[161Tb]Tb-PSMA-617 radioligand therapy in patients with mCRPC: preliminary dosimetry results and intra-individual head-to-head comparison to [177Lu]Lu-PSMA-617

Rationale: Evaluation of alternative radionuclides for use in prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT) is currently focusing on 161Tb, which may provide advantages by emitting additional Auger and conversion electrons. In this pilot study, we present preliminary dosimetry data for [161Tb]Tb-PSMA-617 RLT in a direct comparison with [177Lu]Lu-PSMA-617. Method: Six patients with metastatic castration-resistant prostate cancer (mCRPC) underwent treatment with [177Lu]Lu-PSMA-617 and subsequently - after inadequate response - with [161Tb]Tb-PSMA-617. Whole-body planar and SPECT imaging-based dosimetry of organs at risk (kidneys and salivary glands) and tumor lesions were calculated using IDAC for 177Lu and OLINDA/EXM for 161Tb. The therapeutic index (TI) of mean tumor-absorbed doses over relevant organs at risk was calculated. Results: Mean absorbed doses to organs at risk of PSMA-RLT were slightly higher for [161Tb]Tb-PSMA-617 compared to [177Lu]Lu-PSMA-617 (kidneys: 0.643 ± 0.247 vs. 0.545 ± 0.231 Gy/GBq, factor 1.18; parotid gland: 0.367 ± 0.198 vs. 0.329 ± 0.180 Gy/GBq, factor 1.10), but markedly higher regarding tumor lesions (6.10 ± 6.59 vs 2.59 ± 3.30 Gy/GBq, factor 2.40, p < 0.001). Consequently, the mean TI was higher for [161Tb]Tb-PSMA-617 compared to [177Lu]Lu-PSMA-617 for both, the kidneys (11.54 ± 9.74 vs. 5.28 ± 5.13, p = 0.002) and the parotid gland (16.77 ± 13.10 vs. 12.51 ± 18.09, p = 0.008). Conclusion: In this intra-individual head-to-head pilot study, [161Tb]Tb-PSMA-617 delivered higher tumor-absorbed doses and resulted in superior TI compared to [177Lu]Lu-PSMA-617. This preliminary data support 161Tb as a promising radionuclide for PSMA-RLT in mCRPC.


Introduction
Prostate cancer continues to rank as the second most prevalent form of malignant disease among men globally in 2022 [1].Patients with prostate cancer frequently progress to the state of metastatic castration-resistant prostate cancer (mCRPC) which is unresponsive to physical or chemical castration and is associated with a relatively poor prognosis [2,3].Common treatments for mCRPC patients include new androgen axis drugs as abiraterone or enzalutamide [4,5], chemotherapy with docetaxel or cabazitaxel [6,7], bone seeking radiation therapy with Ra-223 [8], and PARP inhibitors as e.g.Olaparib [9].In addition to this treatments, the targeted radioligand therapy (RLT) that specifically targets prostate specific membrane antigen (PSMA) has proven to be a promising approach for reducing total tumor burden Ivyspring International Publisher and improving survival [10][11][12].Recently, PSMA-RLT with 177 Lu was approved by the FDA and EMA [13,14].Due to its favorable characteristics, the beta-emitting 177 Lu is currently the most abundantly used radionuclide [15].These properties correspond to a cytotoxicity that frequently achieves a satisfying anti-tumor effect while maintaining a favorable adverse events profile [16][17][18][19][20].However, a fraction of patients still presents to be non-or low responders to PSMA-RLT with 177 Lu.Therefore, the research for new radionuclides in RLT is ongoing, with the aim to improve PSMA-RLT.Some studies suggested the use of alpha emitters such as 225 Ac, which showed considerable success, even after non-response to 177 Lu [21][22][23].PSMA-RLT with 225 Ac was used both as monotherapy [21] and as tandem therapy in combination with 177 Lu [22,23].However, in many cases PSMA-RLT with 225 Ac showed relevant side effects, especially when applied as monotherapy [21].
A new emerging candidate of interest to clinicians and researchers is 161 Tb, which has similar chemical properties and physical decay characteristics to the established 177 Lu [24].Shared characteristics between the two radionuclides include similar mean β-particle energy ( 161 Tb: 154 keV vs. 177 Lu: 133 keV) and γ-ray emission ( 161 Tb: 74.6 keV/10.2%;48.9 keV/17.0%vs. 177 Lu: 208.4 keV/10.4%;112.9 keV/6.2%)as well as similar half-life ( 161 Tb: 6.906 d vs. 177 Lu: 6.647 d) [25].However, in contrast to 177 Lu, 161 Tb emits a high proportion of conversion and low-energy Auger electrons.These electrons have an ultra-short tissue range (< 500 nm) resulting in a high linear energy transfer (LET) (4 -26 keV/µm) providing higher local dose densities [26,27].Preclinical studies utilizing cell-based in vitro assays have indicated higher efficacy of 161 Tb over 177 Lu [27][28][29][30], a dose-dependent delay in tumor growth and a prolonged survival in mice treated with [ 161 Tb]Tb-PSMA-617 were observed [31].A theoretical study based on clinical data has recently shown that the dose per unit activity in tumor tissue can be increased in RLT by replacing 177 Lu with 161 Tb [32].Similar to 177 Lu, 161 Tb can also be produced in a nuclear reactor.Although initially less available than 177 Lu, there is increasing commercial availability of 161 Tb reaching high level of specific activity and chemical purity.However, experience with 161  In this pilot study, we present a preliminary dosimetry analysis investigating the potential of [ 161 Tb]Tb-PSMA-617 for RLT in patients with mCRPC.The dosimetric evaluation of [ 161 Tb]Tb-PSMA-617 RLT was performed in an intra-individual head-to-head comparison with [ 177 Lu]Lu-PSMA-617.]Tb-PSMA-617 RLT, antihormonal treatment with ADT and NAAD were continued unchanged to avoid altering PSMA expression and biasing the treatment effect [36,37].

Patients and study objective
The objective of this study was to calculate estimates of absorbed doses of target tumor lesions and organs for [ 161 Tb]Tb-PSMA-617 and to compare these estimates with those for [ 177 Lu]Lu-PSMA-617 from the previous cycle.

Imaging
For dosimetric calculations, scintigraphy was performed after injection of [ 161 Tb]Tb-PSMA-617.Scintigraphic images were acquired on a hybrid scanner, the Philips BrightView XCT (Philips Medical Systems, Hamburg, Germany).The scanner was equipped with low-energy, high resolution (LEHR) parallel-hole collimators for imaging 161 Tb and with medium-energy collimators for imaging 177 Lu.For imaging with 161 Tb an uniformity correction map was acquired as described in the supplemental data.On days 1, 2, and 4 after injection (approximately 24 hours, 48 hours, and at least 96 hours post-injection), planar whole-body images were acquired.On day 1 after injection, a SPECT/CT scan of the head and neck ("head and neck SPECT/CT") was performed.Additionally, on day 2 post injection, another SPECT/CT scan, from the liver down to the pelvis ("abdomen-SPECT/CT"), was acquired.
The energy windows for 161 Tb and 177 Lu imaging were set to 74.6 keV and 208 keV, respectively, with a width of 20% as proposed by MIRD and used in previous studies on 177 Lu imaging [39,40].In order to perform scatter correction on the whole-body images based on the dual-energy window technique (DEW) [39], respective low scatter windows were set at 69.4 keV for 161 Tb and at 187 keV for 177 Lu, both with a width of 15% [39].Other image protocol parameters applied for both radionuclides were as follows: the scanning speed for whole body acquisition was 15 cm/min on day 1 and day 2 and 12 cm/min on day 4.The matrix size was 256 × 1024, and the pixel size 4.66 × 4.66 mm 2 .Prior to administering the radiopharmaceutical, a whole-body blank scan and a whole-body transmission scan of the patient were acquired using a flat phantom filled with aqueous solution of 161 Tb and 177 Lu, respectively.The corresponding images were used for attenuation correction of the planar whole-body data.For both radionuclides, 60 SPECT projections over 360° projections were acquired with a frame-time duration of 20 s for head and neck and a frame-time of 30 s for abdomen SPECT, respectively.The matrix size was 128 × 128, and the pixel size 4.66 × 4.66 mm 2 .CT images were acquired in low-dose technique using an X-ray tube voltage of 120 keV and a tube current of 10 mA.The matrix and the pixel size were 256 × 256 and 2.33 × 2.33 mm 2 , respectively.CT data was applied to calculate an attenuation map at 100 keV, which was then converted to the respective emission energies and applied for attenuation and scatter correction of SPECT data [41].Iterative SPECT image reconstruction parameters were chosen based on the recommendations proposed in the MIRD pamphlets 23 and 26 [42,43].An iterative 3D-ordered subset expectation maximization (OSEM) algorithm was applied employing 3 iterations, 8 subsets, Butterworth filtering (0.5, 10th order), and a slice thickness of 4.66 mm.CT images were converted to a matrix with a pixel size of 128 × 128 and 4.66 × 4.66 mm 2 and then fused with the SPECT slices.

Radiation dosimetry
Dosimetry calculations for both radionuclides, 161 Tb and 177 Lu, were based on the MIRD scheme and included the following tissues: kidneys, liver, salivary glands (parotid gland and submandibular gland) and tumor lesions.According to the MIRD dosimetric approach the time-dependent activity of the organs and lesions need to be determined.This evaluation comprises delineation of corresponding region-ofinterest (ROI) and volume-of-interest (VOI) and calculation of the proportionate injected activities [%] for each time point [44].The applied software packages were QDOSE (ABX-CRO, Dresden, Germany) and OLINDA/EXM version 1.0 [45].The dosimetric workflow established for 177 Lu [46] was applied analogously for 161 Tb.Planar whole-body images were quantified on a pixel-by-pixel basis, using the conjugate-view method [39].To convert count rate to activity for planar scintigraphy respective calibration factors were used as described in supplemental data.All whole-body images were co-registered using non-rigid registration methods.Boundary ROI enclosing the organs as well as background ROI close to the respective organs or tumor lesions were manually drawn in the whole-body images of the first time point of the 177 Lu scintigraphy and then copied on to the planar whole-body images of the other time points and the planar whole-body scintigrams of 161 Tb.Tumor lesions (bone metastases or lymph node metastases) presenting no overlap with tissues of high uptake were selected for analysis exclusively.Attenuation correction was performed according to MIRD [39] using the respective blank and the respective patient whole body transmission scan thereby taking into account the body and organ thicknesses of the patient determined by CT. Background correction included determination of the activity per pixel in the respective background ROI and subsequently scaling to the number of pixels in the organ ROI.Delineation of the organ within the manually drawn boundary ROI on both the anterior and the posterior image was performed by an experienced physicist and the responsible physician.For this purpose, a threshold-based segmentation was applied.The planar-derived time-activity curves were created by mono-exponential regression of the serially measured activities using weighted least squares method.
In the SPECT/CT images, boundary VOI were manually drawn which enclosed the source organs avoiding neighboring structures.Volume and activity estimation were performed within the boundary using a fuzzy locally adaptive Bayesian (FLAB) segmentation algorithm for automatic volume delineation [47].The measured voxel values were converted to activity using the camera calibration factor and then corrected by applying the respective volume-dependent recovery coefficients (compare supplemental data, Table S1) and combined with the time-activity data from the planar images.Here, SPECT activity estimation was used to rescale the planar-derived time-activity curve [39,42,46].
The rescaled time-activity curve was fitted by monoexponential regression and the time-integrated activities (TIA) in the source regions determined as the area under the curve by analytical integration and used to calculate the respective time-integrated activity coefficients (TIAC) [46].For [ 177 Lu]Lu-PSMA-617, this last step was performed in QDOSE whereas for [ 161 Tb]Tb-PSMA-617, the rescaled activity data was imported into the software OLINDA/EXM [45] to perform the respective calculations.Here, the absorbed doses to the tumor lesions and the salivary glands were calculated using the spheres model and the respective reference man for the kidneys and the liver.Estimation of the absorbed dose for [ 177 Lu]Lu-PSMA-617 was performed using the IDAC 2.1 software implemented in QDOSE [48].Here, the IDAC reference man was applied for the kidneys and the liver and the spheres model for the salivary glands and the tumor lesions, respectively.
The volumes of the tumor lesions were determined from the pre-therapeutic 68 Ga-PSMA-11 PET/CT images.For this purpose, a volume-ofinterest with an isocontour of 20-40% of SUVmax was drawn using a dedicated workstation (Syngo.Via, Siemens Healthcare, Erlangen, Germany).Organ masses for the salivary glands were taken from International Commission on Radiological Protection (ICRP) publication 89 with 25 g estimated weight for the parotid and 12.5 g for the submandibular gland [49].

Individual Therapeutic Index (TI) and relative Therapeutic Index (rTI)
To evaluate the potential therapeutic effect of the radiopharmaceutical PSMA-617 in relation to organs at risk when labeled with both, the radionuclides 161 Tb and 177 Lu, the individual therapeutic index (TI) was applied [50].TI was defined by calculating the mean radiation dose absorbed in tumor lesions divided by the mean radiation dose delivered to a relevant organ at risk.As in the case of PSMA-RLT the relevant organs at risk are known to be the kidneys and the salivary glands [10,17], the TI for the kidneys (TI-kidney) and exemplarily for the salivary glands, the TI for the parotid gland (TI-parotid) were determined.Furthermore, the ratio of the TI for [ 161 Tb]Tb-PSMA-617 to the TI for [ 177 Lu]Lu-PSMA-617 was calculated for each organ at risk and reported as relative therapeutic index (rTI-kidney and rTI-parotid).A rTI value > 1 is considered as an indication of favorable energy deposition by [ 161 Tb]Tb-PSMA-617.

Patient-based outcome and adverse events
To evaluate the efficacy of one cycle of [ 161 Tb]Tb-PSMA-617, serum PSA was measured at baseline and 5 ± 2 weeks after the [ 161 Tb]Tb-PSMA-617 RLT.Relative PSA change was calculated to assess biochemical response using the Prostate Cancer Working Group 3 (PCWG 3) criteria [51].Blood tests including hemoglobin, leukocytes and platelets, and creatine-based estimated glomerular filtration rate (GFR) were performed to assess safety profile and adverse events.In addition, xerostomia was assessed using a dedicated questionnaire.Adverse events were graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.Furthermore, change in pain rated by visual analog scale (VAS) ranging from 0 -10 was analyzed as an additional marker for quality of life.

Statistical Analysis
All continuous data reported is expressed as mean ± standard deviation and range.A paired non-parametric Wilcoxon matched-pairs signed rank test was performed to compare absorbed lesion doses.Statistical analyses were conducted using GraphPad Prism (GraphPad Software; Version 8.0, San Diego, USA).

Dosimetry of normal organs after administration of [ 161 Tb]Tb-PSMA-617
Physiological uptake was observed in the salivary and lacrimal glands, kidneys, liver, intestine and urinary tract.Figure 1  The monoexponential curve-fitting parameters, the time-integrated activity coefficients (TIAC) for each source organ and the respective estimated absorbed doses according to OLINA/EXM are summarized in Table 2.Among the normal tissues, the liver received the lowest (0.148 ± 0.080 Gy/GBq) whereas the kidneys received the highest absorbed doses for [ 161 Tb]Tb-PSMA-617 with 0.643 ± 0.247 Gy/GBq, followed by the salivary glands (submandibular gland: 0.372 ± 0.188 Gy/GBq; parotid gland: 0.367 ± 0.198 Gy/GBq).In comparison, the estimated absorbed doses in normal organs post administration of [ 177 Lu]Lu-PSMA-617 are also presented in Table 2.
Figure 2 shows the mean estimated absorbed doses in normal organs post administration of [ 161 Tb]Tb-PSMA-617 vs. [ 177 Lu]Lu-PSMA-617 over all patients and Table 3 presents the respective individual organ doses.In comparison, the respective monoexponential curve-fitting parameters and time-integrated activity coefficients (TIAC) for [ 177 Lu]Lu-PSMA-617 are presented in the supplemental data (Table S2 ).In order to present TIAC of kidney and liver in relation to organ function parameters, corresponding data are also provided in the supplemental data (Table S3).

Therapeutic Index TI and relative Therapeutic Index rTI
The mean TI for the kidneys, the liver and the salivary glands are presented in Figure 5A

Patient-based outcome and adverse events
After the applied one cycle of [ 161 Tb]Tb-PSMA-617, three patients experienced a decrease of PSA value by 53.4%, 24.2% and 18.6%, respectively.In the remaining three patients the PSA value increased by 18.0%, 48.6% and 73.2%, respectively.Patient individual PSA values and change are summarized in the supplemental data (Table S5).Based on biochemical response assessment by PCWG 3 criteria with defining progressive disease (PD) as PSA increase > 25%, partial remission (PR) as PSA decrease > 50%, and stable disease in any other case: 1 patient showed PR, 3 patients SD, and 2 patients PD.The patient with PR and one of the patients with SD were matched with the two patients who had received only [ 177 Lu]Lu-PSMA-617 monotherapy in the past.The remaining 2 patients with SD and 2 patients with PD had been previously augmented with [ 225 Ac]Ac-PSMA-617.After one cycle of [ 161 Tb]Tb-PSMA-617, the glomerular filtration rate (GRF) was mainly stable, with only one patient experiencing an increase in CTCAE (from 0 to 1).Furthermore, only one patient experienced a relevant decrease in hemoglobin, leukocytes, and platelets with an increase in CTCAE from 2 to 3, 1 to 2, and 1 to 3, respectively.However, this increase in anemia, leukocytopenia, and thrombocytopenia was more likely due to tumor progression (∆PSA +72.3% and increasing bone marrow involvement).Increasing xerostomia was observed in two patients (CTCAE from 0 to 1 and 1 to 2), but these two patients were pretreated with 225 Ac.In addition, a reduction in pain (as indicated by a in VAS from 8 to 7 and 2 to 1) was observed in two patients; only one patient experienced an increase in pain (VAS from 2 to 3).

Discussion
In this pilot study, we present first data on therapeutic radiation dosimetry regarding normal organs and tumor lesions for [ 161 Tb]Tb-PSMA-617 compared to [ 177 Lu]Lu-PSMA-617 in 6 patients with mCRPC.
Comparing the biodistribution of [ 161 Tb]Tb-PSMA-617 to that of [ 177 Lu]Lu-PSMA-617, a similar distribution pattern was observed over time with intense uptake of radiolabeled PSMA ligands in salivary glands, kidneys, liver, and small intestine and a high retention in tumor lesions.Quantitative results in this cohort of patients indicate that [ 161 Tb]Tb-PSMA-617 provides notably higher absorbed dose to tumor lesions in comparison to [ 177 Lu]Lu-PSMA-617.Furthermore, mean absorbed doses to the relevant organs at risk of PSMA-RLT were only slightly higher for [ 161 Tb]Tb-PSMA-617 compared to [ 177 Lu]Lu-PSMA-617.
The high tumor doses delivered by 161 Tb might be explained by the physical decay characteristics of 161 Tb co-emitting a high proportion of conversion and low-energy Auger electrons.The benefit of those electrons has previously been demonstrated by several groups applying Monte Carlo simulation on 161 Tb to assess electron doses and distribution [26,27].The work of these groups demonstrated that 161 Tb is a radionuclide particularly appropriate for irradiation of micro-metastases due to the short range of these electrons and therefore, at least in the context of micro-metastases, 161 Tb seems to hold decisive advantages over 177 Lu.In addition, recently published studies using in vitro methods and mice models confirm the beneficial effects of RLT with 161 Tb and an enhanced therapeutic efficacy of 161 Tb over 177 Lu [29,30].Exemplarily, it was demonstrated that the exposure to [ 161 Tb]Tb-PSMA-617 in comparison to [ 177 Lu]Lu-PSMA-617 reduced both the viability and the survival of PC-3 PIP tumor cells.Moreover, in PC-3 PIP tumor bearing mice treated with [ 161 Tb]Tb-PSMA-617 an improved inhibition of tumor growth as well as prolonged survival of tumor affected animals was observed [29].In addition, a recently published theoretical paper by Verburg et al. showed that 161 Tb, due to its physical properties, delivers a higher absorbed dose to tumor lesions than 177 Lu by a theoretical factor of about 1.4 if an identical biodistribution is considered [32].The factor of 2.4 estimated in our pilot study, therefore allows the assumption that a biological component must also be taken into account.
Besides the high absorbed doses of [ 161 Tb]Tb-PSMA-617 in tumor lesions, a low physiological uptake by normal organs is a required property to use this radionuclide in RLT.With respect to PSMA-RLT, the kidneys and in addition the salivary glands are usually regarded as dose-limiting organs at risk [10,17].It was observed, that the radiation dose to the kidneys may increase the risk of late renal function impairment, especially in late-stage mCRPC patients [54].The VISION study reported that also dry mouth was one of the most common adverse events for [ 177 Lu]Lu-PSMA-617 RLT [10].In our cohort, the mean absorbed doses delivered to the relevant organs at risk of PSMA-RLT were higher for [ 161 Tb]Tb-PSMA-617 compared to [ 177 Lu]Lu-PSMA-617 but only by a factor of 1.18 for the kidneys (0.643 ± 0.247 Gy/GBq vs. 0.545 ± 0.231 Gy/GBq) and of 1.10 for the parotid glands (0.367 ± 0.198 Gy/GBq vs. 0.329 ± 0.180 Gy/GBq).Although the renal doses in our cohort vary from patient to patient (range: 0.283 -0.974 mGy/MBq), they are in line with the wide range of values that has been reported previously in several studies for [ 177 Lu]Lu-PSMA-617 (ranging from 0.4 ± 0.2 Gy/GBq to 0.8 ± 0.3 Gy/GBq) [52,55] Lu]Lu-PSMA-617 RLT.This result appears to be clinically relevant since higher observed TI might allow, by adjusting the administered activity accordingly, to either I) increase the dose delivered to the tumor while the organs receive the equivalent dose compared to 177 Lu, or II) decrease the dose to the organs thereby reducing the risk of adverse events while achieving an equivalent dose to the tumor.
Regarding the salivary glands, our values of absorbed doses for [ 161 Tb]Tb-PSMA-617 as well as for [ 177 Lu]Lu-PSMA-617 are lower than the values previously published by others.Several authors reported mean absorbed doses ranging from 0.58 to 1.41 Gy/GBq for [ 177 Lu]Lu-PSMA-617 [46,52,55], and similar values for [ 177 Lu]Lu-PSMA-I&T (ranging from 0.55 to 0.8 Gy/GBq) [50,53].This may probably be explained by the intense pretreatment of the patients in our cohort, including PSMA-RLT with multiple cycles of 177 Lu as well as 225 Ac labeled ligands, potentially providing particular impact on the salivary glands [21].Two patients in our cohort experienced worsening of xerostomia (from grade 0 to 1 and 1 to 2), one of the most common adverse events of RLT.The VISION study reported grade 1 / 2 xerostomia in 38.8% patients, the REALITY study in 20.9% patients receiving [ 177 Lu]Lu-PSMA-617 [10,16].In comparison, higher frequency of xerostomia was observed after alpha-emitting [ 225 Ac]Ac-PSMA-617 treatment, e.g. of 85% reported by Sathekge et al. and of 100% by Feuerecker et al. [21,56].As in the latter study the patients were pretreated by [ 177 Lu]Lu-PSMA-617, the increased frequency was explained by the cumulative toxicity of both [ 177 Lu]Lu-PSMA-617 and [ 225 Ac]Ac-PSMA-617 RLT.The two patients of our cohort had also already been intensively pretreated with 177 Lu as well as with 225 Ac, so that the xerostomia was probably caused by the intensive cumulative irradiation including alpha radiation and not clearly attributable to one cycle of 161 Tb.Moreover, the calculated TI for the salivary glands in our cohort were 1.34 (parotid gland) and 1.70 (submandibular gland) times higher for [ 161 Tb]Tb-PSMA-617 than for [ 177 Lu]Lu-PSMA-617.Like the rTI-kidney, the rTI-parotid favored [ 161 Tb]Tb-PSMA-617 in 5 of 6 patients, suggesting an improved ratio of energy deposition in the tumor lesions compared to the parotid glands.
Based on the demonstrated dosimetric results, 161 Tb reveals superiority over 177 Lu in terms of absorbed tumor dose and thus potential antitumor effect.Consequently, there might be a potential opportunity for patients progressing on 177 Lu-based PSMA-RLT to benefit from a switch to 161 Tb-based treatment, as may be supported by the data of the two patients pretreated exclusively with multiple cycles of [ 177 Lu]Lu-PSMA-617.After one cycle of [ 161 Tb]Tb-PSMA-617, one patient showed PR and the other SD.However, in contrast, PSMA RLT with 161 Tb does not seem to be a promising option in patients previously not responding adequately to [ 225 Ac]Ac-PSMA-617; in our 4 patients with this mentioned condition, no significant imaging response or PSA response could be observed.Future studies to investigate [ 161 Tb]Tb-PSMA-617 RLT in patients with inadequate response to [ 177 Lu]Lu-PSMA-617 RLT seem to be of particular interest.In addition, the use of 161 Tb as an alternative to 177 Lu when initiating PSMA RLT could be a focus of future trials.
Our pilot study has certain limitations.First, the study suffers from its retrospective nature and the small cohort of patients.Further studies are necessary, involving a larger number of patients to confirm the results and enable more detailed analyses.The results and comparison may be biased by the time between the two compared cycles, in particular by therapy-related changes or a possible tumor progression.The present study does not determine the clinical impact of higher tumor-absorbed radiation doses delivered by 161 Tb, but might serve as a rational starting point for future studies.Furthermore, adverse events were only analyzed in short term after the cycle of [ 161 Tb]Tb-PSMA-617 RLT.Generally, using a new radionuclide or radioligand, red bone marrow dosing is an essential issue.However, calculation of the dose in the bone marrow based on scintigraphic imaging would have been error-prone for the present cohort, since the majority of the patients showed multiple tumor lesions in the trunk skeleton.In addition, due to the retrospective character no blood samples for dosimetric calculations were available.It should be noted that in this pilot study we concentrated on the dosimetry of the organs at risk; in future studies other organs such as the intestine or spleen should also be evaluated.Moreover, there are some challenges in dosimetric imaging of 161 Tb.The energies of photons emitted by 161 Tb are all at low energies resulting in a higher scatter fraction and increased attenuation compared to 177 Lu photons.For this reason, additional uniformity correction was needed as a minimum prerequisite for imaging with 161 Tb.To further improve SPECT image quality with 161 Tb by reducing noise level and increasing contrast, the use of Monte Carlo-based reconstruction algorithm could be taken into account [57].However, to date such reconstruction algorithms are rarely available, especially in commercial systems.Furthermore, the clinical value of images obtained with those algorithms has yet to be proven.In addition, patient comfort and management allowed planar scintigraphy only at 3 time points and only one SPECT/CT imaging per day.However, several studies have shown that dosimetric estimation based on this scintigraphy concept is reliable for PSMA-RLT and PRRT [46,55,58,59].

Conclusion
This intra-individual head-to-head pilot study reveals that [ 161 Tb]Tb-PSMA-617 delivers markedly higher tumor-absorbed doses compared to [ 177 Lu]Lu-PSMA-617, whereas the absorbed doses of the relevant organs at risk were only slightly higher.In particular, superior TI-kidney and TI-parotid were observed for [ 161 Tb]Tb-PSMA-617 in 5/6 patients.This supports 161 Tb as a promising candidate for use as radionuclide in PSMA-RLT.Further studies with larger patient cohorts, ideally in a prospective setting, are recommended to confirm this observation.
depicts a representative example of [ 161 Tb]Tb-PSMA-617 planar whole-body scintigraphy demonstrating long-term retention of [ 161 Tb]Tb-PSMA-617 in the metastases with relatively low residual uptake in normal organs.

Figure 1 :
Figure 1: Representative example of whole-body scintigrams acquired at three different time-points post administration of [ 161 Tb]Tb-PSMA-617.

Figure 3 :
Figure 3: Absorbed doses in tumor lesions determined after application of [ 161 Tb]Tb-PSMA 617 and [ 177 Lu]Lu-PSMA 617, respectively.A: for all patients and lesions, B: mean tumor lesion absorbed dose per patient, C: absorbed dose in each individual tumor lesion.

Table 1 :
Patient characteristics