Chopra Arvind
National Center for Biotechnology Information, NLM, NIH, Bethesda, MD 20894,
Somatostatin (SS) is a cyclic peptide that is primarily expressed in the central nervous system and some peripheral tissues (1). Receptors for SS have been identified in the central nervous system, cells of neuroendocrine origin, the gastrointestinal tract, and even in lymphocytes (2). The SS receptor has a seven-transmembrane domain structure and belongs to the G-protein–coupled receptor family. Five subtypes of the SS receptor have been identified, and each subtype is produced from a single gene located on a different chromosome. This indicates tissue-specific regulation of SS receptor expression and suggests that each subtype has a distinct function in the various organs (2). Because of its several physiological functions, SS is considered to be a neurotransmitter or a hormone that acts through the autocrine and paracrine processes (3). In general, SS inhibits the production of hormones from various glands. SS has been evaluated for the treatment of various diseases, including cancers of endocrine origin as a result of hyperactive glands. However, SS has a short plasma half-life because of rapid enzymatic degradation and has been observed to be ineffective for such therapy (2). The development of SS analogs resistant to enzymatic degradation, but with a biological activity similar to SS, led to the application of these analogs for the treatment of cancerous tumors (4, 5). The mechanism by which SS and its analogs inhibit tumor growth was detailed by Moody et al. (6). A cyclic octapeptide SS analog, octreotide, was synthesized and conjugated with diethylenetriamine pentaacetic acid (DTPA) for chelating radioactive indium (In) to obtain In-DPTA-octreotide (In-DPTA-OCT). On binding to the SS receptor, In-DPTA-OCT is rapidly internalized and results in accumulation of the radiochemical in the tumor cells. Subsequently, the tumors can be detected by scintigraphy and treated with radiolabeled peptides (6). Although In-DPTA-OCT is considered suitable for the detection and diagnosis of tumors bearing SS receptors, the use of In as a radionuclide has some limitations. This radioelement has limited availability, a long physical half-life (67 h), high gamma energy that results in increased radiation exposure of the patient, and suboptimal image characteristics (7, 8). Therefore, Decristoforo et al. used radioactive technetium (Tc) with a half-life of 6 h to generate Tc-labeled hydrazinonicotinamide-Tyr-octreotide (Tc-HYNIC-TOC), a radiochemical with superior imaging properties compared to In-DPTA-octreotide (9). This chapter describes the synthesis, and , and clinical studies performed with Tc-HYNIC-TOC.
生长抑素（SS）是一种环肽，主要在中枢神经系统和一些外周组织中表达（1）。已在中枢神经系统、神经内分泌起源的细胞、胃肠道甚至淋巴细胞中鉴定出SS受体（2）。SS受体具有七跨膜结构域，属于G蛋白偶联受体家族。已鉴定出SS受体的五种亚型，每种亚型由位于不同染色体上的单个基因产生。这表明SS受体表达具有组织特异性调节，提示每种亚型在各个器官中具有独特功能（2）。由于其多种生理功能，SS被认为是一种通过自分泌和旁分泌过程起作用的神经递质或激素（3）。一般来说，SS抑制各种腺体激素的产生。由于腺体功能亢进，SS已被评估用于治疗各种疾病，包括内分泌源性癌症。然而，由于酶促降解迅速，SS的血浆半衰期较短，并且已观察到其对这种治疗无效（2）。对酶促降解具有抗性但具有与SS相似生物活性的SS类似物的开发，导致了这些类似物在癌性肿瘤治疗中的应用（4,5）。Moody等人详细阐述了SS及其类似物抑制肿瘤生长的机制（6）。合成了一种环八肽SS类似物奥曲肽，并将其与二乙烯三胺五乙酸（DTPA）缀合以螯合放射性铟（In），得到铟-二乙烯三胺五乙酸-奥曲肽（In-DTPA-OCT）。与SS受体结合后，In-DTPA-OCT迅速内化，导致放射化学物质在肿瘤细胞中积累。随后，可通过闪烁显像检测肿瘤并用放射性标记肽进行治疗（6）。尽管In-DTPA-OCT被认为适用于检测和诊断携带SS受体的肿瘤，但使用In作为放射性核素存在一些局限性。这种放射性元素可用性有限、物理半衰期长（67小时）、γ能量高导致患者辐射暴露增加以及图像特征欠佳（7,8）。因此，Decristoforo等人使用半衰期为6小时的放射性锝（Tc）生成锝标记的肼基烟酰胺-酪氨酸-奥曲肽（Tc-HYNIC-TOC），一种与In-DTPA-奥曲肽相比具有优异成像特性的放射化学物质（9）。本章描述了Tc-HYNIC-TOC的合成、……以及临床研究。
