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The first long-term safety data with a 212 Pb-labelled radiopharmaceutical reported significant renal adverse events beyond two years of follow-up. Understanding pharmacokinetic drivers of doses for alpha-emitting radioligand therapy (RLT) is critical to optimizing molecules. We aimed to compare the dosimetry and therapeutic index (TI) of a single pharmaceutical, rhPSMA-10.1, labeled with 225 Ac or 212 Pb, using human pharmacokinetic data. Dosimetry from a Phase 1 trial of [ 177 Lu]Lu-rhPSMA-10.1 in 13 patients was used to generate time–activity curves for tumors and organs-at-risk. These were used to model [ 225 Ac]Ac-rhPSMA-10.1 and [ 212 Pb]Pb-rhPSMA-10.1 dosimetry by substituting the physical half-life and decay properties of 177 Lu with the alpha-emitters’. Absorbed doses and TIs were calculated. The impact of daughter radionuclide translocation on organ doses and TIs was modeled. To deliver 5Gy (RBE5) to tumors, a ∼29-fold higher administered activity of 212 Pb was required vs 225 Ac (131 MBq versus 4.6 MBq). At this tumor dose, the activity of 212 Pb resulted in 2.5-fold and 2.2-fold higher absorbed doses to kidneys and salivary glands vs 225 Ac. Consequently, 225 Ac demonstrated an improved TI, with a ∼3-fold higher tumor:kidney dose ratio (9.85 versus 3.36) and a ∼2.2-fold higher tumor:salivary gland ratio (15.9 versus. 7.1). When modeling a worst-case scenario for daughter translocation, 225 Ac maintained a superior TI. Importantly, based on rhPSMA-10.1’s pharmacokinetics, to achieve 120Gy (RBE5) to tumors would result in 12.1Gy (RBE5) and 35.7Gy (RBE5) delivered to the kidneys for 225 Ac and 212 Pb, respectively. Modeling daughter translocation, these values become 39.1Gy (RBE5) and 114.3Gy (RBE5) , respectively, which may explain recently reported safety data from 212 Pb-labelled RLT (Figure 5). The physical half-life of 225 Ac is better suited to rhPSMA-10.1’s pharmacokinetics than the shorter half-life 212 Pb. This results in enhanced TI for [ 225 Ac]Ac-rhPSMA-10.1, delivering lower absorbed doses to organs-at-risk for a fixed tumor dose. 212 Pb-labelling may lead to high renal absorbed doses driven by demetallation.