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.

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