A; PpIX, protoporphyrin IX; KA, kainic acid; TSPO, translocator protein; VT, distribution volume; TBAH, tetrabutyl ammonium hydroxide; n.d.c. RCYs, non-decay-corrected radiochemical yields; TLE, temporal lobe epilepsy; P2X7R, purinergic receptor P2X7; ALS, amyotrophic lateral sclerosis; PRAX-1, PBR-associated protein 1; SUVR, standard uptake volume ratio; dMCAO, distal middle cerebral artery occlusion; BP, binding potential; VDAC, voltage-dependent anion channel; ANT, adenine nucleotide transporter; BMSC, bone marrow stromal cells; EP, epilepsy; ROS, reactive oxygen species; MDD, major depressive disorder; AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid; SUV, standard uptake volume; HD, Huntington's disease; QA, quinolinic acid; BBB, blood‒brain barrier; CBD, corticobasal degeneration; PCA, posterior cortical atrophy; MS, multiple sclerosis; MRI, magnetic resonance imaging; CNS, central nervous system; OCD, obsessive compulsive disorder; PSP, progressive supranuclear palsy; SAH, subarachnoid hemorrhage; MAO-B, monoamine oxidase B; SNR, signal to noise ratio; RRMS, relapsing remitting multiple sclerosis
• ISSN: 2211-3835; 2211-3843
• DOI: 10.1016/j.apsb.2020.08.006

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.
The 18 kDa translocator protein (TSPO) expression in the central nervous system is upregulated in response to glial cell activation. There is a great potential for the future application of TSPO radioligands as diagnostic and prognostic tools, as well as for assessing therapeutic interventions for neurologic diseases. [Display omitted]