Gallium Dotatate Ga-68

01. 综述介绍 美国FDA批准的[177Lu]Lu-DOTA-TATE、[177Lu]Lu-PSMA-617等药物及其配套诊断剂，推动了靶向放射性药物治疗在肿瘤学临床实践中的广泛应用，开启了放射性药物的新时代。新一代放射性药物借助靶向载体，实现精准输送，避免靶外沉积，有望提升肿瘤诊断治疗效率和生物安全性。众多研究正开发针对更广谱疾病靶点的新型放射性药物，其在体内展现出高肿瘤摄取率、长滞留时间及良好药代动力学特性等卓越性能。 2025年1月3日，第十三、十四届全国政协常委，中国工程院院士（医药卫生学部），中国医学科学院学部委员，中国医学科学院药物研究所执行所长、北京协和医学院特聘教授，兰州大学一级教授、兰州大学原副校长，深圳大学院士工作站讲席教授，中国药学会副理事长，中华医学会常务理事，国家药典委员会执行委员，长江学者，国家杰青王锐教授与中国医学科学院药物研究所胡宽教授为共同通讯于《Signal Transduction and Targeted Therapy》( IF 40.8 )期刊发表题为“Radiopharmaceuticals and their applications in medicine”的综述，本综述全面总结了放射性药物的演变，涵盖FDA批准及临床在研的药物，并探讨细胞死亡机制，强调了治疗性放射性药物在精准医学推进中的重要性和未来前景。本文仅做概述，请检索原文拜读：https://doi-org.libproxy1.nus.edu.sg/10.1038/s41392-024-02041-6 02. 综述概览 自20世纪40年代初使用镭-223和碘-131治疗癌症以来，放射性药物的研究已经开展了至少80年，至今已有超过60种放射性药物被批准用于诊断或治疗各种癌症、神经退行性疾病和心血管疾病。自Lutathera（[177Lu]Lu-DOTA-TATE）、Pluvicto（[177Lu]Lu-PSMA-617）及诊断核药Netspot（[68Ga]Ga-DOTA-TATE）和Locametz（[68Ga]Ga-PSMA-11）获批以来，靶向放射性药物因其在癌症治疗中的卓越表现，引发了越来越多的关注。 推动核医学发展的三大关键因素是：放射性核素、设备以及药物。从天然放射性核素到人工放射性核素，新放射性核素的不断发现，为核医学的诞生与发展奠定了坚实基础。随着放射性核素在临床领域的广泛应用，其在疾病诊断与治疗中的重要作用日益凸显，这进一步激发了对各种先进诊断设备的强烈需求，促使相关设备研发与技术不断取得突破，从而推动核医学整体向前迈进。国际放射防护委员会（ICRP）发布的放射性核素目录涵盖了约1200种放射性核素，然而在临床和科学研究中，仅有几十种被广泛运用。 目前全球有67种放射性药物被批准，其中54种用于疾病诊断，用于成像的放射性药物在市场上广泛应用于恶性肿瘤、神经退行性疾病、心血管疾病以及其他疾病（如肾病综合征和肝肺综合征）的诊断。临床上使用的有34种SPECT放射性药物和20种PET放射性药物。对于SPECT检测的放射性核素，99mTc占70.6%，123I、111In、67Ga、125I和201Tl分别占11.8%、8.8%、2.9%、2.9%和2.9%。对于PET检测的放射性核素，18F因其适中的半衰期（109.8分钟）、灵活的回旋加速器生产以及成熟的标记方法而占据主导地位（65.0%）。此外，68Ga、11C、13N、64Cu和82Rb分别占15.0%、5.0%、5.0%、5.0%和5.0%。值得注意的是，68Ga在未来有潜力与177Lu或90Y作为诊断治疗对，64Cu也因其较长的半衰期（12.8小时）、在PET/CT成像中的高分辨率和检测率以及良好的安全性而受到越来越多的关注。 成像类放射性药物主要涵盖肿瘤成像（46.3%）、中枢神经系统成像（20.4%）、心血管成像（14.8%）、肾脏成像（7.4%）、肺部成像（3.7%）、肝脏成像（3.7%）以及骨骼成像（3.7%）等七个领域。诊断类核药的关键难题在于其在正常组织中的非特异性摄取，这会导致靶外或非靶向病变的摄取，进而干扰精准的临床诊断。例如，在区分神经炎症与神经退行性疾病相关区域、良性前列腺炎与前列腺癌时，可能会出现诊断混淆。此外，对于某些靶点（如PSMA）表达水平较低的患者，可能会遭遇检测陷阱，而结合能力较弱的诊断剂则可能无法有效检测低表达肿瘤。因此，亟需优化假阳性和假阴性诊断模式，以提升放射性药物诊断的准确性与效率。 目前全球有13种治疗性放射性药物被批准，且都用于治疗癌症。早期市场上的放射性药物缺乏肿瘤特异性，安全性不足。为了提高肿瘤的吸收和滞留，新的靶向放射性核素共轭小分子、肽和抗体已经得到了很好的开发，能够更精准地将放射性核素递送至肿瘤部位，从而提高治疗效果并减少对正常组织的损伤。治疗性药物虽能延长晚期癌症患者的生存期，但在临床实践中观察到的全身毒性，如骨髓抑制、口干和肾脏损伤等，可能引发严重的副作用。其他不良影响，包括耐药性和复发的可能性，亦需加以解决。总体而言，基于已获批的放射性药物，放射性核素在各领域的应用潜力巨大，仍有广阔的发展空间。此外，已获批的放射性药物可为研究人员提供宝贵的参考和指导，助力加速新药的研发进程。 确定合适的靶点对于核药的临床转化至关重要，这篇综述回顾了具有显著临床进展或显著癌症靶向能力的有前途的肿瘤靶点及其相关的放射性药物；讨论了这些靶点在其他领域的潜在应用，例如在心血管成像中使用肿瘤特异性靶点，预测未来将实现临床应用；总结了这些靶点的药理学特征，以及对代表性放射性药物的当前研究和临床进展，并对其未来发展提供了见解；介绍了涉及肿瘤定向放射性药物靶点的临床评估放射性药物的化学结构，以下仅做部分展示，建议读者朋友检索原文仔细拜读。 FAP, PSMA, SSTR 靶点的化学结构及相关信息： Integrin、CXCR4、GRPR、UPAR、NTSR-1和Nectin-4的化学结构及相关信息： 涉及免疫相关靶点的化学结构及相关信息： 涉及神经系统疾病靶点的化学结构及相关信息： 放射性药物的治疗效果是通过放射性核素产生的电离辐射实现的，这种辐射会导致DNA损伤和靶向细胞死亡。尽管对放射性药物治疗（RPT）的确切机制和独特要素了解不足，但多项研究揭示了放疗引起的辐射诱导细胞死亡所涉及的多个关键细胞过程。这篇综述对放射性药物治疗机制的当前理解进展进行了总结，基于对放疗引起的生物学效应的知识评估放射性药物诱导细胞毒性的潜在机制，包括直接DNA细胞死亡、活性氧（ROS）介导的细胞死亡和免疫原性细胞死亡。 03. 小结 未来放射性药物的研发还需重点关注的临床需求如下：一方面，要聚焦如何突破现有诊断局限，实现对那些隐匿性强、当前方法难以察觉疾病的精准、早期诊断，为患者的后续治疗争取宝贵先机；另一方面，对于那些接受化疗、放疗、免疫检查点阻断或靶向治疗后疗效欠佳的癌症患者，如何改善他们的预后，也是亟待攻克的难关。未来仍需要临床医生和不同领域研究人员的通力协作，为放射性药物的蓬勃发展注入源源不断的动力，推动其迈向更为广阔的未来。 文末附上了原文链接，方便读者检索拜读。 ●肾癌诊断核药赛道迎来重磅进展！ ●Alpha-9的GRPR核药随感笔记 ●近期颗粒酶B新核药的临床研究 ●ESMO 2024：核药笔记 声明：本文观点仅代表小核本人，视角局限，欢迎批评指正；如需转载，请务必注明文章作者和来源。如有其它问题，请在本平台留言或联系xiaoheshuoheyao777@163.com，小核将在第一时间处理。 内容编辑 | 小核 排版设计 | 小核 媒体合作 | 科研宣传 | 转载开白 xiaoheshuoheyao777（小核微信）

This article will inventory the anti-tumor targets in the GPCR family and the therapeutic drugs that have been marketed. 01 GnRHRGonadotropin-Releasing Hormone Receptor is a member of the seven-transmembrane GPCR (G protein-coupled receptor) family. It is expressed on the surface of pituitary gonadotropin cells, as well as lymphocytes, mammary glands, ovaries, and prostates. Upon binding with gonadotropin-releasing hormone, the receptor associates with G proteins that activate the phosphatidylinositol-calcium second messenger system. Activation of the receptor ultimately leads to the release of gonadotropins: luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Leuprolide (Leuprorelin) is a synthetic analogue of gonadotropin-releasing hormone (GnRH) developed by Takeda Pharmaceuticals, commonly used for treating certain types of hormone-dependent cancers, such as prostate and breast cancers, as well as non-cancerous conditions like endometriosis, uterine fibroids, and certain types of infertility. Leuprolide mimics the natural GnRH signals in the brain, initially causing a transient increase in hormone levels, followed by suppression of hormone production, thereby reducing symptoms and growth of these hormone-dependent diseases. Leuprolide is an injectable, administered via subcutaneous or intramuscular injection. Due to its control over hormone levels, Leuprolide is also used in treating precocious puberty in children. Additionally, GnRH analogues such as Goserelin developed by AstraZeneca, Buserelin by Sanofi, Nafarelin by Pfizer, and Gonadorelin by Mitsubishi Tanabe are all agnostic drugs of the GnRHR type. In recent years, antagonist drugs targeting GnRHR have also been reported for the treatment of certain hormone-dependent diseases. For instance: Degarelix is a GnRH receptor antagonist developed by Ferring Pharmaceuticals for the treatment of prostate cancer. It is also the first antagonist drug targeting the GnRHR globally, inhibiting the production of sex hormones (such as testosterone) by blocking the GnRH receptor, thereby suppressing the growth of prostate cancer cells. It is typically administered as an injection, rapidly reducing testosterone levels to castration levels. Ferring Pharmaceuticals subsequently licensed the commercial rights for Degarelix to Astellas and Pfizer. Relugolix is another GnRH receptor antagonist used for treating advanced prostate cancer. It also works by blocking the GnRH receptor and lowering sex hormone levels. Relugolix is also under investigation for the treatment of uterine fibroids and endometriosis. Relugolix was originally developed by Takeda Pharmaceuticals and is the first small molecule drug globally targeting the GnRH receptor. Linzagolix is an oral GnRH receptor antagonist for the treatment of various hormone-dependent diseases including endometriosis and uterine fibroids. Linzagolix has been approved in the European Union and the UK for treating moderate to severe symptoms associated with uterine fibroids. 02 SSTRThe Somatostatin Receptor Type (SSTR) belongs to the GPCR (G-protein-coupled receptor) family and comprises five subtypes (SSTR1-SSTR5). SSTRs play a critical role in the endocrine and nervous systems and are potential targets for the treatment of multiple diseases, particularly neuroendocrine tumors (NETs). Somatostatin (SST) is the natural ligand for SSTRs, and cortistatin (CST) is a neuropeptide that also binds with high affinity to all subtypes of SSTRs. Due to the high sequence homology between different SSTR subtypes, developing drugs that can selectively modulate specific subtypes presents a challenge, but this is essential for minimizing off-target effects. In targeted SSTR therapies, peptide radioligand therapies represent a significant research focus. For instance, Novartis's (177Lu)Lutathera, a peptide radioligand therapy targeting SSTR2, has been approved for the treatment of adult patients with SSTR-positive gastroenteropancreatic neuroendocrine tumors. The illustration below shows the differential tissue distribution of various SSTRs. Exploring dual-target drugs is an innovative direction, where the advantage of bi-targeted radiopharmaceuticals lies in the potential synergistic effects between the two targets, thereby enhancing safety and efficacy. Radiopharmaceutical development is exploring new indications such as pancreatic cancer, renal cancer, stomach cancer, thyroid cancer, lung cancer, and Parkinson's disease to broaden the therapeutic spectrum. Somatostatin is a polypeptide hormone composed of 14 amino acid residues, including a single disulfide bond. This hormone inhibits the secretion of growth hormone, insulin, glucagon, gastrin, pancreatic enzymes, and thyrotropin. However, due to its very short half-life in the body (less than 3 minutes), its therapeutic value is limited. Research on the β-turn pharmacophore of somatostatin has led to the development of more biologically stable and potent analogs. Octreotide was developed based on this lead sequence and approved for treating acromegaly, adenomas, and pancreatic, breast, and prostate tumors. DOI: 10.3390/molecules25174012 Subsequent research has pushed the development of selective receptor antagonists such as lanreotide, vapreotide, and pasireotide, and has introduced peptide imaging and peptide receptor radionuclide therapy. In these radiological therapies, radioactive elements like 111In, 90Y, 68Ga, or 99mTc are linked to selective somatostatin analogs through chelating groups, which led to the approval of radiopharmaceutical preparations such as 111In-labeled pentetreotide, 99mTc-labeled depreotide, 68Ga-labeled DOTA-TATE and DOTA-TOC, and 64Cu-labeled DOTA-TATE. These drugs are used for tumor detection. Several synthetic peptides and radiopharmaceuticals targeting SSTRs have been approved for market, with representative drugs including: Octreotide, developed by Novartis as a synthetic octapeptide somatostatin analog, is an SSTR agonist. Clinically, it is primarily used to treat conditions such as acromegaly, thyrotoxicosis, gastrointestinal fistulas, and symptoms and signs associated with gastroenteropancreatic neuroendocrine tumors. Octreotide inhibits the secretion of growth hormone, thyroid-stimulating hormone, insulin, and glucagon by binding to SSTRs, especially subtypes SSTR2 and SSTR5. Pentetreotide is another synthetic octapeptide that, unlike Octreotide, forms the radioactive drug 111In-pentetreotide by binding to the radiolabeled isotope Indium-111 via the chelator DTPA. This compound enables the use of Pentetreotide in single photon emission computed tomography (SPECT) imaging to detect tumors expressing SSTRs. It has a relatively fast renal clearance rate, offering a significant advantage over the first-generation [123I-Tyr3]-octreotide, a radioactive iodine-labeled octapeptide somatostatin analog. However, it has shortcomings, such as the need for a high tumor/noise intensity ratio, lower imaging resolution, medium affinity for receptors, and high γ-energy, which results in a higher radiation dose to patients. 111In-pentetreotide Lanreotide is a synthetic somatostatin analog, belonging to octapeptide derivatives. It has structural and functional similarities to Octreotide, but with different pharmacokinetic properties that make it a long-acting somatostatin analog. Gallium Dotatate Ga-68, developed by Advanced Accelerator Applications, is a radioactive diagnostic agent that uses DOTA to chelate Gallium-68 for positron emission tomography (PET) imaging, mainly targeting neuroendocrine tumors (NETs) expressing somatostatin receptors. The three radioactive drugs differ slightly in pharmacokinetic properties, primarily due to variations in affinity for specific receptor subtypes. [68Ga]-DOTATATE specifically binds to SSTR2, indicating its primary interaction with this receptor subtype; [68Ga]-DOTATOC has high affinity for SSTR2 and moderate affinity for SSTR5; while [68Ga]-DOTANOC shows high affinity for SSTR2, SSTR3, and SSTR5, making it a broad-target drug for multiple receptor subtypes. Lutetium Lu-177 dotatate, another therapeutic radiopharmaceutical developed by Advanced Accelerator Applications, targets tumor cells by binding to SSTR, particularly SSTR2 subtype. This binding allows the radioactive isotope Lutetium-177 to emit β-particles, thereby killing tumor cells. Yttrium-90 (a pure high-energy β-emitter with a half-life T1/2 = 64 hours) and Lutetium-177 (a moderate energy β-emitter with a half-life T1/2 = 6.7 days) are the most commonly used elements in peptide receptor radionuclide therapy. Each has specific advantages for targeted therapy. 90Y has higher particle energy and penetration, useful for treating larger tumors, while 177Lu, emitting lower-energy radiation, is better suited for smaller tumors. Additionally, its γ-radiation energy allows for scintigraphy scanning and dose determination during therapy. The image above shows [68Ga]-DOTATOC (commercial name Somakit®) and [177Lu]-DOTATATE (commercial name Lutatherav®), which are used to treat patients with progressive metastatic midgut neuroendocrine tumors. In October 2017, Novartis acquired French innovator Advanced Accelerator Applications for $3.9 billion to build and expand its radioligand therapy platform. In 2018, Novartis further invested $2.1 billion to acquire the biopharmaceutical company Endocyte, gaining more radiopharmaceutical candidates. Through these acquisitions, Novartis has established and expanded its radioligand therapy platform, holding several marketed products like Lutathera (177Lu-DOTATATE) and 68Ga-Edotreotide, along with many in development, including 177Lu-PSMA-617, 177Lu-PSMA-R2, 177Lu-NeoB, 177Lu-FF58, and 255Ac-PSMA-617. According to the Synapse database, multiple drugs targeting SSTRs or selectively targeting different SSTR subtypes are approved for the market or are in clinical research, with radiopharmaceuticals and diagnostics focusing on this target being particularly noteworthy. How to obtain the latest research advancements in the field of biopharmaceuticals? In the Synapse database, you can keep abreast of the latest research and development advances in drugs, targets, indications, organizations, etc., anywhere and anytime, on a daily or weekly basis. Click on the image below to embark on a brand new journey of drug discovery!