Synthesis and preliminary biological evaluation of radiolabeled 5-BDBD analogs as new candidate PET radioligands for P2X4 receptor

• Published in: Bioorganic & medicinal chemistry Vol. 25; no. 14; pp. 3835 - 3844
• Main Authors: Wang, Min, Gao, Mingzhang, Meyer, Jill A., Peters, Jonathan S., Zarrinmayeh, Hamideh, Territo, Paul R., Hutchins, Gary D., Zheng, Qi-Huang
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 15.07.2017; Elsevier
• Subjects: Adenosine Triphosphate - chemistry; Adenosine Triphosphate - metabolism; Azirines - chemical synthesis; Azirines - chemistry; Azirines - metabolism; Binding, Competitive; Biochemistry & Molecular Biology; Carbon Radioisotopes - chemistry; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Competitive binding assay; Dihydropyridines - chemical synthesis; Dihydropyridines - chemistry; Dihydropyridines - metabolism; Fluorine Radioisotopes - chemistry; HEK293 Cells; Humans; Isotope Labeling; Life Sciences & Biomedicine; P2X4 receptor; Pharmacology & Pharmacy; Physical Sciences; Positron emission tomography (PET); Positron-Emission Tomography; Protein Binding; Radiolabeled 5-BDBD analogs; Radioligand depletion experiment; Radiopharmaceuticals - chemical synthesis; Radiopharmaceuticals - chemistry; Radiopharmaceuticals - metabolism; Radiosynthesis; Receptors, Purinergic P2X4 - chemistry; Receptors, Purinergic P2X4 - genetics; Receptors, Purinergic P2X4 - metabolism; Recombinant Proteins - biosynthesis; Recombinant Proteins - chemistry; Science & Technology; Competitive binding assay; Positron emission tomography (PET); Radiolabeled 5-BDBD analogs; Radioligand depletion experiment; P2X4 receptor; Radiosynthesis; AGENT; 1ST RADIOSYNTHESIS; BROMINATION; FULLY AUTOMATED SYNTHESIS; TAU TRACER; PURINERGIC RECEPTORS
• ISSN: 0968-0896; 1464-3391; 1464-3391
• DOI: 10.1016/j.bmc.2017.05.031

[Display omitted] 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-[11C]methyl-1,3-dihydro-2H-benzofuro[3,2-e][1,4]diazepin-2-one (N-[11C]Me-5-BDBD analog, [11C]9) and 5-(3-Bromophenyl)-1-[11C]methyl-1,3-dihydro-2H-benzofuro[3,2-e][1,4]diazepin-2-one (N-[11C]Me-5-BDBD, [11C]8c) were prepared from their corresponding desmethylated precursors with [11C]CH3OTf through N-[11C]methylation and isolated by HPLC combined with SPE in 30–50% decay corrected radiochemical yields with 370–1110GBq/µmol specific activity at EOB. 5-(3-[18F]Fluorophenyl)-1,3-dihydro-2H-benzofuro[3,2-e][1,4]diazepin-2-one ([18F]F-5-BDBD, [18F]5a) and 5-(3-(2-[18F]fluoroethoxy)phenyl)-1,3-dihydro-2H-benzofuro[3,2-e][1,4]diazepin-2-one ([18F]FE-5-BDBD, [18F]11) were prepared from their corresponding nitro- and tosylated precursors by nucleophilic substitution with K[18F]F/Kryptofix 2.2.2 and isolated by HPLC-SPE in 5–25% decay corrected radiochemical yields with 111–740GBq/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.