161Tb-PSMA radioligand therapy in prostate cancer: current evidence and future perspectives

Prostate-specific membrane antigen (PSMA), a type II transmembrane glycoprotein, is overexpressed on the membranes of prostate cancer cells. Lutetium-177 (¹⁷⁷Lu)- labelled PSMA-targeted radioligand therapy (PRLT) is employed in treating metastatic castration-resistant prostate cancer (mCRPC) that no longer responds to conventional therapies. However, some patients develop resistance or exhibit limited responsiveness, resulting in disease progression. Terbium-161 (¹⁶¹Tb) shares physical properties with ¹⁷⁷Lu, as both isotopes emit β^- particles. Notably, ¹⁶¹Tb also emits internal conversion and Auger electrons, offering potential advantages in the effective targeting of small lesions. This dual-emission mechanism enables the treatment of lesions of varying sizes, generating growing interest in ¹⁶¹Tb-labelled radioligand therapy for prostate cancer. This review summarizes current evidence on ¹⁶¹Tb-PSMA, including its mechanism of action, radiolabeling and quality-control procedures, dosimetry, preclinical results, and clinical outcomes, highlighting its therapeutic promise. Future investigations should further validate the safety and efficacy of ¹⁶¹Tb-PSMA radioligand therapy, while enhancing its accessibility and clinical translation.

1 Introduction

Prostate cancer (PCa) is the most prevalent malignant tumor of the male genitourinary system. According to GLOBOCAN 2022 data, PCa ranks second in global incidence and fifth in mortality among malignancies affecting men (1). In China, PCa is the sixth most commonly diagnosed cancer and the seventh leading cause of cancer-related death (2), with the number of new cases increasing annually. A significant proportion PCa cases are diagnosed at intermediate or advanced stages. Approximately 5%–15% PCa cases are metastatic at initial diagnosis; this proportion can increase to 20%–25% or even higher in countries with limited medical resources (3). Androgen deprivation therapy (ADT) is as a cornerstone in the treatment of newly diagnosed hormone-sensitive PCa (HSPC) and advanced PCa. ADT is utilized across all treatment stages of PCa, except for very-low-risk and low-risk early localized PCa, and plays a critical role, particularly in HSPC (4–6). Patients with metastatic PCa initially respond to ADT; however, 10%–20% patients with PCa progress to castration-resistant PCa (CRPC) within a 5-year follow-up period (7), and ultimately, nearly all patients progress to CRPC (8). Despite significant advances in therapy, the prognosis for individuals with metastatic castration-resistant PCa (mCRPC) remains poor, posing a major challenge in PCa management (9).

Over the past 2 decades, treatment options for mCRPC have expanded to include chemotherapy, next-generation endocrine therapies, poly (ADP-ribose) polymerase inhibitors, sipuleucel-T immunotherapy, and immune checkpoint inhibitors (5). These approaches have improved disease control and prolonged overall survival. Nevertheless, therapeutic options remain limited for patients whose disease progresses after standard treatments, underscoring the urgent need for novel therapeutic strategies.

In recent years, radioligand therapy (RLT) targeting prostate-specific membrane antigen (PSMA) has gained prominence as a treatment for mCRPC (10). Lutetium-177 (¹⁷⁷Lu)- PSMA-617 RLT effectively prolongs progression-free survival, particularly in individuals with larger lesions. However, β^- particles emitted by ¹⁷⁷Lu may be insufficient to eradicate microlesions due to their limited energy and short tissue penetration range, highlighting the need for radionuclides that can more effectively target microscopic disease. Terbium-161 (¹⁶¹Tb) is an emerging therapeutic radionuclide. Like ¹⁶¹Tb and ¹⁷⁷Lu emit β^- particles, but ¹⁶¹Tb offers a distinct advantage through the additional emission of internal conversion and Auger electrons, enabling more effective elimination of microlesions (11). Consequently, the use of ¹⁶¹Tb has garnered growing interest.

2 Mechanism of PSMA theranostics

PSMA, a type II transmembrane glycoprotein (12), is typically overexpressed in primary PCa and its metastases, with particularly high expression levels observed in mCRPC (13, 14). Consequently, PSMA represents an optimal molecular target for both diagnostic and therapeutic applications in mCRPC. PSMA ligands labelled with diagnostic radionuclides (^99mTc, ¹⁸F) and therapeutic radionuclides (¹⁷⁷Lu, ¹⁶¹Tb), selectively bind to PSMA expressed on the extracellular membrane of PCa cells. These ligand–receptor complexes undergo internalization and are subsequently transported into the cells, where they release γ particles for PSMA-based imaging or emit α particles, β^- particles, internal conversion electrons, and Auger electrons that cause irreversible damage to critical biomolecules in tumor cells, such as double-strand DNA breaks, ultimately leading to PCa cell death (15) (Figure 1). Notably, PSMA expression is heterogeneous, particularly considering the effects of ADT on PSMA expression (16). Although the literature lacks consistency, most studies indicate that short-term ADT upregulates PSMA expression (16, 17). Consequently, ADT may affect the therapeutic outcomes of PSMA-targeted radioligand therapy (PRLT). Currently, second-generation antiandrogens are emerging as potential endoradiosensitizers in mCRPC patients (16). Some studies have found that ADT combined with PRLT can result in superior clinical outcomes (18–20).

Figure 1

Figure 1. Mechanism of action for PSMA theranostics. AE, Auger electrons; IC, internal conversion electrons; PRLT, PSMA-targeted radioligand therapy; PSMA, prostate-specific membrane antigen.

3 Properties and advantages of ¹⁶¹Tb

While β^- particles remain the most established modality for RLT, increasing research attention has shifted toward α particles and Auger electrons to improve therapeutic efficacy. These particles possess shorter path lengths, higher linear energy transfer (LET), and greater relative biological effectiveness, resulting in enhanced cytotoxic potential and the capacity to overcome tumor cell resistance to radiopharmaceuticals (21–23) (Figure 2). Representative examples include Actinium-225 (²²⁵Ac), which emits α particles during decay (24), and ¹⁶¹Tb, which emits Auger electrons upon decay (25). ¹⁶¹Tb shares similar physical properties with ¹⁷⁷Lu, including comparable half-life and β^- particle energies. The key distinction lies in its emission profile: ¹⁶¹Tb releases approximately 12.4 internal conversion and Auger electrons below 50 keV per decay. As a result, the total energy deposited per decay is about 202.5 keV for ¹⁶¹Tb, compared with 147.9 keV for ¹⁷⁷Lu, indicating a higher overall energy delivery at the cellular level.

Figure 2

Figure 2. Nature and characteristics of different particles. LET, linear energy transfer.

Table 1 summarizes the decay characteristics of ¹⁶¹Tb and ¹⁷⁷Lu (26, 27). Auger electrons are characterized by their ultra-short tissue penetration range (≤500 nm) and high LET of approximately 4–26 keV/μm. This combination markedly enhances the local radiation dose delivered to microscopic disease foci, enabling the effective eradication of circulating tumor cell clusters, micrometastases, and minimal residual disease (28, 29). The presence of such microscopic lesions is strongly associated with poor clinical outcomes in individuals with cancer (30). Consequently, ¹⁶¹Tb-PSMA holds considerable promise in the treatment of mCRPC.

Table 1

Table 1. Decay characteristics of ¹⁶¹Tb and ¹⁷⁷Lu.

4 Production, radiolabeling, and quality control of ¹⁶¹Tb-PSMA radiopharmaceuticals

¹⁶¹Tb can be produced through two principal approaches: accelerator-based and reactor-based production. In the accelerator-based method, Nigron et al. (31) synthesized ¹⁶¹Tb via the gadolinium-160 (¹⁶⁰Gd)(d,n) ¹⁶¹Tb reaction, achieving a yield of 10.3 MBq/μA/h and a radionuclidic purity of 86%. Similarly, Fedotova et al. (32) produced ¹⁶¹Tb via the ^natDy(γ, pxn)¹⁶¹Tb reaction, yielding 14.4×10³ Bq·μA⁻¹·h⁻¹·cm²·g _Dy2O3⁻¹. However, accelerator-based production of ¹⁶¹Tb inevitably results in the formation of long-lived impurities, such as terbium-160 (¹⁶⁰Tb) and other terbium or dysprosium isotopes. Without highly efficient separation technologies, accelerator methods are unlikely to be suitable for large-scale ¹⁶¹Tb production (31, 32). Alternatively, in reactor-based production,¹⁶¹Tb is generated via neutron irradiation of ¹⁶⁰ Gd targets. Gracheva et al. (33) reported that a single irradiation cycle yielded ¹⁶¹Tb with a radioactive specific activity of 11–21 MBq/μL, radionuclidic purity ≥99%, and total activity up to 20 GBq. The resulting ¹⁶¹Tb-DOTATOC complexes exhibited excellent stability and high radiochemical purity, confirming their clinical suitability. Table 2 summarizes the production characteristics and parameters of reactor-generated ¹⁶¹Tb (33–35). These findings indicate that reactor-based production supports scalable and consistent generation of ¹⁶¹Tb, providing a reliable source of medical isotopes for the development and clinical application of ¹⁶¹Tb-labelled radiopharmaceuticals.

Table 2

Table 2. Characteristics and production parameters of reactor-produced ¹⁶¹Tb.

Owing to the similar chemical properties of ¹⁶¹Tb and ¹⁷⁷Lu, synthesis protocols established for ¹⁷⁷Lu-based agents can be directly adapted for the preparation of ¹⁶¹Tb radiopharmaceuticals. This chemical compatibility enables the translational application of experience gained from ¹⁷⁷Lu production, thereby accelerating the clinical adoption of ¹⁶¹Tb-labelled compounds (36). Established methods have been developed for the labelling and quality control of ¹⁶¹Tb-PSMA ligands. Müller et al. (23) prepared ¹⁶¹Tb-PSMA-617 by adding ¹⁶¹TbCl₃ to a mixture containing PSMA-617, sodium acetate (0.5 M), and hydrochloric acid (0.05 M). The solution was incubated at 95°C for 10 min at pH 4.5, yielding ¹⁶¹Tb-PSMA-617 with a specific activity of 100 MBq/nmol. High-performance liquid chromatography (HPLC) confirmed a radiochemical purity of ≥ 98%. Radiolysis was observed after 1 h; however, the addition of L-ascorbic acid prevented decomposition. The formulation demonstrated excellent stability at 1 h, 4 h, and 24 h, with radiochemical purity maintained at ≥ 98%. Uygur et al. (37) developed and optimized an alternative labelling method. Specifically, 1 mL of sodium acetate buffer and 185 MBq of ¹⁶¹TbCl₃ were added to a vial containing 50 μL of ascorbic acid. Following incubation of the reaction mixture (pH 4.5) at 95°C for 10 min, 25 μL of PSMA-617 was added. The mixture was then incubated again at 95°C for approximately 25 min and cooled to room temperature. Quality control using thin-layer chromatography and HPLC confirmed a radiochemical purity of 97.98% ± 2.01%, consistent with the 98% reported by Müller et al. (23). Stability testing showed that radiochemical purity remained >95% for up to 72 h. Subsequently, this team adapted this method to meet in-house Good Manufacturing Practice (GMP) compliance for first-in-human administration and evaluated it in a 77-year-old patient with mCRPC, demonstrating favorable biodistribution and urinary excretion (38).

5 Dosimetry of ¹⁶¹Tb-PSMA radiopharmaceuticals

Theoretical modelling indicates that ¹⁶¹Tb delivers higher radiation doses than ¹⁷⁷Lu, particularly in micrometastases disease. In 2016, Hindié et al. (28) demonstrated, using Monte Carlo CELLDOSE simulations, that ¹⁶¹Tb deposits greater absorbed doses in spherical targets than ¹⁷⁷Lu. This advantage arises not only from the β^- emissions of ¹⁶¹Tb being approximately 15% more energetic than those of ¹⁷⁷Lu, but, more importantly, from the substantial contribution of Auger electrons emitted by ¹⁶¹Tb to the overall absorbed dose. The magnitude of this contribution is strongly dependent on tumor size. At the cellular or cell-cluster scale, the dose delivered to the nucleus—or to centrally located nuclei within clusters—by ¹⁶¹Tb exceeds that of ¹⁷⁷Lu, regardless of whether the radionuclide is localized on the cell membrane, within the cytoplasm, or in the nucleus (29). Each medical radioisotope has an optimal curative range determined by lesion size. These calculations highlight that ¹⁶¹Tb offers a distinct advantage over ¹⁷⁷Lu for targeting single tumor cells or micrometastases <1 mm, with the benefit becoming increasingly pronounced as lesion size decreases. However, due to intrinsic tumor heterogeneity, radionuclides are not uniformly distributed within all lesions, leading to spatial variations in absorbed dose.

To address this, Larouze et al. (29) in 2023 incorporated heterogeneity factors into absorbed-dose simulations for both ¹⁷⁷Lu and ¹⁶¹Tb. Their results showed that ¹⁶¹Tb delivered a two- to three-fold higher radiation dose to the cell nucleus and a two- to six-fold higher dose to the cell membrane compared with ¹⁷⁷Lu. Thus, even when accounting for intra-tumoral non-uniformity,¹⁶¹Tb may eradicate tumor cell clusters more effectively than ¹⁷⁷Lu (30). Verburg et al. (26) reported similar findings using OLINDA V2.2.3 dosimetry software and an adult anthropomorphic model based on clinical data from ¹⁷⁷Lu-PSMA-617. When substituting ¹⁷⁷Lu with ¹⁶¹Tb, the results indicated a 40% increase in the absorbed dose per unit activity for ¹⁶¹Tb compared with ¹⁷⁷Lu. Bernhardt et al. (39) employed a dynamic metastatic progression model to evaluate the therapeutic potential of ¹⁶¹Tb in disseminated PCa. Their modelling estimated the absorbed dose required to achieve metastatic disease control and revealed that ¹⁶¹Tb-PSMA ligands exhibited the greatest potential to enhance treatment response rates in advanced metastatic PCa. The low-energy electron emissions of ¹⁶¹Tb provide a distinct radiobiological advantage for the selective targeting of small tumors and micro-metastases.

6 Preclinical studies of ¹⁶¹Tb-PRLT

Both cellular and animal studies have demonstrated that ¹⁶¹Tb-labelled radiopharmaceuticals are more effective than ¹⁷⁷Lu-labelled agents in suppressing tumor cell viability. Early preclinical investigations conducted in 1995 confirmed the feasibility of ¹⁶¹Tb for intraoperative imaging and radionuclide therapy applications (40). Subsequent animal studies comparing ¹⁷⁷Lu and ¹⁶¹Tb-based agents revealed superior inhibition of tumor cell viability by ¹⁶¹Tb (41–43). Tschan et al. (44) compared the dosimetry and therapeutic efficacy of ¹⁶¹Tb and ¹⁷⁷Lu-labelled PSMA ligands in mice with PCa.¹⁶¹Tb/¹⁷⁷Lu-SibuDAB exhibited longer blood retention and higher tumor uptake than ¹⁶¹Tb/¹⁷⁷Lu-PSMA-I&T. Notably, the tumor-absorbed dose for ¹⁶¹Tb-SibuDAB was approximately fourfold higher than that of ¹⁶¹Tb-PSMA-I&T, resulting in markedly improved tumor growth suppression without nephrotoxicity or other adverse effects. Compared with ¹⁷⁷Lu, ¹⁶¹Tb increased the tumor radiation dose by about 40%.

Another preclinical study using PCa cell lines and xenograft models demonstrated that, at equivalent activity levels,¹⁶¹Tb -PSMA-617 significantly reduced PC-3PIP cell viability and survival compared with ¹⁷⁷Lu-PSMA-617. Statistically significant differences (p <0.05 for both) were observed across activity concentrations of 0.1–10 MBq/mL and 0.05–5.0 MBq/mL. Moreover, mice treated with ¹⁶¹Tb-PSMA-617 exhibited dose-dependent increases in median survival—36 days and 65 days at injected activities of 5.0 MBq/mouse and 10 MBq/mouse, respectively—compared with 19 days in untreated controls. Collectively, these findings confirm that ¹⁶¹Tb-PSMA-617 provides superior in vitro and in vivo efficacy relative to ¹⁷⁷Lu-PSMA-617, consistent with theoretical dose calculations indicating an additive therapeutic contribution from internal conversion and Auger electrons emitted by ¹⁶¹Tb (23).

7 Clinical studies of ¹⁶¹Tb-PRLT

In 2023, the Nuclear Medicine team at Saarland University Medical Centre, Germany, evaluated the therapeutic efficacy of ¹⁶¹Tb-PSMA-617 in patients with advanced mCRPC. One patient who had progressed after treatment with ¹⁷⁷Lu-PSMA-617 exhibited markedly reduced PSA levels, decreased tumor burden, and alleviation of bone pain following ¹⁶¹Tb-PSMA-617 therapy. These findings suggest that ¹⁶¹Tb-PSMA-617 holds significant promise for treating mCRPC, particularly in patients for whom ¹⁷⁷Lu-PSMA-617 therapy has failed (45). In the same year, the Nuclear Medicine team at the King Hussein Cancer Centre in Amman, Jordan, reported the first human SPECT imaging results following ¹⁶¹Tb-PSMA RLT. A 69-year-old patient with mCRPC received 5,550 MBq of ¹⁶¹Tb-PSMA-617 and tolerated the treatment well, with no acute or early adverse effects reported. Whole-body planar and SPECT/CT imaging were performed to obtain time–activity distribution data for ¹⁶¹Tb-PSMA-617 in tumor lesions and dose-limiting organs (46).

In 2024, the Saarland University Medical Centre conducted a clinical study involving six patients with mCRPC who had previously received ¹⁷⁷Lu-PSMA-617 or combination therapy with ¹⁷⁷Lu-PSMA-617 and ²²⁵Ac-PSMA-617 but experienced progression or limited therapeutic response. Using radiation dose analysis software, SPECT imaging data were processed to compare absorbed doses in tumor lesions and dose-limiting organs between ¹⁷⁷Lu-PSMA-617 and ¹⁶¹Tb-PSMA-617. The calculated therapeutic indices were 1.18 for the kidneys, 1.10 for the parotid glands, and 2.40 for tumor lesions. Compared with ¹⁷⁷Lu-PSMA-617, ¹⁶¹Tb-PSMA-617 delivered higher absorbed doses to tumors with only marginal increases in organ doses, supporting ¹⁶¹Tb as a promising therapeutic radionuclide for PRLT and warranting larger prospective trials (47). A retrospective study conducted at the King Hussein Cancer Centre evaluated the safety and efficacy of ¹⁶¹Tb-PSMA-617 and ¹⁷⁷Lu-PSMA-617 in heavily pre-treated patients with mCRPC who had undergone prior surgery, ADT, chemotherapy, and radiotherapy. Across 148 therapy cycles administered to 53 individuals (144 cycles of ¹⁷⁷Lu-PSMA-617 and four cycles of ¹⁶¹Tb-PSMA-617), approximately half (n = 26) achieved a partial response, and one-quarter (n = 13) maintained a favorable biochemical response. Only 18 individuals (34%) experienced mild, self-limiting adverse effects (48).

Abdlkadir et al. (49) reported a case of dual-radionuclide therapy in a patient with mCRPC resistant to ¹⁷⁷Lu-PSMA therapy. Combined administration of ¹⁶¹Tb-PSMA and ¹⁷⁷Lu-PSMA resulted in marked reductions in serum PSA and tumor burden, suggesting a potential synergistic effect of this dual-isotope regimen. Chirindel et al. (50) evaluated the novel radiopharmaceutical ¹⁶¹Tb-SibuDAB in a patient with mCRPC and compared it with ¹⁷⁷Lu-PSMA-I&T. The results demonstrated that ¹⁶¹Tb-SibuDAB delivered higher tumor doses and exhibited a longer effective half-life, supporting its value in targeting micrometastatic lesions. Importantly, no adverse reactions were reported.

Buteau et al. (51) assessed the safety and efficacy of ¹⁶¹Tb-PSMA-I&T in patients with mCRPC. No dose-limiting toxicities occurred, and only two participants (7%) experienced grade 3 treatment-related adverse events. There were no dose reductions, treatment delays, or treatment-related deaths. The PSA50 response rate was 70%, the PSA90 response rate was 40%, the median PSA progression-free survival was 9 months, and the median radiographic progression-free survival was 11 months. Organ dosimetry analyses showed that absorbed doses to normal tissues remained within accepted safety thresholds. Mean absorbed doses (Gy/GBq) were 0.15 for the parotid glands, 0.36 for the kidneys, 0.08 for the liver, and 0.06 for the spleen, confirming that radiation exposure to potential dose-limiting organs remained well within tolerable limits. Sezgin C et al. (38) reported the treatment of a 77-year-old patient with mCRPC who received two cycles of ¹⁶¹Tb-PSMA-617 treatment without adverse events; however, both PSA levels and imaging findings indicated disease progression. The authors also focused on temporal changes in activity levels and their implications for radiation safety. The mean external dose rate of ¹⁶¹Tb-PSMA-617 was 56 μSv/h at 6 h post-injection and decreased to 14 μSv/h at 24 h post-injection. These findings are valuable for establishing patient-isolation criteria and radiation-safety protocols. Kucuk et al. (52) enrolled seven patients with mCRPC who had progressed after at least 2 cycles of ¹⁷⁷Lu-PSMA. Of the seven patients, four (57%) demonstrated objective imaging response and four (57%) showed at least a 50% decline in PSA levels. Treatment was well tolerated, with only mild adverse events (grades 1–2) and no toxicity greater than grade 3. Organ dosimetry confirmed favorable absorbed dose distributions. Table 3 summarizes clinical studies of ¹⁶¹Tb-PRLT.

Table 3

Table 3. Clinical studies of ¹⁶¹Tb-PRLT.

Several clinical trials are currently underway to evaluate the safety and efficacy of ¹⁶¹Tb-labelled PSMA ligands. The Australian VIOLET trial (NCT05521412) (53), a Phase I/II study investigating ¹⁶¹Tb-PSMA-I&T in patients with mCRPC, has released preliminary data (refer to the preceding section and Table 3 for details). Additional studies on ¹⁶¹Tb-PSMA-617 with similar objectives are in progress in Germany (REALITY trial, NCT04833517). The Swiss PROGNOSTICS trial (NCT06343038) is a dose-escalation Phase Ia/b study evaluating ¹⁶¹Tb-SibuDAB for PRLT in patients with mCRPC. In China, an early-phase clinical trial (NCT06827080) assessing the safety, tolerability, and efficacy of ¹⁶¹Tb-NYM032 in patients with mCRPC is ongoing. Table 4 provides an overview of the ongoing clinical trials investigating ¹⁶¹Tb-PRLT.

Table 4

Table 4. Clinical trials of ¹⁶¹Tb-PRLT.

8 Discussion

Over the past decade, ¹⁷⁷Lu-PRLT has achieved remarkable success in the treatment of mCRPC. In the VISION trial (20), ¹⁷⁷Lu-PSMA-617 combined with standard care significantly improved median overall survival compared with standard care alone (15.3 months vs. 11.3 months), achieving a 38% reduction in mortality risk. The study also found a remarkable improvement in radiographic progression-free survival (8.7 months vs. 3.4 months), corresponding to a 60% reduction in the risk of radiographic progression or death. The U.S. Food and Drug Administration and the European Medicines Agency have approved ¹⁷⁷Lu-PSMA-617 for the treatment of adults with PSMA-positive mCRPC following prior ADT and chemotherapy. ¹⁷⁷Lu-PRLT demonstrates a favorable safety profile, prolongs survival, and improves quality of life in patients with mCRPC (54–56).

However, with successive treatment cycles, approximately 17%–30% of patients develop resistance to ¹⁷⁷Lu-PRLT, resulting in disease progression (57). This resistance may be partly attributed to the physical characteristics of β^- particles, which exhibit medium-to-high energy and low LET. These particles predominantly induce single-strand DNA breaks and dispersed double-strand breaks, leading to relatively modest cytotoxicity. Furthermore, the penetration range of β^- particles occurs at the tissue scale, approximately 2 mm for ¹⁷⁷Lu. Although this provides broad radiation coverage and is advantageous for treating macroscopic tumor volumes, the range exceeds the dimensions of microlesions. Consequently, a substantial portion of the emitted energy is deposited outside the target region, reducing the effectiveness of microlesion eradication. Furthermore, persistent microlesions may compromise long-term disease control (58).

¹⁶¹Tb has been recognized as a promising novel medical radioisotope with the potential to replace or complement ¹⁷⁷Lu therapy. ¹⁶¹Tb exhibits physical characteristics similar to those of ¹⁷⁷Lu, with both isotopes capable of emitting β^- particles. However, ¹⁶¹Tb provides an additional advantage through the emission of internal conversion electrons and Auger electrons, enabling the effective elimination of microlesions. These electrons have an ultra-short tissue range resulting in a high LET providing higher local dose densities. Both Monte Carlo simulations and preclinical studies have demonstrated that ¹⁶¹Tb-PSMA delivers a significantly higher radiation dose to tumor lesions and exhibits superior therapeutic efficacy compared to ¹⁷⁷Lu-PSMA. Limited clinical studies have also confirmed the favorable therapeutic efficacy of ¹⁶¹Tb-PSMA. Meanwhile, the safety profile of ¹⁶¹Tb-PSMA is also encouraging. The primary adverse events are hematological toxicities, with some patients reporting dry mouth, fatigue, and nausea. Overall, ¹⁶¹Tb-PSMA is well-tolerated, with most adverse events being mild (grade 1-2). Grade 3 adverse events were uncommon, and no grade 4 adverse events were reported. However, clinical studies on ¹⁶¹Tb-PSMA remain limited, and real-world data are scarce. The currently published literature consists predominantly of case reports, with a lack of large-scale prospective studies. Large-scale, prospective cohort studies are essential to further evaluate critical clinical endpoints, such as safety, therapeutic efficacy, and treatment durability, and to establish robust, standardized criteria for assessing radiopharmaceutical treatment response.

Additionally, the successful translation of ¹⁶¹Tb from preclinical to clinical use largely depends on isotope availability. Like other reactor-produced radionuclides, ¹⁶¹Tb production faces key challenges, including restricted reactor capacity and logistical barriers to downstream application. As theranostic radionuclides continue to gain clinical prominence, the imbalance between production and global demand is expected to become increasingly evident. Furthermore, as an emerging isotope, ¹⁶¹Tb requires harmonized production protocols, secure supply chain management, and GMP-compliant quality control systems to ensure consistent radiochemical purity, safety, and efficacy. Fortunately, the close physicochemical similarity between ¹⁶¹Tb and ¹⁷⁷Lu allows existing infrastructure, logistics, operational procedures, and radiation safety protocols used for ¹⁷⁷Lu-labelled agents to be readily adapted for ¹⁶¹Tb-based compounds. This operational compatibility facilitates knowledge transfer from established ¹⁷⁷Lu experience and supports the streamlined clinical adoption of ¹⁶¹Tb-labelled therapeutics.

9 Conclusion

This review provides a comprehensive synthesis of the mechanism of action, radiolabeling and quality control, dosimetry, preclinical evaluation, and clinical investigations of ¹⁶¹Tb-PSMA. Overall, ¹⁶¹Tb-labelled RLT—exemplified by ¹⁶¹Tb-PSMA—demonstrates considerable therapeutic promise. Continued research aimed at improving isotope accessibility, standardization, and clinical translation remains essential to fully realize its potential.

Author contributions

LX: Conceptualization, Investigation, Methodology, Writing – original draft, Writing – review & editing. ZZ: Methodology, Writing – original draft, Writing – review & editing. RL: Methodology, Writing – original draft, Writing – review & editing. FL: Writing – original draft, Writing – review & editing. BH: Writing – review & editing. PZ: Writing – review & editing. XY: Conceptualization, Funding acquisition, Supervision, Writing – review & editing. ZC: Conceptualization, Funding acquisition, Project administration, Writing – review & editing.

Funding

The author(s) declared that financial support was received for this work and/or its publication. This research was funded by the Key Project of the Sichuan Natural Science Foundation (grant number 2025ZNSFSC0049), the 2024 Clinical Special Fund Project of Mianyang Central Hospital (grant number 2024LC001), and Mianyang Science and Technology Bureau (Mianyang Science and Technology Program (grant number 2023ZYDF073).

Acknowledgments

The authors thank all co-workers involved in this work for their support and assistance.

Conflict of interest

The authors declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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The author(s) declared that generative AI was not used in the creation of this manuscript.

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