Nephron-Level Dosimetry Reveals Increased Absorbed Dose Heterogeneity of ¹⁶¹Tb- Versus ¹⁷⁷Lu-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. <b>Methods:</b> 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. <b>Results:</b> 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. <b>Conclusion:</b> 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.