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，因为它们是从卵巢分泌的，但它们也在其他组织中合成，包括男性的组织。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;但它们也对非生殖组织有众所周知的作用，如肝脏和骨骼。最近，这些性类固醇已被证明参与大脑中其他先前未被怀疑的活动，如学习，记忆和细胞保护，涉及阿尔茨海默氏病，中风，抑郁症和精神分裂症等病理状态。雌激素在所有细胞中的作用是由雌激素受体（ER）介导的;其中有两种主要形式，ER 1和ER 2。它们都存在于大脑中，并且通过雌激素剥夺或其他因素改变其浓度被认为会导致上述病理。我们的目的是开发两种雌激素标记的放射性示踪剂123 I用于SPECT成像ER在大脑中。我们将开发两种123 I-雌激素，112-甲氧基-[161- 123 I]碘雌二醇（其特异性结合ER 1）和112-甲氧基-（E-171- 2 '-[123 I]碘乙烯基）-雌二醇（其同等地结合ER 1和ER 2）的快速和高产率合成方法。这些放射性雌激素将被注射到活狒狒体内，通过ER介导的结合集中示踪剂的大脑区域将被成像。用特异性结合ER 1和ER 2的化合物阻断示踪剂浓度的对照实验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患有主要神经精神疾病的人类的这种重要受体系统，并允许开发更好的治疗方法。据认为，产生雌激素反应的蛋白质（雌激素受体）的脑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。本申请的目的是合成两种不同的放射性雌激素标记的123 I和证明它们可以用于活狒狒成像的两个主要的雌激素受体，ER 1和ER 2，在大脑中。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.