Nephron-Level Dosimetry Reveals Increased Absorbed Dose Heterogeneity of <sup>161</sup>Tb- Versus <sup>177</sup>Lu-DOTATATE in Murine Kidneys Despite Similar Pharmacokinetics.

Abstract

The β--emitter 161Tb is emerging as a promising radionuclide for radiopharmaceutical therapy because of its increased yield of low-energy electrons compared with 177Lu. This results in an increased localized absorbed dose, potentially influencing nephrotoxicity with 161Tb. Because of the excretion and reabsorption in specific kidney tissues of radiopharmaceuticals, substructure-level dosimetry is of interest for improving understanding of radiation-induced kidney damage in radiopharmaceutical therapy. This study investigated the renal dosimetry of [161Tb]Tb-DOTATATE and [177Lu]Lu-DOTATATE in C57BL6/Jjr mice using 2 different dosimetry frameworks. Methods: Detailed biodistribution data were assessed at 5 time points postinjection (15 min, 1 h, 4 or 4.5 h, 24 h, and 72 h). The activity in different nephron substructures was determined by γ-counting of the entire kidney and quantitative digital autoradiography acquisition of kidney sections. Tissue-level activity was distributed between nephron substructures. Simplistic dosimetry assuming uniform absorbed dose distribution was compared with nephron-substructure-level dosimetry based on a multinephron computational model. Results: Both radiopharmaceuticals exhibited similar pharmacokinetics, with rapid renal clearance and peak uptake at 15 min postinjection. 161Tb resulted in a significantly increased absorbed dose heterogeneity across nephron substructures compared with 177Lu. Absorbed doses to proximal tubules were on average 71% higher than to glomeruli for 161Tb and 28% higher for 177Lu. Simplistic whole-kidney dosimetry underestimated proximal tubule absorbed doses by up to 35% for 161Tb and 24% for 177Lu and over- or underestimated glomerular absorbed doses, particularly for 161Tb. The highest absorbed doses were observed in the juxtamedullary nephrons for both radionuclides, reflecting their distinct morphology. Conclusion: Nephron-substructure-level dosimetry revealed substantial absorbed dose heterogeneity for both radiopharmaceuticals, which is not considered with simplistic whole-organ dosimetry. Small-scale dosimetry enables identification of possible dose-limiting nephron substructures, informing future nephroprotective strategies and improving the translational evaluation of novel radioligands.