RATIONAL DESIGN OF BREAST TUMOR IMAGING AGENTS

大多数人类乳腺肿瘤中存在的雌激素受体 为雌激素提供选择性摄取机制。因此，原则上，它 应该可以用伽马射线对人类乳腺肿瘤进行成像 具有合适的结合选择性和足够高的雌激素 特定的活性，从而定位原发和转移的肿瘤 雌激素受体呈阳性，并原位测定其受体含量。 我们已经开发出一种结合选择性的测量方法(结合选择性 索引)，可用于协助开发最佳成像 探员们。以这一指标为指导，我们制备了16个三角洲溴化物 雌激素，用BR-77标记，具有高比活性，我们有 表明雌激素对它们有很高的选择性 目标组织。它们还可以用来对动物的乳腺肿瘤进行成像。 在初步研究中，在人类乳腺癌患者中。然而， 在人类中有效使用肿瘤显像剂需要更短的时间 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。 雌激素将与正电子断层扫描结合使用 探测器提供人类乳房肿瘤的三维图像。我们 我还将研究卤化氟化和向五二烯基铁中添加氟化物 阳离子络合物作为氟化更一般发展的一部分 适用于无载体稀释的F-18标记方法。目标是 放射类雌激素对组织和乳腺肿瘤摄取的选择性 将在实验动物身上进行研究。我们还将尝试验证一个 药代动力学模型将使受体部位浓度和 通过分析靶组织和血液活性来确定亲和力 配置文件。 这种显像剂的成功开发应该有助于 检测乳腺肿瘤并提高对 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.