Modified benzoxazolone derivative as 18‐kDa TSPO ligand

Abstract

We have synthesized six new congeners of acetamidobenzoxazolone for Translocator Protein [18 kDa, TSPO] imaging. The best in vitro binding affinity (10.8 ± 1.2 nm) for TSPO was found for N-methyl-2-(5-(naphthalen-1-yl)-2-oxobenzo[d]oxazol-3(2H)-yl)-N-phenylacetamide, (NBMP). NBMP was synthesised by Suzuki coupling reaction between 2-(5-bromo-2-oxo-1,3-benzoxazol-3(2H)-yl)-N-phenylacetamide and napthalene-1-boronic acid. Computational docking and simulation studies showed not much impact of intersubject variability on binding which is one of the major drawbacks of several TSPO ligands. These findings suggested that NBMP may become a promising marker for visualization of neuroinflammation via TSPO targeting.

The 18-kDa Translocator Protein PET Tracers as a Diagnostic Marker for Neuroinflammation: Development and Current Standing

“…111 The main advantage with NBMP is its facile synthesis by the reaction among 2-(5-bromo-2-oxo-1,3-benzoxazol-3(2H)-yl)-N-phenylacetamide and napthalene-1-boronic acid through the Suzuki coupling reaction and better bioavailability, plasma clearance, and suitable metabolic strength in human and rat liver S-9 fractions. 111,112 Both radiotracers ([ 18 113 Some Major Drawbacks of Second Generation Tracers. Despite various efforts to prepare new TSPO PET tracers in clinical studies over past 25 years, several major restrictions are still associated with TSPO as a molecular biomarker of neuroinflammation.…”

“… 111 The main advantage with NBMP is its facile synthesis by the reaction among 2-(5-bromo-2-oxo-1,3-benzoxazol-3(2H)-yl)- N -phenylacetamide and napthalene-1-boronic acid through the Suzuki coupling reaction and better bioavailability, plasma clearance, and suitable metabolic strength in human and rat liver S-9 fractions. 111 , 112 Both radiotracers ([ 18 F]FEBMP and [ 18 F]FPBMP) have lower lipophilicity compared with reference compound [ 11 C]PK11195, suggesting effective initial brain accumulation for [ 18 F]FEBMP and [ 18 F]FPBMP, the opposite of [ 11 C]( R )-PK11195.…”

Mapping of Translocator Protein (18 kDa) in Peripheral Sterile Inflammatory Disease and Cancer through PET Imaging

“…As TSPO forms a complex with two other proteins in the outer mitochondrial membrane: an adenine nucleotide transporter and a voltage-dependent anion channel, this trimeric protein complex may well be disturbed during leukocyte homogenization. Therefore, to counteract these shortcomings, tremendous efforts have been made for the development of second-generation TSPO PET ligands. − …”

Modified benzoxazolone (ABO‐AA) based single photon emission computed tomography (SPECT) probes for 18 kDa translocator protein

“…A new skeleton acetamidobenzoxazolone (ABO) which has been derived from RoS‐4,864 by opening the diazepine ring and reorganizing it (Fukaya et al, ; Fukaya et al, ) to overcome the problems of intersubject variability and nonspecific binding (Tiwari, Yui, et al, ). In recent past, our group has explored this skeleton for diagnostic application using positron emission tomography (PET) with 11 C and 18 F radionuclides such as 2‐[5‐(4‐[ 11 C]Methoxyphenyl)‐2‐oxo‐1,3‐benzoxazol‐3(2 H )‐yl]‐ N ‐methyl‐ N ‐phenylacetamide ( 11 C‐MBMP), 2‐[5‐(4‐[ 18 F] fluoroethoxy/propoxyphenyl)‐2‐oxo‐1,3‐benzoxazol‐3(2 H )‐yl]‐ N ‐methyl‐ N ‐phenylacetamide ( 18 F‐FEBMP and 18 F‐FPBMP) and using single photon emission computed tomography (SPECT) with 99m Tc such as 99m Tc‐MBIP (Kumari et al, ; Srivastava, Kaul, Ojha, Kumar, & Tiwari, ; Tiwari, Fujinaga, et al, ; Tiwari, Yui, et al, ; Tiwari, Ji, et al, ).…”

“…N-phenylacetamide ( 18 F-FEBMP and 18 F-FPBMP) and using single photon emission computed tomography (SPECT) with 99m Tc such as 99m Tc-MBIP (Kumari et al, 2017;Srivastava, Kaul, Ojha, Kumar, & Tiwari, 2016;Tiwari, Ji, et al, 2015).…”