Design, synthesis and biological evaluation of methyl-2-(2-(5-bromo benzoxazolone)acetamido)-3-(1H-indol-3-yl)propanoate: TSPO ligand for SPECT. Issue 115 (8th December 2016)

• Record Type: Journal Article
• Authors: Srivastava, Pooja; Kaul, Ankur; Ojha, Himanshu; Kumar, Pravir; Tiwari, Anjani K.
• Is Part Of: RSC advances. Volume 6:Issue 115(2016)
• Page Start: 114491
• Page End: 114499
• Publication Date: 2016-12-08
• Subjects: Chemistry -- Periodicals; 540.5
• DOI: 10.1039/c6ra19514h
• Languages: English
• ISSNs: 2046-2069

Abstract

Abstract : The translator protein (TSPO, 18 kDa), a transmembrane mitochondrial protein, has been explored as an important biomarker by researchers for inflammation, immune modulation and cell proliferation. Here we report a new SPECT agent 99m Tc-MBIP for TSPO imaging and quantification. Abstract : The translator protein (TSPO, 18 kDa), a transmembrane mitochondrial protein, has been explored as an important biomarker by researchers because of its involvement in inflammation, immune modulation and cell proliferation. Recently, our group has explored a modified benzoxazolone derivative for diagnostic applications that has overcome few problems of first and second generation TSPO PET ligands. In this study, a new skeleton acetamidobenzoxazolone–indole, a conjugation of two TSPO pharmacophoric moieties benzoxazolone and indole, has been designed, synthesized and evaluated for TSPO targeting for SPECT. The methyl-2-(2-(5-bromo benzoxazolone)acetamido)-3-(1 H -indol-3-yl)propanoate (MBIP) ligand was designed on the basis of pharmacophore modeling done on benzoxazolone based TSPO ligands which was then validated computationally for TSPO binding through docking studies (PDB ID: ; Web:4RYO, ; Web:4RYQ, and ; Web:4UC1 ) which showed a comparable Glide G score as compared to known ligands like PK11195, PBR28, and FGIN-127. MBIP was synthesized by amidation reaction of 2-(5-bromo-benzoxazolone)acetic acid with tryptophan methyl ester hydrochloride (yield 62%). The compound was synthesized and characterized using spectroscopic techniques like 1 H-NMR, 13 C-NMR, and mass spectroscopy. Purification was carried out by column chromatography and analytical HPLC (purity > 97%). The purified compound was labelled with 99m Tc (radiochemical yield > 96%). The radiolabelled compound showed >94% stability in solution and >91% stability in serum after 24 h indicating the stable nature of the radio complex. A biodistribution study on BALB/c mice showed uptake of 99m Tc-MBIP in TSPO rich organs and appropriate pharmacokinetics of excretion and release for a SPECT agent. Further evaluation of the 99m Tc-MBIP may prove it as a potential candidate for TSPO targeting using SPECT.