Acetamidobenzoxazolone scaffold as a promising translocator protein (18 kDa, TSPO) marker for neuroinflammation imaging: Advancement in last decennial period

Abstract

Inflammation has been linked to the onset and progression of a wide range of neuropathological disorders. The well-conserved outer mitochondrial membrane 18 kDa translocator protein (TSPO) is perceived as an in vivo neuroinflammation marker. A dearth of a reference region, genetic disparity influencing the ligand's affinity for TSPO, and a substantial signal in the endothelium of the brain veins contributes toward complications in quantifying TSPO positron emission tomography (PET) image. Up to the present time several radiotracers based on different pharmacophore such as (R)[ 11 C]PK11195, [ 18 F]DPA714, [ 11 C]PBR28, [ 11 C]ER176, and many more have been recognized for envisaging the prominent TSPO level observed in neurological conditions. Recently acetamidobenzoxazolone (ABO) scaffold, a bicyclic ring system composed of a phenyl ring fused to a carbamate and its substituted radiolabelled analogues especially at C-5 position has evidenced encouraging outcomes as next generation of TSPO PET ligands. Diverse ABO framework-based TSPO ligands have been designed embracing imperative aspects such as lipophilicity, metabolic profile, and capability to penetrate the blood-brain barrier apart from least effect of polymorphism (rs6971). Over the years numerous systematic literature reviews compiling different structural class of TSPO ligands characterized on the grounds of their binding affinity and metabolite profile have been reported but none is especially focused toward a fascinating benzoxazolone scaffold. This review exclusively bestows an overview of the recent advancements on ABO derivatives with neuroinflammation imaging potential and emphases on the structural features accountable for visualizing TSPO in-vivo with collation of published reports during last 10 years.

Evaluation of advanced, pathophysiologic new targets for imaging of CNS

“…The effective first‐generation tracers for TSPO is [ 11 C]PK11195 and has been utilized extensively in preclinical and clinical research but still suffers from number of significant drawbacks such as limited BBB permeability and strong nonselective plasma binding, which result in low signal‐to‐noise ratios in the resulting reconstructed PET pictures. Later, some second‐generation tracers, such as [ 11 C]DAA1106, [ 11 C]PBR28, [ 18 F]FEPPA, [ 11 C]PBR06, [ 18 F]DPA‐714, [ 11 C]AC5216, [ 18 F]F‐DPA, and [ 11 C]MBMP were designed to get over [ 11 C]PK11195's restrictions (Adhikari et al, 2021, 2022). However, these TSPO tracers have different binding potencies in the human brain depending on rs6971 polymorphisms, which creates greater subject variability.…”

Comparison of PIC and EDTA-coupled acetamidobenzoxazolone probes as a specific marker for a 18 kDa protein (TSPO)

“…[22][23][24][25][26][27][28][29][30][31][32][33][34][35][36] Development of diagnostic markers for TSPO to study its role in immunomodulatory actions of the body, is one of the most critical issues of biomedical imaging. [37][38][39][40][41][42] Thus, in the last few decades, attempts have been taken to develop a novel diagnostic tool for locating neuroinflammation and even to monitor the injury level or the recovery level after treatment.…”