18F-PSMA-1007

01. 背景简介2025年6月10日，瑞士生物技术公司Philochem AG与百时美施贵宝（Bristol-Myers Squibb）旗下全资子公司RayzeBio共同宣布达成一项具有里程碑意义的战略合作：Philochem将其自主研发的前列腺癌靶向放射性药物OncoACP3的全球独家开发、生产及商业化权益授予RayzeBio。此项交易潜在总价值高达13.5亿美元（约合人民币97亿元），创下本领域交易纪录。根据双方签署的授权协议，RayzeBio将向Philochem支付3.5亿美元的预付款，并承诺在达成特定开发、注册及销售里程碑后，支付最高可达10亿美元的额外款项。此外Philochem还将获得基于OncoACP3全球净销售额的分层特许权使用费，其比例将随销售额增长从个位数提升至低双位数。目前该交易已进入监管审批流程，预计将于2025年第三季度完成全部审批程序后正式生效。酸性磷酸酶3（ACP3）作为前列腺癌治疗的新型靶点，较传统PSMA靶点具有显著临床优势：其在癌变组织中特异性高表达，而在健康组织（除正常前列腺外）几乎不表达，展现出近乎完美的肿瘤选择性。这一特性有效解决了PSMA靶向治疗面临的关键临床挑战——既克服了部分患者因PSMA低表达/不表达导致的治疗失效问题，又显著降低了唾液腺和肾脏等正常组织的放射性损伤风险。更重要的是，ACP3与PSMA不存在交叉耐药性，为对现有PSMA靶向疗法耐药的患者提供了全新的治疗选择，有望填补当前临床治疗空白。临床前研究数据充分验证了ACP3靶向放射性药物的突破性优势：68Ga-OncoACP3（诊断用）和177Lu-OncoACP3（治疗用）在肿瘤组织中表现出快速的特异性积累特性，同时保持对正常器官的极低摄取水平。这种"高靶向效率"与"超低背景信号"的双重特性，不仅显著提升了肿瘤/背景信号比（如177Lu-OncoACP3在极低剂量5-20MBq/小鼠时仍显示显著抗肿瘤活性），更规避了传统核药对肾脏、唾液腺等非靶组织的损伤风险。其独特的药代动力学特征——包括肿瘤滞留时间延长和肝胆系统主导的排泄途径——为开发"同类最优"（Best-in-Class）前列腺癌靶向诊疗一体化方案奠定了坚实基础。02. 研究内容本研究共纳入10例男性前列腺癌患者，中位年龄为67岁，年龄范围为52至79岁。所有患者在注射121 MBq（3.2 mCi）[68Ga]Ga-OncoACP3-DOTA后49分钟（中位时间，范围38-66分钟）接受了PET/CT扫描。在研究过程中，未观察到任何副作用。此外，8例患者在注射212 MBq（5.7 mCi）[18F]F-PSMA-1007后116分钟（中位时间）接受了PET/CT或PET/MRI，时间间隔为30天（中位时间：19天）。这张对比图直观展示了新型示踪剂[⁶⁸Ga]Ga-OncoACP3-DOTA与传统[¹⁸F]F-PSMA-1007在前列腺癌显像中的性能差异。10例患者（#1-#10）的全身PET成像显示：红色箭头标注的原发灶、绿色箭头的淋巴结转移和蓝色箭头的骨转移在两种示踪剂下的显影效果存在显著差异。结果显示，[68Ga]Ga-OncoACP3-DOTA PET成像显示了良好的生物分布，主要通过肝脏和肾脏排泄。与PSMA PET相比，ACP3 PET在肝脏和肾脏的摄取显著较低（肝脏平均SUVmean：ACP3为4.3，PSMA为13.2，p < 0.001；肾脏实质平均SUVmean：ACP3为7.0，PSMA为14.5，p < 0.001）。此外未观察到[68Ga]Ga-OncoACP3-DOTA对任何健康器官的明显特异性结合（见图1），骨骼、骨骼肌、肺和脂肪的背景摄取相似且较低（所有ACP3 SUVmean ≤ 1）。在那些表现出特异性PSMA摄取的器官中，ACP3的摄取显著较低（腮腺平均SUVmean：ACP3为1.3，PSMA为17.3，p < 0.001；泪腺平均SUVmean：ACP3为1.2，PSMA为8.6，p < 0.001）。唯一例外的是，与PSMA相比，ACP3在血液中的保留量更高（血液平均SUVmean：ACP3为4.0，PSMA为1.1，p < 0.001）。这张对比图显示[⁶⁸Ga]Ga-OncoACP3-DOTA在3名患者（#8、#9、#10）注射后早期（38-52分钟）与晚期（109-227分钟）扫描的最大强度投影对比图。可见转移灶摄取随时间增加（箭头标示）及胆汁排泄增多现象。ACP3 PET在所有10位患者中均清晰地显示出前列腺癌的病灶表现，涵盖了局部区域疾病、淋巴结以及骨转移等多种情况。在8位同时接受ACP3和PSMA PET检查的患者中，有5位患者的健康前列腺组织显示出相似的摄取水平（p > 0.05）。在3位患者的局部前列腺癌病灶中，有2位患者的对比度倾向于ACP3更优（SUVmax ACP3与PSMA的对比：14.1与5.0，30.5与7.1，无局灶性摄取与13.9）。在2位患者的淋巴结转移病灶中，ACP3检测到的淋巴结数量更多，且摄取水平更高（检测到的淋巴结数量ACP3与PSMA的对比：10与7，14与8；平均SUVmax：36.7与17.0，18.7与9.2）。虽然骨转移检测结果存在个体差异（1/6例ACP3更优，2/6例PSMA更优，3/6例相当），但延迟扫描（平均180分钟）显示ACP3具有独特的药代动力学优势：血液放射性降低50%的同时，转移灶摄取增加161%。这些数据充分证明[68Ga]Ga-OncoACP3-DOTA PET在前列腺癌诊疗、特别是转移灶检测方面具有重要临床价值。03. 小结目前68Ga-OncoACP3作为诊断探针已进入I期临床试验（NCT06840535），初步数据进一步验证了其优异的肿瘤选择性和成像靶向性，为后续治疗性核药的精准应用奠定了基础。●Debiopharm携手Alkyon共推下一代放射性配体疗法●基于[188Re]Re的新型FAP诊疗核药！●新型FAP探针及其首个临床转化研究●新型PSMA双模态探针及其首个临床研究声明：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）

Radiopharmaceuticals, which combine radioactive isotopes with specific molecular carriers, are ushering in a new era of personalized medicine. These specialized drugs precisely target diseased tissues within the human body and release ionizing radiation for diagnostic or therapeutic purposes, significantly enhancing the accuracy and effectiveness of disease management. From traditional thyroid function tests to their current widespread application in cancer, cardiovascular diseases, and neurodegenerative disorders, the development of radiopharmaceuticals reflects how advancements in science and technology are driving innovation in medicine. With the advent of cutting-edge technologies such as radioligand therapies (RDCs), radiopharmaceuticals are not only improving the accuracy of tumor diagnostics but also offering new treatment options for previously intractable diseases. Notably, innovative drugs such as 177Lu-PSMA-617 and 18F-PSMA-1007 are leading the way in precision medicine for malignancies like prostate cancer and renal cell carcinoma. Mechanism of Action of RadiopharmaceuticalsRadiopharmaceuticals, also known as radioactive drugs or radionuclide formulations, are specialized agents that utilize radioactive isotopes bound to specific molecular carriers for medical diagnosis and treatment. These compounds can selectively target specific areas of the body—such as tumors or other diseased tissues—and emit ionizing radiation to fulfill their intended function. Over the past decades, the application of radiopharmaceuticals has expanded from traditional thyroid diagnostics to the treatment and imaging of cancer, cardiovascular conditions, and neurodegenerative diseases. With technological progress, especially in radioligand therapy, radiopharmaceuticals can act more precisely on target cells while minimizing damage to surrounding healthy tissues. The introduction of alpha-particle emitters has brought new hope to therapy, thanks to their higher cytotoxicity and shorter range, making them especially suitable for hard-to-treat tumors. Mechanism of Action of RDC Drugs1The mechanism by which radiopharmaceuticals function in cancer treatment relies on the ionizing radiation emitted by radioactive isotopes. This radiation damages the DNA of cancer cells, inhibiting their division and proliferation. Different isotopes emit various types of radiation, such as beta particles or alpha particles, each affecting cancer cells differently. Beta particles, which have moderate penetration ability, can affect cancer cells several cell diameters away, creating a "crossfire effect" that extends the therapeutic range. In contrast, alpha particles possess extremely high energy density and short range, enabling them to inflict severe damage within a limited area—often requiring only a few alpha particles to pass through a cancer cell nucleus to achieve cytotoxicity. One of the key advantages of radiopharmaceuticals lies in their high specificity and low systemic toxicity. By conjugating radioactive isotopes to targeting ligands—such as antibodies or specific peptides—the isotopes can accumulate selectively in tumor sites, substantially increasing the local radiation dose while minimizing exposure to healthy tissue. This strategy not only improves therapeutic efficacy but also reduces the incidence of side effects. In addition, some radiopharmaceuticals can also serve diagnostic purposes, allowing physicians to monitor disease progression in real time during treatment—thus achieving a theranostic (therapy + diagnostic) approach. Another benefit is their low likelihood of inducing drug resistance. Because their mechanism of action differs from that of conventional chemotherapeutics, cancer cells have a harder time developing resistance. Therefore, radiopharmaceuticals can be used as standalone therapies or in combination with other modalities, such as immunotherapy, to enhance overall treatment outcomes. Radioligand therapy (RLT), also known as radioimmunotherapy or radionuclide-conjugated drug therapy, involves binding a radioactive isotope to a molecule that targets specific cancer cells. This approach uses the emitted particles from radioactive substances to damage cancer cell DNA, thereby halting their growth and division. RLT plays a pivotal role in precision medicine, offering highly selective treatment of tumors while minimizing collateral damage to healthy tissues. The core of RLT lies in the use of radioligands—compounds composed of four key elements: a targeting moiety (e.g., antibody, peptide, or small molecule), a linker, a chelator, and a radioactive isotope. Once administered, these radioligands seek out and bind to overexpressed biomarkers on cancer cell surfaces. Upon binding, the isotope emits radiation that directly damages the cancer cell’s DNA, leading to cell death. Additionally, the so-called “bystander effect”—in which ionization of nearby water molecules produces free radicals—can also contribute to the destruction of adjacent cancer cells. Application of Radiopharmaceuticals in Cancer Treatment1）177Lu-PSMA-617 177Lu-PSMA-617 is an innovative targeted radioligand therapy specifically designed for the treatment of metastatic castration-resistant prostate cancer (mCRPC). This therapy achieves high selectivity and precision in targeting prostate cancer cells by combining Lutetium-177—a radioactive isotope that emits beta particles—with a small-molecule compound that specifically binds to prostate-specific membrane antigen (PSMA). Schematic overview of the structure of a PSMA receptor1177Lu-PSMA-617 circulates in the bloodstream, identifying and binding to prostate cancer cells that overexpress PSMA. PSMA is highly expressed on the surface of prostate cancer cells and their metastases, while its expression in normal tissues is minimal. This allows the drug to effectively target cancer cells while sparing most healthy tissues. Once bound to PSMA on the surface of cancer cells, 177Lu-PSMA-617 is internalized. Inside the cell, Lutetium-177 emits beta particles that cause DNA damage, impairing the cancer cell's ability to replicate or inducing cell death directly. Although these beta particles are potent enough to destroy cancer cells, their limited penetration range—typically just a few millimeters—means that surrounding healthy tissues are largely unaffected. This reduces systemic side effects and enhances the safety profile of the treatment. The VISION study demonstrated that 177Lu-PSMA-617 in combination with the best standard of care (SOC) provides significant benefits over SOC alone in terms of prolonging overall survival (OS) and radiographic progression-free survival (rPFS). Specifically, patients treated with 177Lu-PSMA-617 showed higher overall survival rates and longer progression-free periods, along with improved objective response rates and disease control rates. Despite its high specificity and efficacy, 177Lu-PSMA-617 is not without side effects. For instance, salivary gland dysfunction may occur due to off-target uptake, as salivary glands also express PSMA. Therefore, during clinical application, physicians must closely monitor patients and take appropriate measures to manage and mitigate potential adverse effects. 2) 177Lu-Rosopatamab Tetraxetan TLX591 (177Lu-Rosopatamab Tetraxetan) is another radiolabeled compound that targets prostate-specific membrane antigen (PSMA). It couples the radioactive isotope 177Lutetium with the monoclonal antibody rosopatamab tetraxetan. Rosopatamab tetraxetan specifically recognizes and binds to PSMA, which is overexpressed on the surface of prostate cancer cells. 177Lutetium serves as a beta particle emitter, delivering cytotoxic radiation that damages the DNA of cancer cells. Upon administration, rosopatamab tetraxetan seeks out and attaches to PSMA-positive prostate cancer cells, enabling 177Lutetium to emit beta radiation with sufficient energy to destroy nearby tumor cells while limiting damage to distant healthy tissue, thus preserving normal function. Multiple completed Phase I and II clinical trials have shown that TLX591 has a favorable safety and efficacy profile, and have validated the effectiveness of optimized fractionated dosing regimens. The ProstACT SELECT study demonstrated that, in patients with progressive mCRPC who had already undergone treatment, the median radiographic progression-free survival (rPFS) following TLX591 therapy was 8.8 months, indicating significant clinical benefit. Moreover, TLX591 is currently being evaluated in a Phase III international, multicenter, randomized controlled trial named ProstACT GLOBAL—the first such study targeting PSMA-positive mCRPC patients—to further assess its efficacy and safety compared to standard-of-care therapies. Grand Pharmaceutical has acquired the rights to develop and commercialize TLX591 in the Chinese market through a collaboration with Telix Pharmaceuticals. This strategic partnership not only facilitates the introduction of innovative therapies in China but also enhances the company’s global R&D and manufacturing capabilities, supporting the advancement of cutting-edge cancer diagnosis and treatment solutions. With TLX591's promising performance in the international market and its progressing rollout in China, it is expected to offer a new therapeutic option for prostate cancer patients in the coming years. Application of Radiopharmaceuticals in Early Tumor Diagnosis1) 18F-PSMA-1007 18F-PSMA-1007 is a positron emission tomography (PET) imaging agent specifically used for the diagnosis and staging of prostate cancer. This radiotracer targets prostate-specific membrane antigen (PSMA), which is highly expressed in prostate cancer cells, particularly in cases of recurrence or metastasis. By labeling a small-molecule PSMA inhibitor with the radioisotope fluorine-18 (18F), 18F-PSMA-1007 enables highly sensitive and specific detection of prostate cancer lesions. 18F-PSMA-1007 PET/CT (arrow) staining of the PSMA-positive primary tumor2For patients who experience a rise in serum PSA levels after radical prostatectomy, recurrence is often suspected. However, traditional imaging techniques frequently fail to precisely localize recurrent lesions. 18F-PSMA-1007 PET/CT has demonstrated significant advantages in detecting small lesions in such patients due to its high sensitivity and specificity, enabling earlier detection of recurrence and timely adjustment of therapeutic strategies. In patients with PSA levels in the “gray zone” (i.e., between 4 and 10 ng/mL), determining the presence of prostate cancer poses a diagnostic challenge. 18F-PSMA-1007 PET/CT, when combined with PSA-derived indicators such as PSA density (PSAD), can improve diagnostic accuracy in this group and reduce the number of unnecessary biopsies. This approach not only helps avoid overdiagnosis and overtreatment but also provides more precise therapeutic guidance for patients who do have prostate cancer. 18F-PSMA PET/CT for primary staging showed high PSMA uptake in the prostate gland2By leveraging radiomics models based on 18F-PSMA-1007 PET/CT, researchers can extract numerous features from PET images and analyze them using machine learning algorithms to effectively distinguish prostate cancer from benign prostatic hyperplasia (BPH). This enhances diagnostic accuracy and contributes to more evidence-based clinical decision-making. Studies also suggest that 18F-PSMA-1007 PET/CT can be used to predict the pathological grade of prostate cancer, which is critical for prognosis assessment. This imaging technique provides important insights into tumor biology, enabling the formulation of personalized treatment plans. Compared to conventional 18F-FDG PET/CT, 18F-PSMA-1007 PET/CT offers higher sensitivity and specificity in detecting bone metastases from prostate cancer. This improves the detection of distant metastases, which is particularly important in managing advanced prostate cancer. Moreover, for suspected metastatic cases, the combined use of 18F-FDG and 18F-PSMA-1007 PET/CT can further enhance staging accuracy and guide clinical treatment decisions. 2) TLX250-CDx (89Zr-TLX250) TLX250-CDx (89Zr-TLX250) is a radiopharmaceutical diagnostic conjugate (RDC) that targets carbonic anhydrase IX (CA9) and is specifically designed for the diagnosis of clear cell renal cell carcinoma (ccRCC). Zirconium-89 (89Zr) is a positron-emitting isotope with a physical half-life of approximately 78.4 hours, making it well-suited for use with monoclonal antibodies due to its alignment with the biological distribution timeline of antibodies in the body. This allows 89Zr-labeled antibodies to achieve optimal tumor accumulation, thereby improving imaging sensitivity and specificity. The anti-CA9 antibody used in TLX250-CDx binds selectively to the CA9 protein, which is overexpressed on the surface of cancer cells. CA9 expression is minimal in normal tissues but significantly elevated in various cancers, especially ccRCC, making it an ideal diagnostic target. Scheme of the bioconjugation and radiolabeling of 89Zr-TLX2504Once injected into the patient, TLX250-CDx circulates through the bloodstream and accumulates at tumor sites due to its high affinity for CA9. Using PET imaging, detailed in vivo images can then be generated, revealing the tumor’s location, size, and potential metastasis. This method not only improves diagnostic accuracy but also avoids the risks associated with invasive procedures such as biopsies. In the pivotal Phase III ZIRCON clinical trial, TLX250-CDx demonstrated outstanding performance. For patients suspected of having ccRCC but not yet diagnosed, the agent achieved a sensitivity of 86% and specificity of 87% in diagnosing ccRCC, with a positive predictive value (PPV) of 93%. These results suggest that TLX250-CDx could become a vital non-invasive diagnostic tool, enabling more precise clinical decision-making. In addition to ccRCC, ongoing research is exploring the utility of TLX250-CDx in other CA9-expressing cancers, such as bladder cancer and urothelial carcinoma. These cross-indication studies could expand the market potential of TLX250-CDx and provide effective diagnostic solutions for a broader range of cancers. ZIRCON is a global Phase III clinical trial designed to evaluate the efficacy and safety of TLX250-CDx in diagnosing ccRCC. The results have been encouraging: for patients with renal masses identified by CT or MRI but not definitively diagnosed as ccRCC, TLX250-CDx PET imaging showed 86% sensitivity and 87% specificity, with a PPV of 93%. These figures far exceed the U.S. FDA’s predefined thresholds (sensitivity and specificity ≥70%), indicating that TLX250-CDx has strong potential to become a new clinical diagnostic standard for ccRCC. Beyond its diagnostic role in ccRCC, TLX250-CDx has shown promise in other cancer types. Studies are underway to assess its use in triple-negative breast cancer (TNBC), non-muscle-invasive bladder cancer (NMIBC), and urothelial carcinoma. If approved, TLX250-CDx would become the first commercially available imaging agent for ccRCC, addressing a significant unmet need. Given the often asymptomatic nature of early-stage kidney cancer, many patients are diagnosed at an advanced stage. Therefore, the early diagnostic capabilities provided by TLX250-CDx could substantially improve treatment outcomes and quality of life. ConclusionRadiopharmaceuticals offer tremendous potential in the diagnosis and treatment of cancer and other diseases due to their high selectivity and low systemic toxicity. They enhance diagnostic accuracy and enable earlier detection, while also providing safer and more effective therapeutic options for patients. For instance, 177Lu-PSMA-617 and TLX591 target prostate-specific membrane antigen (PSMA), bringing new hope to patients with metastatic castration-resistant prostate cancer (mCRPC); while 18F-PSMA-1007 and TLX250-CDx have shown remarkable success in the early diagnosis of prostate cancer and clear cell renal cell carcinoma (ccRCC), respectively. Furthermore, the use of these agents supports the development of theranostics—combining diagnosis and treatment—allowing clinicians to monitor disease progression in real-time and tailor treatment strategies to individual patient needs. 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! Reference 1.Chiliveri SC, Robertson AJ, Shen Y, Torchia DA, Bax A. Advances in NMR Spectroscopy of Weakly Aligned Biomolecular Systems. Chem Rev. 2022 May 25;122(10):9307-9330. doi: 10.1021/acs.chemrev.1c00730. Epub 2021 Nov 12. PMID: 34766756.2.van der Gaag S, Bartelink IH, Vis AN, Burchell GL, Oprea-Lager DE, Hendrikse H. Pharmacological Optimization of PSMA-Based Radioligand Therapy. Biomedicines. 2022 Nov 23;10(12):3020. doi: 10.3390/biomedicines10123020. PMID: 36551776; PMCID: PMC9775864.3.Jochumsen MR, Bouchelouche K. PSMA PET/CT for Primary Staging of Prostate Cancer - An Updated Overview. Semin Nucl Med. 2024 Jan;54(1):39-45. doi: 10.1053/j.semnuclmed.2023.07.001. Epub 2023 Jul 22. 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