奥曲肽及其类似物用于肿瘤诊断的进展

简要综述^111In-奥曲肽和^99Tc^m-NeoTec在肿瘤诊断中的应用，其对类癌、甲状腺髓样癌、来自胰腺或上消化道的神经内分泌肿瘤的诊断和随访有重要价值，对失去摄碘功能的分化型甲状腺癌、甲亢性突眼、肉样瘤病的肉芽肿过程也可得到阳性结果。应用放射性核素标记的生长抑素类似物使肿瘤成功的显像，可发展并应用标记的类似物来治疗这些肿瘤。生长抑素类似物的标记技术扩展了应用其他肽类进行分子显像的研究兴趣。     

放射性核素标记生长抑素类似物在淋巴瘤中的应用

生长抑素类似物如奥曲肽、depreotide等与生长抑素受体作用时间长、亲和力高,并可被放射性核素标记,用于肿瘤的生长抑素受体显像和治疗。淋巴瘤细胞表达该受体,因此可利用生长抑素受体对其进行显像和治疗。大量临床和实验研究均表明,放射性核素标记生长抑素类似物的生长抑素受体显像可对淋巴瘤进行诊断、分期、治疗和预后的评价,也可作为常规影像学显像、67Ga和PET显像诊断、评价淋巴瘤的一种有力补充。而在淋巴瘤治疗中的应用应当慎重,如何能获得最佳治疗效果而又将其副作用减小到最低程度是今后研究的主要课题之一。     

放射性核素标记生长抑素类似物在淋巴瘤中的应用

生长抑素类似物如奥曲肽、depreotide等与生长抑素受体作用时间长、亲和力高，并可被放射性核素标记，用于肿瘤的生长抑素受体显像和治疗。淋巴瘤细胞表达该受体，因此可利用生长抑素受体对其进行显像和治疗。大量临床和实验研究均表明，放射性核素标记生长抑素类似物的生长抑素受体显像可对淋巴瘤进行诊断、分期、治疗和预后的评价，也可作为常规影像学显像、67Ga和PET显像诊断、评价淋巴瘤的一种有力补充。而在淋巴瘤治疗中的应用应当慎重，如何能获得最佳治疗效果而又将其副作用减小到最低程度是今后研究的主要课题之一。     

生长抑素类似物介导靶向显像及治疗的研究现状和进展

放射性核素标记生长抑素类似物对神经内分泌肿瘤进行靶向诊断和靶向治疗已得到临床广泛认可。大多数生长抑素类似物仅对生长抑素受体2具有较高的亲和力,限制了其在临床中的应用。新一代生长抑素类似物如:1,4,7,10-四氮杂环十二烷-N,N',N",N'"-四乙酸-1-萘丙氨酸-奥曲肽(DOTA-NOC)等,可与更多亚型的生长抑素受体结合且具有更高的亲和力,可由发射不同射线的多种核素标记,已引起广泛重视。该文在介绍常规生长抑素类似物的基础上,着重讨论新的生长抑素类似物、新的螯合剂、新的标记核素及其新的组合,展望生长抑素受体介导肿瘤显像及治疗的前景。     

生长抑素类似物介导靶向显像及治疗的研究现状和进展

放射性核素标记生长抑素类似物对神经内分泌肿瘤进行靶向诊断和靶向治疗已得到临床广泛认可.大多数生长抑素类似物仅对生长抑素受体2具有较高的亲和力,限制了其在临床中的应用.新一代生长抑素类似物如:1,4,7,10-四氮杂环十二烷-N,N',N",N'"-四乙酸-1-萘丙氨酸-奥曲肽(DOTA-NOC)等,可与更多亚型的生长抑素受体结合且具有更高的亲和力,可由发射不同射线的多种核素标记,已引起广泛重视.该文在介绍常规生长抑素类似物的基础上,着重讨论新的生长抑素类似物、新的螯合剂、新的标记核素及其新的组合,展望生长抑素受体介导肿瘤显像及治疗的前景.     

生长抑素受体肿瘤显像的临床应用及研究进展

神经内分泌肿瘤及一些非神经内分泌肿瘤细胞表面均有生长抑素受体高表达。生长抑素类似物如奥曲肽等对生长抑素受体具有亲和力高、作用时间长等特点,并可被放射性核素标记进行肿瘤阳性显像,这对生长抑素受体阳性肿瘤的诊断、分期及预后评价具有较为重要的临床价值,也可作为常规影像学检查的一种有力补充。     

生长抑素受体显像剂99Tcm-奥曲肽的SPECT研究

核医学SPECT在20世纪已进入分子显像时代,受体显像尤其是生长抑素受体显像更是目前核医学显像研究的热点.利用111In、123I、99Tcm、90Y等放射性核素标记生长抑素类似物奥曲肽进行生长抑素受体显像的方法,已经比较成熟,且部分已用于临床显像.该文对99Tcm标记奥曲肽的方法(直接法、间接法)、99Tcm-奥曲肽SPECT显像方法及其临床应用等作简要概述.     

放射性核素在嗜铬细胞瘤诊断与治疗中的应用进展

嗜铬细胞瘤（PCC）是一种罕见的神经内分泌肿瘤（NET）,准确的定位诊断是进行治疗的关键。目前包括放射性碘标记的间碘苄胍(MIBG)扫描、PET、放射性核素标记的生长抑素类似物（SSTR）扫描等核医学功能显像对PCC的诊断有较高的价值。同时,放射性碘标记的MIBG及肽类受体介导的放射性核素治疗对于PCC的姑息性治疗也有一定价值。笔者对放射性核素在PCC诊断与治疗中的应用进行综述,以期为临床制定个性化治疗方案提供帮助。     

神经内分泌肿瘤PET/CT的应用现状与进展

神经内分泌肿瘤（NETs）是一组异质性肿瘤,18F-FDG不是NETs的理想显像剂,大多数NETs分化良好、生长缓慢,通常糖代谢水平很低,18F-FDG PET显像对分化差、侵袭性强的神经内分泌癌的诊断灵敏度较高。11C-5-羟基色氨酸、18F-氟代多巴、18F-多巴和11C-多巴等胺前体类PET显像剂在类癌、胰岛细胞癌、嗜铬细胞瘤、副神经节瘤、甲状腺髓样癌、高胰岛素血症等实体肿瘤的成像诊断中具有独特价值。最近研发的68Ga-DOTA-peptide（其中,DOTA为1,4,7,10-四氮杂环十二烷-N,N′,N″,N″′-四乙酸）中几种新型的生长抑素类似物PET已用于NETs的诊断和肽受体的放射性核素治疗。68Ga-DOTA-peptide PET/CT显像可改善半数以上NETs患者的病程和治疗计划,是一种极具发展前景的NETs显像模式。     

生长抑素类似物及其标记核素

利用标记小肽进行功能显像有望开创核素显像与肿瘤生物学研究的新纪元。为了提高肿瘤生长抑素受体显像的特异性和敏感性,从受体亚型水平开发受体显像剂,以及研究适合临床应用的简捷标记方法是今后的重要课题。综述了新的核素标记的生长抑素多肽受体配体的研究及其药代动力学性质并评价了其用于肿瘤受体显像的可行性。     

Radiolabeled peptides in diagnosis and tumor imaging: clinical overview

The authors briefly review radiopeptides currently approved for use in the United States. They present a short review of the peptide somatostatin's actions and also note the five somatostatin receptors (SSTRs) to which the peptide and its synthetic analogs octreotide, lanreotide, and vapreotide bind. The many conditions besides neuroendocrine tumors having SSTRs are listed. Labeled octreotide and the other two analogues have a strong affinity for SSTR2 and SSTR5, which thereby produce positive imaging. The various neuroendocrine tumors best imaged by somatostatin receptor scintigraphy (SRS) are discussed, and the exceptions (insulinoma and medullary thyroid carcinoma) are noted to be seen better with labeled VIP and (99m)Tc-dimethylsuccinic acid (DMSA), respectively. SRS and VIP receptor scintigraphy are also noted to image many nonneuroendocrine tumors, which often have appropriate receptors. Several of the currently emerging and very effective new imaging techniques are described. These include (99m)Tc-DMSA for medullary thyroid carcinoma, (18)F dihydroxyphenylalanine positron emission tomography, and C(11) 5-hydroxytryptophan positron emission tomography scanning for all neuroendocrine tumor, but especially carcinoid tumor, metastases. The special role of SRS in identifying gastric carcinoid tumors in hypergastrinemic patients is reviewed. Various pitfalls in interpreting SRS are presented and receptor-enhancing techniques described. Besides use of SRS (mainly Octreoscan, Mallinckrodt Medical, St. Louis, MO) only for detecting and localizing primary tumors and metastases for staging, there are many additional special uses for clinical management of SRS-positive tumors. These include the intraoperative use of the handheld gamma-detecting probe. A brief enumeration is given of the most promising of other non-SST G-protein-coupled receptors and ligands currently under development. Finally, we have posed a number of questions for which answers are needed in the immediate future to facilitate better imaging. Extrapolations of current knowledge and experience with radiolabeled peptide pharmaceutical imaging are converted to reasonable speculations of anticipated future developments in this field.     

Radiopeptide imaging and therapy in Europe

Receptor targeting with radiolabeled peptides has become an important topic, particularly in nuclear oncology. Strong research efforts are under way in radiopharmaceutical science laboratories and in nuclear medicine departments in Europe. The target receptors belong to the large family of G-protein-coupled receptors. The prototypes of these radiopeptides are based on analogs of somatostatin targeting somatostatin receptor-positive tumors, particularly well-differentiated neuroendocrine tumors. These radiopeptides have an important impact not only on diagnosis but also on targeted radionuclide therapy of these tumors. Besides the registered radiopeptide (111)In-pentetreotide, efficient SPECT tracers labeled with (99m)Tc and PET agents based on generator-produced (68)Ga have been developed and used in the clinic. In parallel to the development of diagnostic agents, radiopeptides labeled with the β(-) emitters (90)Y and (177)Lu are also widely used. Because the same chelators and therefore the same conjugates can be used in diagnosis and therapy, they constitute ideal theranostic pairs. This progress is driven not only by scientists and clinicians but also by patient interest groups. New radiopeptides targeting other G-protein-coupled receptors are entering the clinic, among them glucagon-like peptide 1 receptor-targeting molecules. This receptor is overexpressed on literally all benign insulinomas. (111)In-labeled derivatives of the insulinotropic 39-mer peptide exendin-4 were beneficial in the pre- and perioperative localization of these benign lesions. In contrast, lack of localization may indicate malignant insulinoma. The bombesin- and gastrin-releasing peptide receptor family is potentially important because these receptors are overexpressed on major human tumors such as prostate tumors, breast tumors, gastrointestinal stromal tumors, and vessels of ovarian cancer. (99m)Tc-labeled peptides for SPECT and (68)Ga-, as well as (64)Cu-labeled agonists or antagonists, have been studied in breast tumors, prostate tumors, gastrointestinal stromal tumors, and gliomas with considerable success. A phase I therapeutic study with a (177)Lu-labeled agonist has been completed. There are not enough clinical data available to reveal the significance of these new modalities in patient care, but several phase I studies are under way in larger patient cohorts using PET agents. Another G-protein-coupled receptor with high overexpression on human tumors is the gastrin/cholecystokinin-2 receptor. It is overexpressed in more than 90% of cases of medullary thyroid cancer, in small cell lung cancer, and in a subgroup of neuroendocrine tumors. Correlating with in vitro receptor localization using autoradiography of 27 patients with metastasized medullary thyroid cancer, SPECT or planar imaging of these patients resulted in a 95% sensitivity of tumor localization. Finally, another G-protein-coupled receptor is found in brain tumors and peritumoral vessels. Literally all cases of glioblastoma multiforme overexpress the neurokinin type 1 receptor; the natural ligand is substance P, which was metabolically stabilized, labeled with (90)Y and (213)Bi, and injected into resection cavities or directly into tumors, which were critically located via a catheter system. The major advantage of this approach appeared to be the facilitated resectability of tumors, particularly in those patients who had been treated up front with the locoregional approach. It appears that neoadjuvant treatment before resection is a valid concept. Finally, another peptide family, the arginine-glycine-aspartate-based radiotracers, has made it to the clinic labeled with a variety of radioisotopes for monitoring the integrins α(v)β(3) overexpressed during tumor angiogenesis.     

Peptide receptor imaging and therapy.

This article reviews the results of somatostatin receptor imaging (SRI) in patients with somatostatin receptor-positive neuroendocrine tumors, such as pituitary tumors, endocrine pancreatic tumors, carcinoids, gastrinomas, and paragangliomas, or other diseases in which somatostatin receptors may also be expressed, like sarcoidosis and autoimmune diseases. [(111)In-DTPA0]octreotide is a radiopharmaceutical that has great potential for helping visualize whether somatostatin receptor-positive tumors have recurred. The overall sensitivity of SRI to localize neuroendocrine tumors is high. In several neuroendocrine tumor types, inclusion of SRI in the localization or staging procedure may be very rewarding in terms of cost effectiveness, patient management, or quality of life. The value of SRI in patients with other tumors, such as breast cancer or malignant lymphomas, or in patients with granulomatous diseases has to be established. The application of radiolabeled peptides may be clinically useful in another way: after the injection of [(111)In-DTPA0]octreotide, surgeons can detect tumor localizations by a probe that is used during the operation. This may be of particular value if small tumors with a high receptor density are present (e.g., gastrinomas). As the success of peptide receptor scintigraphy for tumor visualization became clear, the next logical step was to try to label these peptides with radionuclides emitting alpha or beta particles, or Auger or conversion electrons, and to perform radiotherapy with these radiolabeled peptides. The results of the described studies with 90Y- and (111)In-labeled octreotide show that peptide receptor radionuclide therapy using radionuclides with appropriate particle ranges may become a new treatment modality. One might consider the use of radiolabeled somatostatin analogs first in an adjuvant setting after surgery of somatostatin receptor-positive tumors to eradicate occult metastases and second for cancer treatment at a later stage.     

Diagnosis and therapy of carcinoid tumors—current state of the art and future directions

Carcinoid tumors account for less than 1% of all malignancies and the majority arise in the gastrointestinal system. These tumors are slow growing compared with adenocarcinomas and they differ from the other neuroendocrine malignancies by their protean clinical presentation. Carcinoid tumors were previously considered indolent, but they can manifest malignant characteristics with metastatic spread which often results in a poor prognosis.Although there have been advances in diagnostic and treatment modalities, carcinoid tumors are still often diagnosed late, often when the tumor has metastasized and patients develop carcinoid syndrome. Diagnosis, prognosis and treatment options are based on biochemical markers and imaging investigations. High concentration of urinary 5-HIAA, elevated plasma serotonin and chromogranin A levels help to establish the initial diagnosis of carcinoid tumors. In addition to the CT and MRI, molecular imaging modalities such as OctreoScan, MIBG imaging and more recently PET imaging are vital in detection of primary malignancy and metastatic involvement.Surgery is the mainstay of treatment of nonmetastatic carcinoid tumors. Cytotoxic chemotherapy is not beneficial due to the chemoresistant nature of these tumors. Because carcinoid tumors express somatostatin receptors, somatostatin analogues, which inhibit the release of serotonin and other neuroendocrine peptides, are often used, but their use is limited to symptom control. Treatment using high doses of radionuclides such as radiolabeled somatostatin analogues and MIBG is a more recent option which offers a definite advantage in management. In this article, we review typical features of the carcinoid tumors, examine contemporary methods of detecting and assessing carcinoid tumors and discuss the role of various diagnostic and therapeutic options.     

New trends in peptide receptor radioligands.

The high level expression of somatostatin receptors (SSTR) on various tumor cells has provided the molecular basis for successful use of radiolabeled octreotide/lanreotide analogs as tumor tracers in nuclear medicine. The vast majority of human tumors seem to overexpress the one or the other of five distinct hSSTR sub-type receptors. Whereas neuroendocrine tumors frequently overexpress hSSTR2, intestinal adenocarcinomas seem to over-express more often hSSTR3 or hSSTR4, or both of these hSSTR. In contrast to 111In-DTPA-DPhe1-octreotide (OCTREOSCAN) which binds to hSSTR2 and 5 with high affinity (Kd 0.1-5 nM), to hSSTR3 with moderate affinity (Kd 10-100 nM) and does not bind to hSSTR1 and hSSTR4, 111In/90Y-DOTA-lanreotide was found to bind to hSSTR2, 3, 4, and 5 with high affinity, and to hSSTR1 with lower affinity (Kd 200 nM). Based on its unique hSSTR binding profile, 111In-DOTA-lanreotide was suggested to be a potential radioligand for tumor diagnosis, and 90Y-DOTA-lanreotide suitable for receptor-mediated radionuclide therapy. As opposed to 111In-DTPA-DPhe1-octreotide and 111In-DOTA-DPhe1-Tyr3-octreotide, discrepancies in the scintigraphic results were seen in about one third of (neuroendocrine) tumor patients concerning both the tumor uptake as well as detection of tumor lesions. On a molecular level, these discrepancies seem to be based on a "higher" high-affinity binding of 111In-DOTA-DPhe1-Tyr3-octreotide to hSSTR2. Other somatostatin analogs with divergent affinity to the five known hSSTR subtype receptors have also found their way into the clinics, including 99mTc-HYNIC-octreotide or 99mTc-depreotide (NEOSPECT; NEOTECT). Most of the imaging results are reported for neuroendocrine tumors (octreotide analogs) or non-small cell lung cancer (99mTc-depreotide), indicating high diagnostic capability of this type of receptor tracers. Consequently to their use as receptor imaging agents, hSSTR recognizing radioligands have also been implemented for experimental receptor-targeted radionuclide therapy. The study "MAURITIUS" (MulticenterAnalysis of a Universal Receptor Imaging and Treatment Initiative, a eUropean Study), a Phase IIa study, showed in patients with a calculated tumor dose >10 Gy/GBq 90Y-DOTA-lanreotide, the proof-of-principle for treating tumor patients with receptor imaging agents. Overall treatment results in >60 patients indicated stable tumor disease in roughly 35% of patients and regressive disease in 15% of tumor patients with different tumor entities. No acute or chronic severe hematological toxicity, change in renal or liver function parameters due to 90Y-DOTA-lanreotide, was reported. 90In-DOTA-DPhe1-Tyr3-octreotide may show a higher tumor uptake in neuroendocrine tumor lesions and may therefore provide even better treatment results in tumor patients, but there is only limited excess to long-term and survival data at present. Besides newer approaches and recent developments of 188Re-labeled radioligands no clinical results on the treatment response is available yet. In conclusion, several radioligands have been implemented on the basis of peptide receptor recognition throughout the last decade. A plentitude of preclinical data and clinical studies confirm "proof-of-principle" for their use in diagnosis as well as therapy of cancer patients. However, an optimal radiopeptide formulation does not yet exist for receptor-targeted radionuclide therapy.     

Radiolabeled peptides in the diagnosis and therapy of oncological diseases.

There has been an exponential growth in the development of radiolabeled peptides for diagnostic and therapeutic applications in oncology. Peptides have fast clearance, rapid tissue penetration, low antigenicity and can be produced easily and inexpensively. However, peptides have problems with in vivo catabolism, unwanted physiological effects, and chelate attachment. The approved 111In-DTPA-OctreoScan, a somatostatin receptor binder, is well established for diagnosis of neuroendocrine tumors. NeoTect, an approved, 99mTc-labeled, somatostatin-receptor-binding analogue has good specificity for lung cancer detection. The receptors for Vasoactive Intestinal Peptide, Cholecystokinin-B/gastrin, Bombesin, Epidermal Growth Factor, and Alpha Melanocyte Stimulating Hormone and the Integrin, alpha(v)beta(3), are under active investigation as targets. Octreotide and its analogues labeled with 111In, 90Y, 64Cu or 177Lu are under study for the treatment of patients with promising results.     

放射性核素标记奥曲肽诊断小细胞肺癌的研究进展

小细胞肺癌是神经内分泌肿瘤,起源于APUD(胺前体摄取脱羧化)细胞。其细胞表面高水平表达SSTR(生长抑素受体)。奥曲肽是SST(生长抑素)的八肽类似物,它保留了SST类似的活性结构而且有更强的生物学效应和更长的生物半衰期,不易被降解。用放射性核素标记奥曲肽来诊断小细胞肺癌是一种较为理想的无创伤性检查方法。     

Ga-66 labeled somatostatin analogue DOTA-DPhe1-Tyr3-octreotide as a potential agent for positron emission tomography imaging and receptor mediated internal radiotherapy of somatostatin receptor positive tumors

Radionuclide labeled somatostatin analogues selectively target somatostatin receptor (SSTR)-expressing tumors as a basis for diagnosis and treatment of these tumors. Recently, a DOTA-functionalized somatostatin analogue, DOTATOC (DOTA-DPhe1-Tyr3-octreotide) has been developed. This compound has been shown to be superior to the other somatostatin analogues as indicated by its uniquely high tumor-to-non-target tissue ratio. DOTATOC can be labeled with a variety of radiometals including gallium radioisotopes. Gallium-66 is a positron emitting radionuclide (T(1/2) =9.5 hr; beta+=56%), that can be produced in carrier free form by a low-beam energy cyclotron. In this study we investigated SSTR targeting characteristics of 66Ga-DOTATOC in AR42J rat pancreas tumor implanted nude mice as a potential agent for diagnosis and receptor-mediated internal radiotherapy of SSTR-expressing tumors. We compared our results with 67Ga- and 68Ga- labeled DOTATOC. The radiolabeling procedure gave labeling yield ranged from 85-95% and radiochemical and chemical purity was > 95%. In-vitro competitive binding curves and in-vivo competitive displacement studies with an excess of unlabeled peptide indicates that there is specific binding of the radioligand to SSTR. Animal biodistribution data and serial microPET images demonstrated rapid tumor uptake and rapid clearance from the blood and all tissues except kidney. Maximum % ID/g values for tumor were 10.0 +/- 0.7, 13.2 +/- 2.1 and 9.8 +/- 1.5 for 66Ga-, 67Ga-, and 68Ga-DOTATOC, respectively. Calculated tumor, kidney and bone marrow doses for 66Ga-DOTATOC based on biodistribution data were 178, 109 and 1.2 cGy/MBq, respectively.We conclude that 66Ga labeled DOTATOC can be used for PET diagnosis and quantitative imaging-based dosimetry of SSTR positive tumors. 66Ga-DOTATOC may also be used in higher doses for ablation of these tumors. However, kidney is the critical organ for toxicity (tumor/kidney ratio = 1.64), and high kidney uptake must be eliminated before devising a therapy protocol.     

Role of positron emission tomography/computed tomography in adrenal and neuroendocrine tumors: fluorodeoxyglucose and nonfluorodeoxyglucose tracers

Positron emission tomography (PET) has seen an increasing clinical utilization in the last decade, such that it is now a standard oncology imaging modality. Its success is based on the detection of altered fluorine-18 fluorodeoxyglucose (18F-FDG) biodistribution, reflecting glucose transport/metabolism in malignant tumor tissues. Integrated PET/computed tomography cameras combine functional and anatomical information in a synergistic manner that improves diagnostic interpretation, and newer positron-emitting radiopharmaceuticals have been developed to expand the application of non-FDG PET imaging. The increasing use of cross-sectional imaging procedures has led to a more frequent detection of incidental adrenal masses. Although conventional imaging modalities such as computed tomography and MRI can characterize the majority of these lesions, 18F-FDG PET has been reported as a useful tool to distinguish benign from malignant etiologies in indeterminate adrenal masses. Although 18F-FDG PET has enjoyed success in staging a wide range of cancers, including detection of adrenal metastases and evaluation of adrenocortical carcinoma, it has had limited impact for the evaluation of neuroendocrine tumors. Positron-emitting amine precursor and somatostatin analogs have been validated in research settings to provide accurate imaging of enterochromaffin and chromaffin neuroendocrine tumors and medullary thyroid cancer. The aim of this review article is to provide an overview of the role of 18F-FDG and newer positron-emitting radiopharmaceuticals in the evaluation of adrenal and neuroendocrine tumors.     

Present status and progress of endocrine nuclear medicine

The author reviewed present status and progress of endocrine nuclear medicine including thyroid, parathyroid, adrenocortical, adrenomedullary and somatostatin receptor imaging and also radionuclide therapy of Basedow's disease, metastatic foci of post-operative thyroid cancer and malignant neural crest tumor. Relatively new imaging agents include 99mTc-MIBI and 99mTc-tetrofosmin for parathyroid imaging and 111In-pentetreotide for somatostatin receptor imaging. It is hoped that therapy of malignant neural crest tumors such as metastatic pheochromocytoma and neuroblastoma with 131I-MIBG and somatostatin receptor imaging will be available in Japan as soon as possible.