期刊
ORGANIC & BIOMOLECULAR CHEMISTRY
卷 16, 期 47, 页码 9171-9184出版社
ROYAL SOC CHEMISTRY
DOI: 10.1039/c8ob02609b
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资金
- USA National Institutes of Health, the National Institute of Neurological Disorders and Stroke
- USA National Institutes of Health, National Institute on Aging [NS075527, NS103988]
- USA National Institutes of Health, National Institute of Mental Health [MH092797]
- USA National Institutes of Health, National Institute of Biomedical Imaging and Bioengineering [EB025815]
- USA Department of Energy Training Grant titled Training in Techniques and Translation: Novel Nuclear Medicine Imaging Agents for Oncology and Neurology [DE-SC0008432]
- NATIONAL INSTITUTE OF BIOMEDICAL IMAGING AND BIOENGINEERING [P41EB025815] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [R01NS103988, R01NS075527] Funding Source: NIH RePORTER
A series of seventeen hydroxyl-containing sphingosine 1-phosphate receptor 1 (S1PR1) ligands were designed and synthesized. Their in vitro binding potencies were determined using [P-32]S1P competitive binding assays. Compounds 10a, 17a, 17b, and 24 exhibited high S1PR1 binding potencies with IC50 values ranging from 3.9 to 15.4 nM and also displayed high selectivity for S1PR1 over other S1P receptor subtypes (IC50 > 1000 nM for S1PR2-5). The most potent compounds 10a, 17a, 17b, and 24 were subsequently radiolabeled with F-18 in high yields and purities. MicroPET studies in cynomolgus macaque showed that [F-18]10a, [F-18]17a, and [F-18]17b but not [F-18]24 crossed the blood brain barrier and had high initial brain uptake. Further validation of [F-18]10a, [F-18]17a, and [F-18]17b in preclinical models of neuro-inflammation is warranted to identify a suitable PET radioligand to quantify S1PR1 expression in vivo as a metric of an inflammatory response.
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