POTENTIAL TUMOR OR ORGAN IMAGING AGENTS

潜在的肿瘤或器官成像剂

• 批准号: 3163307
• 负责人: RAYMOND E COUNSELL
• 金额: $ 26.2万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 1979
• 资助国家: 美国
• 起止时间: 1979-05-01 至 1994-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3163307
• 关键词: cardiovascular imaging /visualization; chemical synthesis; contrast media; drug delivery systems; drug design /synthesis /production; drug metabolism; human subject; imaging /visualization /scanning; laboratory rat; neoplasm /cancer radionuclide diagnosis; noninvasive diagnosis; nuclear medicine; phospholipids; radionuclide imaging /scanning; radiopharmacology; triglycerides

Since its inception in 1965, the long term goals of this project have been to design, synthesize and evaluate new radiopharmaceuticals as potentials organ or tumor-imaging agents. A specific aim has been to analyze various strategies for accomplishing the site-specific delivery of radiopharmaceuticals to specific tissues. Since these studies have focused on radioiodine as the imaging nuclide, a key factor in achieving the goal has been to select appropriate molecules to serve in the transport of radioiodine to the desired target. Accordingly, the design of the radioiodinated molecules has drawn heavily from current knowledge on the fate and disposition of xenobiotics(e.g. chloroquine-melanin affinity, bretylium-adrenergic neuron) and the synthesis and metabolism of biochemically-important molecules (e.g. cholesterol-adrenal cortex, phospholipid ethers-tumors.) Results with two classes, namely the radioiodinated phospholipid ethers (PLE) and radioiodinated triglyceride analogs, have shown sufficient promise that the current grant period will focus entirely on these agents. For example, several radioiodinated PLE have been shown to accumulate in a variety of tumors including the rat Walker 256 carcinosarcoma, the rabbit Vx2 adenocarcinoma, and human malignant melanoma (HTB63), small cell carcinoma (NCI-69), colon carcinoma(LS-180),and ovarian carcinoma (HTB77)carried in athymic mice. In most instances tumor to blood ratios exceeded 25 and the tumors could be readily imaged in vivo by gamma camera scintigraphy. In a similar manner, certain radioiodinated triglyceride analogs have been shown to be taken up by the liver in concentrations >50% of the administered dose and also to be substrates for both lipoprotein lipase and hepatic lipase such that they are excellent candidates for mapping global and regional hepatic lipid metabolism. Therefore, the goals of this project are (1) to undertake the necessary chemical, pharmacological and toxicological studies with appropriate radioiodinated PLE and triglycerides in order (2) to utilize such data to obtain approval from the Radioactive Drug Research Committee (RDRC) to perform preliminary biodistribution studies in normal volunteers and patients with documented metastatic neoplasms (in the case of PLE) and liver dysfunction (in the case of a triglyceride analog) as a prelude to submission of investigational new drug (I.N.D.) applications for expanded evaluation of clinical efficacy.

自1965年成立以来，该项目的长期目标 已经设计，合成和评估新的放射性药物为 电势器官或肿瘤成像剂。 一个具体的目的是 分析各种策略以完成特定地点的交付 用于特定组织的放射性药物。 由于这些研究有 专注于放射性碘作为成像核素，这是实现的关键因素 目标是选择适当的分子以服务于 放射碘转运到所需的目标。 因此，设计 放射性约束的分子已经从当前的知识中得知 关于异种生物的命运和处置（例如，氯喹黑素蛋白 亲和力，肾上腺肾上腺素能神经元）以及合成和代谢 生物化学重要分子（例如胆固醇 - 肾上腺皮质， 磷脂醚 - 肿瘤。） 结果有两个类别，即放射性菌皮磷脂 以乙醇（PLE）和放射性置的甘油三酸酯类似物已显示 充分承诺当前的赠款期将完全关注 这些代理。 例如，已经显示出几个放射性约束的PLE 积聚在包括大鼠沃克在内的多种肿瘤中256 癌肉瘤，兔VX2腺癌和人类恶性肿瘤 黑色素瘤（HTB63），小细胞癌（NCI-69），结肠 癌（LS-180）和卵巢癌（HTB77）在无胸腺小鼠中。 在大多数情况下，肿瘤与血比超过25，肿瘤可能 通过伽马相机闪烁显像在体内容易成像。 类似 方式，某些放射性置的甘油三酸酯类似物已被证明为 肝脏以较高剂量的50％的浓度吸收 也是脂蛋白脂肪酶和肝脂肪酶的底物 它们是绘制全球和区域绘制的绝佳候选人 肝脂质代谢。 因此，该项目的目标是（1）承担 必要的化学，药理和毒理学研究 适当的放射性固化的PLE和甘油三酸酯，以（2）使用 这样的数据以获得放射性药物研究委员会的批准 （RDRC）在正常情况下进行初步生物分布研究 志愿者和有记录的转移性肿瘤的患者（在这种情况下 PLE）和肝功能障碍（在甘油三酸酯类似物的情况下） 提交调查新药（I.N.D.）申请的前奏 用于扩大临床功效的评估。