RATIONAL DESIGN OF BREAST TUMOR IMAGING AGENTS

雌激素受体存在于大多数人类乳腺肿瘤中 提供雌激素的选择性摄取机制。 因此，原则上， 应该有可能用伽马射线发射成像人类乳腺肿瘤 雌激素具有合适的结合选择性和足够高的 特异性活性，从而定位原发性和转移性肿瘤， 是雌激素受体阳性的，并原位测定其受体含量。 我们开发了一种结合选择性的测量方法（结合选择性 指数），可用于帮助开发最佳成像 剂. 利用该指数作为指导，我们制备了16 δ-溴 雌激素，标记Br-77在高比活性，我们有 表明它们被雌激素高选择性地吸收， 靶组织。 它们也可以用于动物乳腺肿瘤的成像 以及在人类乳腺癌患者中的初步研究。 但 在人类中有效使用肿瘤显像剂将需要更短的时间， 半衰期同位素，能够提供更高分辨率的图像。 因此，我们正在开发几种正电子发射（F-18，C-11）的合成方法。 将与正电子断层扫描结合使用的雌激素 检测器提供人类乳腺肿瘤的三维图像。 我们 我还将研究在铁合金中添加卤素和氟化物 阳离子络合物作为更普遍的发展的一部分， 适用于F-18标记而无需载体稀释的方法。 目标 组织和乳腺肿瘤对γ-发射雌激素的摄取选择性 将在实验动物身上进行研究。 我们还将尝试验证 药代动力学模型，这将使受体位点浓度和 通过分析靶组织和血液活性确定亲和力 数据区. 这种显像剂的成功开发应有助于 乳腺肿瘤的检测和改善对 激素疗法

Estrogen receptors that are present in the majority of human breast tumors provide a selective uptake mechanism for estrogens. Thus, in principle, it should be possible to image human breast tumors with gamma-emitting estrogens haveing suitable binding selectivity and sufficiently high specific activity, and thus to locate primary and metastatic tumors that are estrogen receptor-positive and to assay their receptor content in situ. We have developed a measure of binding selectivity (the binding selectivity index) that can be used to assist in the development of optimal imaging agents. Using this index as a guide, we have prepared 16delta-bromo estrogens, labeled with Br-77 at high specific activity, and we have demonstrated that they are taken up with high selectivity by estrogen target tissues. They could also be used to image mammary tumors in animals and in human breast cancer patients, in preliminary studies. However, the effective use of tumor imaging agents in humans will require shorter half-life isotopes, capable of providing much higher resolution images. Thus, we are developing syntheses of several positron-emitting (F-18, C-11) estrogens that will be used in conjunction with positron tomographic detectors to provide three-dimensional images of human breast tumors. We will also study halofluorination and fluoride additions to iron pentadienyl cation complexes as part of a more general development of fluorination methods suitable for F-18 labeling without carrier dilution. The target tissue and mammary tumor uptake selectivity of the gamma-emitting estrogens will be studied in experimental animals. We will also try to validate a pharmacokinetic model that will enable receptor site concentration and affinity to be determined by analysis of target tissue and blood activity profiles. The successful development of such imaging agents should assist in the detection of breast tumors and improve the prediction of response to hormone therapy.