123I-LIGANDS FOR SPECT IMAGIING THE ESTROGEN RESPONSIVE REGIONS OF THE BRAIN

描述（由申请人提供）：雌激素被认为是女性激素，因为它们从卵巢分泌，但它们也在其他组织中合成，包括男性组织。雌激素在体内有许多不同的作用，大多数是众所周知的，与生殖有关，刺激组织，如：子宫，阴道，乳房，垂体和大脑；但众所周知，它们对肝脏和骨骼等非生殖组织也有作用。最近，这些性类固醇已被证明与大脑中其他先前未被怀疑的活动有关，如学习、记忆和细胞保护，并与阿尔茨海默病、中风、抑郁症和精神分裂症等病理状态有关。雌激素在所有细胞中的作用都是由雌激素受体（ER）介导的；其中有两种主要形式，ER1和ER2。它们都存在于大脑中，通过雌激素剥夺或其他因素改变它们的浓度被认为会导致上述病理。我们打算开发两种用放射性示踪剂123I标记的雌激素，用于SPECT脑内显像。我们将开发两种123I-雌激素，112-甲氧基-[161-123I]碘雌二醇（与ER1特异性结合）和112-甲氧基-（E-171-2'-[123I]碘乙烯基）雌二醇（与ER1和ER2均结合）的快速高产合成方法。这些放射性雌激素将被注射到活狒狒体内，并通过内质网介导的结合对集中示踪剂的大脑区域进行成像。对照实验中，用特异性结合ER1和ER2的化合物阻断示踪剂的浓度，将证实结合的特异性。这些实验将提供一种独特的机制来研究这一重要的受体系统在患有重大神经精神疾病的人类中，并允许开发更好的治疗方法。据认为，大脑中产生雌激素反应的蛋白质（雌激素受体）含量的变化与几种神经系统疾病有关，包括阿尔茨海默病和帕金森病、多发性硬化症和癫痫，以及其他学习和记忆障碍。本应用程序的目的是合成两种不同的放射性雌激素，标记为123I，并证明它们可以在活狒狒中用于成像大脑中的两种主要雌激素受体ER1和ER2。这些研究将证明在人类神经退行性疾病中监测这一重要系统的潜力。

DESCRIPTION (provided by applicant): Estrogens are thought of as female hormones because they are secreted from the ovaries, but they are also synthesized in other tissues, including tissues in men. Estrogens have many different actions in the body, most are well known and are associated with reproduction, the stimulation of tissues such as: uterus, vagina, breast, pituitary and brain; but they also have well-known actions on non-reproductive tissues, such as liver and bone. More recently these sex steroids have been shown to be involved in other previously unsuspected actions in the brain, such as learning, memory and cellular protection, involving them in pathological states such Alzheimer's disease, stroke, depression, and schizophrenia. The action of estrogens in all cells is mediated by the estrogen receptor (ER); of which there are two major forms, ER1 and ER2. They are both present in the brain, and alterations in their concentration through estrogen deprivation or other factors are thought to lead to the above pathologies. It is our intention to develop two estrogens labeled with the radioactive tracer 123I for use in SPECT imaging ERs in the brain. We will develop methods for rapid and high yield synthesis of two 123I-estrogens, 112-methoxy-[161-123I]iodoestradiol (which binds specifically to ER1) and 112-methoxy-(E-171-2'-[123I]iodovinyl)-estradiol (which binds equally to both ER1 and ER2). These radioactive estrogens will be injected into living baboons and the regions of the brain that concentrate the tracers by ER- mediated binding will be imaged. Control experiments in which the concentration of the tracers is blocked with compounds that bind specifically ER1 and ER2 will confirm the specificity of binding. These experiments will provide a unique mechanism to study this important receptor system in humans suffering from major neuropsychiatric disorders and allow the development of better treatments. PUBLIC HEALTH RELEVANCE It is thought that changes in brain content of the proteins that produce estrogenic responses, estrogen receptors, are involved in several neurological disorders, including Alzheimer's and Parkinson's diseases, multiple sclerosis and epilepsy, as well other disorders of learning and memory. The aim of this application is to synthesize two different radioactive estrogens labeled with 123I and demonstrate that they can be used in live baboons to image the two major estrogen receptors, ER1 and ER2, in the brain. These studies will demonstrate the potential of monitoring this important system in neurodegenerative diseases of humans.