Summary: Terbium-161 (161Tb) has emerged as an innovative and potentially more efficient alternative to Lutetium-177 (177Lu) in the field of targeted radionuclide therapy. Building on the existing success of Lutetium-177 Vipivotide tetraxetan (commonly referred to as 177Lu-PSMA-617) in prostate cancer management, 161Tb PSMA-I&T capitalises on the unique physical properties of terbium isotopes, particularly their emission of both beta (β–) and Auger/conversion electrons. This additional emission profile could translate into enhanced therapeutic efficacy by delivering a higher radiation dose to cancer cells. Furthermore, the versatility of the terbium family—specifically the possibility of developing alpha-emitting variants such as 149Tb—provides exciting prospects for customised and multimodal cancer treatments. A Phase 0/I clinical trial is set to begin at the Peter MacCallum Cancer Centre in Melbourne, Australia, heralding a potentially transformative step forward in precision oncology.
Keywords: Terbium-161; PSMA-I&T; Targeted Radioligand Therapy; Auger Electrons; Prostate Cancer; Beta Emission.
Introduction to Targeting Prostate Cancer
Prostate cancer remains one of the most common malignancies affecting men worldwide, and therapeutic strategies continue to evolve to address both early-stage disease and metastatic, treatment-resistant variants. Radionuclide therapies have gained significant traction in this domain because of their capacity to deliver cytotoxic radiation directly to cancerous tissue, thereby minimising harm to healthy cells. The success of Lutetium-177-based treatments, such as 177Lu-PSMA-617 (Vipivotide tetraxetan), has demonstrated the effectiveness of exploiting prostate-specific membrane antigen (PSMA) as a target for selective tumour destruction.
Recent advances in radiochemistry have paved the way for novel isotopes, including Terbium-161 (161Tb), which promises several advantages over established radionuclides. Terbium-161 emits beta minus (β–) radiation suitable for therapeutic applications and an additional spectrum of Auger/conversion electrons that could deliver higher doses of ionising radiation within a very short range. This combination can potentially overcome issues like tumour heterogeneity because even poorly vascularised tumour regions might receive sufficient radiation to achieve a therapeutic effect. Consequently, Terbium-161 PSMA-I&T—an analogue of 177Lu-PSMA-617—is being explored for its clinical potential, and a Phase 0/I trial is about to commence at the Peter MacCallum Cancer Centre in Melbourne, Australia.
In this article, we investigate the key attributes of Terbium-161, discuss its potential advantages over Lutetium-177, and outline the upcoming clinical investigations that may shape the future of prostate cancer management.
Understanding Terbium-161
Terbium is part of the lanthanide series of elements, akin to lutetium in many of its chemical properties. Terbium-161, in particular, is produced from Gadolinium-160 (160Gd) through neutron capture in a nuclear reactor. One of the most intriguing aspects of Terbium-161 is its emission profile, which includes beta particles with energies similar to those of Lutetium-177, making it well-suited for targeted therapy. However, it also releases low-energy Auger electrons and conversion electrons, which can lead to a higher linear energy transfer (LET) in the immediate vicinity of the radionuclide.
Physical Half-life and Emission Spectrum
The physical half-life of Terbium-161 is approximately 6.9 days, which is comparable to the half-life of Lutetium-177, around 6.7 days. This temporal similarity offers a logistical advantage for clinical use because it allows medical practitioners to follow similar preparation, administration, and patient management protocols as they would with Lutetium-177 therapies. The additional emission of Auger and conversion electrons is a significant differentiator, potentially delivering a potent dose of ionising radiation within a small radius of the radioligand’s location. This close-range cytotoxicity might become crucial for targeting micrometastases and single cancer cells that are often missed by conventional treatments.
Development of Terbium Analogues
One of the exciting prospects associated with Terbium-161 is the possibility of developing analogues of the same atom. Specifically, 149Tb stands out as an alpha-emitting isotope of terbium. Alpha particles are known for their extremely high linear energy transfer and short range, making them particularly destructive to cancer cells while sparing nearby healthy tissue. If researchers successfully harness both the beta-emitting (161Tb) and alpha-emitting (149Tb) isotopes under the same chemical platform, this could create a powerful dual-approach strategy, allowing oncologists to customise therapy based on individual patient profiles or even combine isotopes for more comprehensive tumour eradication.
Mechanism of Action and Target
PSMA is a transmembrane protein highly expressed on the surface of prostate cancer cells, making it an ideal target for radioligand therapy. Radiolabelled ligands bind to PSMA, facilitating the internalisation of the radioactive payload into cancer cells. Once inside the cell, the emitted radiation induces DNA damage, leading to apoptosis. In hormone-sensitive as well as castration-resistant prostate cancer, PSMA-targeted therapy has shown remarkable promise in reducing tumour burden and extending survival times.
Carrier/Ligand: PSMA-I&T
PSMA-I&T (Imaging & Therapy) is a ligand that binds specifically to PSMA, akin to PSMA-617, but with slight variations in its chemical composition and binding affinity. The choice of PSMA-I&T for Terbium-161 is not accidental: it has been proven effective in previous studies involving Lutetium-177, and researchers anticipate similar or superior results with 161Tb. By preserving the same targeting moiety, the transition from 177Lu-based therapy to 161Tb-based therapy can be seamless, as healthcare providers are already familiar with the procedures involved in preparing and administering these PSMA-targeted agents.
Radiation Type: Beta Electrons (β–) and More
Whereas Lutetium-177 primarily emits beta electrons, Terbium-161 offers beta electrons and an additional arsenal of Auger/conversion electrons. These Auger electrons possess extremely low penetration depth, which confines the radiation damage to a very localised region around the tumour cell. This characteristic reduces the likelihood of collateral damage to surrounding healthy tissues, thereby potentially improving the therapeutic index. The combination of beta radiation for broader tumour coverage and Auger electrons for focal high-energy deposition may provide a comprehensive attack on cancer cells, including those in micro-metastatic sites.
Clinical Development
Since the success of Lutetium-177 PSMA-targeted therapies, there has been a concerted effort to discover next-generation radionuclides that could offer increased efficacy or improved patient outcomes. Terbium-161 emerged as a leading candidate due to its favourable nuclear properties and the ease with which it can be integrated into existing radioligand frameworks. The demonstration of safety and efficacy in preclinical models has laid the groundwork for translating this technology into early-stage clinical trials, focusing first on the safe dosimetry and optimal administration methods.
Phase 0/I Trial at Peter MacCallum Cancer Centre
A Phase 0/I trial, scheduled to begin at the Peter MacCallum Cancer Centre in Melbourne, Australia, will be one of the first clinical investigations of Terbium-161 PSMA-I&T in humans. The trial aims to evaluate the safety, biodistribution, and preliminary therapeutic impact of 161Tb in patients with advanced prostate cancer. Phase 0 studies typically involve microdoses of the drug or radioligand to gather initial human data on pharmacokinetics and tissue targeting. Once safety and biodistribution are confirmed, researchers will escalate to higher doses under Phase I protocols to assess therapeutic response and refine dosing schedules.
Potential Protocol and Endpoints
The key endpoints for the Phase 0/I trial are expected to include safety metrics (such as incidence of adverse events and dosimetry in critical organs like kidneys and bone marrow), biodistribution (measured via imaging techniques), and preliminary efficacy (assessed through prostate-specific antigen (PSA) levels and imaging of tumour response). If these early-phase studies demonstrate an acceptable safety profile and encouraging signs of efficacy, subsequent Phase II and III studies could follow, potentially confirming 161Tb-PSMA-I&T as a new gold standard in the management of metastatic castration-resistant prostate cancer (mCRPC).
Advantages of Terbium-161 over Lutetium-177
The additional emission of Auger/conversion electrons by Terbium-161 has the theoretical potential to generate more robust tumour cell kill. Although beta particles can travel a few millimetres in tissue, Auger electrons exhibit a very short path length—often only a few nanometres. This short range means that the majority of ionising events occur within the immediate vicinity of the cancer cell. As a result, even subpopulations of cancer cells that may evade the path of beta radiation could be neutralised by the intense local energy deposition of Auger electrons.
High Versatility with Other Terbium Isotopes
The possibility of developing 149Tb for alpha-emitting therapy further underscores the versatility of the terbium family. In concept, a patient could receive an alpha/beta tandem therapy: 149Tb for high-energy, short-range alpha emissions that are especially lethal to malignant cells and 161Tb for a combination of beta emissions and Auger electrons. This dual approach could be used to cover a wide spectrum of tumour presentations, from large metastatic lesions (better tackled by beta particles) to microscopic tumour clusters and single disseminated cells (where alpha particles and Auger electrons might prove advantageous).
Similar Chemistry and Half-life
The half-life of Terbium-161 is roughly 6.9 days, which is closely aligned with Lutetium-177, simplifying logistics for nuclear medicine facilities. The chemical similarity between terbium and lutetium also means that many of the chelators and conjugation methods used for Lutetium-177 can be adapted to Terbium-161 with minimal modifications. This ensures a smoother transition in clinical practice, reducing training requirements and infrastructure changes.
Challenges and Considerations
One of the barriers to widespread clinical adoption of any novel radionuclide is reliable, large-scale production. Terbium-161 is generated by neutron irradiation of Gadolinium-160 targets, but this process must be optimised to ensure a consistent supply of clinical-grade material. Nuclear reactors with adequate capacity to produce the required quantities of Terbium-161 may not be universally available, potentially limiting the initial rollout of this therapy to specialised centres with established radiopharmacy capabilities.
Regulatory Hurdles
As with any new pharmaceutical or radiopharmaceutical agent, Terbium-161 PSMA-I&T must undergo extensive regulatory scrutiny. Authorities will examine everything from the radionuclide’s safety profile and dosimetry to its stability and efficacy in human trials. While the success of Lutetium-177 therapies may smooth the regulatory pathway, each new isotope must meet stringent criteria before receiving approval for commercial use. Consequently, it could be several years before Terbium-161-based treatments reach the broader market.
Financial and Logistical Considerations
New therapies often come with higher costs, reflecting research, development, and manufacturing expenses. Hospitals and cancer centres may need to invest in additional infrastructure, such as shielded rooms and specialised equipment, to handle Terbium-161 safely. Insurance coverage and reimbursement structures will also shape how readily patients can access this therapy. Policymakers and healthcare providers must evaluate cost-effectiveness in comparison to existing treatments, including 177Lu-PSMA-617, to ensure that resources are allocated optimally.
Potential Impact on Prostate Cancer Management
The field of nuclear medicine stands on the cusp of what might be a transformative era in prostate cancer management. Lutetium-177-based therapies have already shifted the paradigm by offering extended survival and improved quality of life to patients with advanced disease. Terbium-161, with its enhanced radiation emission profile, may further refine and bolster these benefits, potentially offering superior tumour control with fewer side effects.
Personalised Medicine Opportunities
Personalised medicine is no longer a distant concept but a reality in oncology. The combination of advanced imaging techniques, genomic profiling, and novel radionuclides could allow clinicians to tailor treatments to each patient’s unique tumour biology. If Terbium-161 PSMA-I&T proves safe and effective, oncologists could adjust the dosing or combine it with other isotopes—such as 149Tb—to create a personalised therapeutic regimen. This approach might be particularly beneficial for patients who have previously developed resistance to standard treatments or for those whose tumours show heterogeneous characteristics.
Synergy with Other Treatments
Radioligand therapy does not exist in isolation. Indeed, combining Terbium-161 with other treatment modalities—such as chemotherapy, immunotherapy, or targeted small molecules—could yield synergistic effects. For example, immunotherapies might be more effective after tumour cells have been sensitised or killed off by radiation, thereby exposing tumour antigens that stimulate an immune response. Meanwhile, chemotherapy agents could be administered in reduced doses alongside Terbium-161, limiting systemic toxicity while enhancing tumour kill. This multimodal approach reflects an emerging trend in oncological practice, aiming to exploit multiple vulnerabilities within the tumour at once.
Future Directions
The successful integration of Terbium-161 PSMA-I&T into clinical practice could open doors to exploring other radiopharmaceuticals that harness similar properties. Researchers are already examining various chelators and ligands to optimise the stability and targeting of 161Tb. In parallel, there is growing interest in the development of alpha-emitting terbium isotopes like 149Tb, which may complement or even supersede beta-emitting counterparts in specific clinical scenarios.
Extending Beyond Prostate Cancer
While the main focus at present lies in prostate cancer due to the proven utility of PSMA as a target, Terbium-161 could theoretically be applied to other malignancies. By simply swapping out the targeting ligand, clinicians might employ 161Tb for conditions such as neuroendocrine tumours or other cancers that exhibit specific molecular targets amenable to radioligand therapy. Such versatility would amplify the clinical impact of Terbium-161, just as Lutetium-177 has moved beyond prostate cancer into broader therapeutic uses.
Academic-Industry Collaborations
Bringing a new isotope to market requires close cooperation between academic research institutions, nuclear reactors, pharmaceutical companies, and healthcare providers. Clinical trials will generate the data needed to convince regulators and investors of Terbium-161 benefits. Still, these trials also hinge on a steady radionuclide supply and advanced radiopharmaceutical manufacturing capabilities. Hence, collaborative frameworks involving universities, cancer centres, and commercial partners will be critical for streamlining development and ensuring timely patient access.
Technological Innovations
Ongoing technological advances in nuclear medicine—such as more sensitive imaging modalities (e.g., PET/CT and PET/MRI), refined dosimetry software, and automated synthesiser modules for radiopharmaceutical production—will play a vital role in the rise of Terbium-161. These innovations can enhance the specificity and safety of radioligand therapies while also improving workflow efficiency and reducing costs. Automated production systems, for instance, minimise human exposure to radioactivity and facilitate batch consistency, thereby raising the overall standard of care.
Conclusion
Terbium-161 PSMA-I&T represents a promising evolution of prostate cancer radioligand therapy. By harnessing the power of both beta and Auger/conversion electrons, 161Tb offers the potential for enhanced tumour cell kill whilst retaining many of the advantageous properties of Lutetium-177, including a compatible half-life and established chelator technology. The capacity to develop alpha-emitting 149Tb analogues points towards a future where clinicians might tailor radionuclide therapy to the individual needs of patients, offering alpha, beta, or even dual-isotope treatments.
As the Phase 0/I trial at the Peter MacCallum Cancer Centre begins, the oncology community will eagerly await the results. Positive findings could accelerate the journey of Terbium-161 from bench to bedside, delivering improved outcomes for patients with advanced prostate cancer who currently have limited treatment options. In parallel, challenges related to production, regulation, and cost must be addressed, but the potential rewards in terms of survivorship and quality of life are substantial.
Radioligand therapy stands at the forefront of modern oncology, uniting molecular targeting with potent radioactive payloads. Terbium-161 is arguably the next step in this lineage, offering both continuity of proven methods and the promise of enhanced efficacy. Should its clinical results prove favourable, 161Tb-based therapies may well redefine the treatment paradigm for prostate cancer and potentially other malignancies. In this rapidly evolving landscape, the story of Terbium-161 PSMA-I&T will surely be one to watch over the coming years.
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