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

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.

Keywords: AD, Alzheimer's disease; ALS, amyotrophic lateral sclerosis; AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid; ANT, adenine nucleotide transporter; Am, molar activities; BBB, blood‒brain barrier; BMSC, bone marrow stromal cells; BP, binding potential; BPND, non-displaceable binding potential; BcTSPO, Bacillus cereus TSPO; CBD, corticobasal degeneration; CNS disorders; CNS, central nervous system; CRAC, cholesterol recognition amino acid consensus sequence; DLB, Lewy body dementias; EP, epilepsy; FTD, frontotemporal dementia; HAB, high-affinity binding; HD, Huntington's disease; HSE, herpes simplex encephalitis; IMM, inner mitochondrial membrane; KA, kainic acid; LAB, low-affinity binding; LPS, lipopolysaccharide; MAB, mixed-affinity binding; MAO-B, monoamine oxidase B; MCI, mild cognitive impairment; MDD, major depressive disorder; MMSE, mini-mental state examination; MRI, magnetic resonance imaging; MS, multiple sclerosis; MSA, multiple system atrophy; Microglial activation; NAA/Cr, N-acetylaspartate/creatine; Neuroinflammation; OCD, obsessive compulsive disorder; OMM, outer mitochondrial membrane; P2X7R, purinergic receptor P2X7; PAP7, RIa-associated protein; PBR, peripheral benzodiazepine receptor; PCA, posterior cortical atrophy; PD, Parkinson's disease; PDD, PD dementia; PET, positron emission tomography; PKA, protein kinase A; PRAX-1, PBR-associated protein 1; PSP, progressive supranuclear palsy; Positron emission tomography (PET); PpIX, protoporphyrin IX; QA, quinolinic acid; RCYs, radiochemical yields; ROS, reactive oxygen species; RRMS, relapsing remitting multiple sclerosis; SA, specific activity; SAH, subarachnoid hemorrhage; SAR, structure–activity relationship; SCIDY, spirocyclic iodonium ylide; SNL, selective neuronal loss; SNR, signal to noise ratio; SUV, standard uptake volume; SUVR, standard uptake volume ratio; TBAH, tetrabutyl ammonium hydroxide; TBI, traumatic brain injury; TLE, temporal lobe epilepsy; TSPO; TSPO, translocator protein; VDAC, voltage-dependent anion channel; VT, distribution volume; d.c. RCYs, decay-corrected radiochemical yields; dMCAO, distal middle cerebral artery occlusion; fP, plasma free fraction; n.d.c. RCYs, non-decay-corrected radiochemical yields; p.i., post-injection.

Graphical abstract

Figure 1

TSPO structure and function. TSPO is mainly expressed in the OMM with five transmembrane alpha helix domains. The topology of TSPO in the membrane is amplified, with amino acids involved in the binding site of PK11195 highlighted. The PK11195 binding site includes the residues R24, E29, L31, L37, P40, S41, W42, W107 and W161. TSPO generally functions as a monomer, but can also form compounds with itself or other proteins, such as VDAC and ANT. Furthermore, PBR-associated protein 1 (PRAX-1), and PBR and protein kinase A (PKA) regulatory subunit RIa-associated protein (PAP7) are correlated with TSPO. PRAX-1 and PAP7 could also promote compound formation or cholesterol targeting to TSPO. TSPO has four dominating functions: (1) binding and transporting cholesterol, a critical function in neurosteroid synthesis and bile salt biosynthesis; (2) protein transport for membrane biosynthesis and other important physiological functions including cell proliferation, differentiation, and apoptosis; (3) binding and importing porphyrin for heme biosynthesis; and (4) adjusting mitochondrial functions.

Figure 2

TSPO radioligands with novel chemical structures.

Figure 3

Chemical structures of new TSPO radioligands with insensitivity to rs6971.