Uddin Md Imam, Evans Stephanie M, Craft Jason R, Marnett Lawrence J, Uddin Md Jashim, Jayagopal Ashwath
Department of Ophthalmology and Visual Sciences, Vanderbilt Eye Institute, Vanderbilt University Medical Center , Nashville, Tennessee 37232, United States.
A. B. Hancock, Jr., Memorial Laboratory for Cancer Research, Department of Biochemistry, Chemistry and Pharmacology, Vanderbilt Institute of Chemical Biology, Center for Molecular Toxicology and Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine , Nashville, Tennessee 37232, United States.
ACS Med Chem Lett. 2015 Feb 12;6(4):445-9. doi: 10.1021/ml5005206. eCollection 2015 Apr 9.
We report the design and synthesis of an activatable molecular imaging probe to detect hypoxia in mouse models of retinal vascular diseases. Hypoxia of the retina has been associated with the initiation and progression of blinding retinal vascular diseases including age-related macular degeneration, diabetic retinopathy, and retinopathy of prematurity. In vivo retinal imaging of hypoxia may be useful for early detection and timely treatment of retinal diseases. To achieve this goal, we synthesized HYPOX-3, a near-infrared (NIR) imaging agent coupled to a dark quencher, Black Hole Quencher 3 (BHQ3), which has been previously reported to contain a hypoxia-sensitive cleavable azo-bond. HYPOX-3 was cleaved in hypoxic retinal cell culture and animal models, enabling detection of hypoxia with high signal-to-noise ratios without acute toxicity. HYPOX-3 fluorescences in hypoxic cells and tissues and was undetectable under normoxia. These imaging agents are promising candidates for imaging retinal hypoxia in preclinical disease models and patients.
我们报告了一种可激活分子成像探针的设计与合成，用于检测视网膜血管疾病小鼠模型中的缺氧情况。视网膜缺氧与包括年龄相关性黄斑变性、糖尿病视网膜病变和早产儿视网膜病变在内的致盲性视网膜血管疾病的发生和发展有关。缺氧的体内视网膜成像可能有助于视网膜疾病的早期检测和及时治疗。为实现这一目标，我们合成了HYPOX-3，一种与暗猝灭剂黑洞猝灭剂3（BHQ3）偶联的近红外（NIR）成像剂，此前已有报道称其含有对缺氧敏感的可裂解偶氮键。HYPOX-3在缺氧的视网膜细胞培养物和动物模型中被裂解，能够以高信噪比检测缺氧情况且无急性毒性。HYPOX-3在缺氧细胞和组织中发出荧光，在常氧条件下无法检测到。这些成像剂有望成为在临床前疾病模型和患者中对视网膜缺氧进行成像的候选物。
