Synthesis and preliminary biological evaluation of radiolabeled 5-BDBD analogs as new candidate PET radioligands for P2X4 receptor. Issue 14 (15th July 2017)

• Record Type: Journal Article
• Authors: Wang, Min; Gao, Mingzhang; Meyer, Jill A.; Peters, Jonathan S.; Zarrinmayeh, Hamideh; Territo, Paul R.; Hutchins, Gary D.; Zheng, Qi-Huang
• Is Part Of: Bioorganic & medicinal chemistry. Volume 25:Issue 14(2017)
• Page Start: 3835
• Page End: 3844
• Publication Date: 2017-07-15
• Subjects: Radiolabeled 5-BDBD analogs -- P2X4 receptor -- Radiosynthesis -- Radioligand depletion experiment -- Competitive binding assay -- Positron emission tomography (PET); Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2017.05.031
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: P2X4 receptor has become an interesting molecular target for treatment and PET imaging of neuroinflammation and associated brain diseases such as Alzheimer's disease. This study reports the first design, synthesis, radiolabeling and biological evaluation of new candidate PET P2X4 receptor radioligands using 5-BDBD, a specific P2X4 receptor antagonist, as a scaffold. 5-(3-Hydroxyphenyl)-1-[ 11 C]methyl-1, 3-dihydro-2 H -benzofuro[3, 2- e ][1, 4]diazepin-2-one ( N- [ 11 C]Me-5-BDBD analog, [ 11 C]9 ) and 5-(3-Bromophenyl)-1-[ 11 C]methyl-1, 3-dihydro-2 H -benzofuro[3, 2- e ][1, 4]diazepin-2-one ( N- [ 11 C]Me-5-BDBD, [ 11 C]8c ) were prepared from their corresponding desmethylated precursors with [ 11 C]CH3 OTf through N -[ 11 C]methylation and isolated by HPLC combined with SPE in 30–50% decay corrected radiochemical yields with 370–1110 GBq/µmol specific activity at EOB. 5-(3-[ 18 F]Fluorophenyl)-1, 3-dihydro-2 H -benzofuro[3, 2- e ][1, 4]diazepin-2-one ([ 18 F]F-5-BDBD, [ 18 F]5a ) and 5-(3-(2-[ 18 F]fluoroethoxy)phenyl)-1, 3-dihydro-2 H -benzofuro[3, 2- e ][1, 4]diazepin-2-one ([ 18 F]FE-5-BDBD, [ 18 F]11 ) were prepared from their corresponding nitro- and tosylated precursors by nucleophilic substitution with K[ 18 F]F/Kryptofix 2.2.2 and isolated by HPLC-SPE in 5–25% decay corrected radiochemical yields with 111–740 GBq/µmol specific activity at EOB. The preliminary biological evaluation of radiolabeled 5-BDBD analogs indicated these new radioligands have similar biological activity with their parent compound 5-BDBD.