Summary

This study explores the use of radiolanthanides in nuclear oncology, focusing on the comparison of ¹⁷⁷Lu and ¹⁶¹Tb, two key β¯-particle-emitting radionuclides with potential theranostic applications. Due to their similar chemical properties, these metals can be stably coordinated with DOTA chelators, enabling their use in various biomolecules without altering pharmacokinetics. Given the challenges in directly comparing radiolanthanides due to availability and decay rates, this study employs inductively coupled plasma mass spectrometry (ICP-MS) for simultaneous quantification of four lanthanides (Lu, Tb, Gd, Eu). Tumor cell uptake and biodistribution studies were performed using DOTATATE, DOTA-LM3, PSMA-617, and OxFol-1 labeled with these lanthanides. Additionally, dual-isotope SPECT/CT imaging was conducted to investigate the in vivo behavior of ¹⁷⁷Lu and ¹⁶¹Tb, providing insights into their medical applications.

Results from nanoScan® SPECT/CT

In vivo dual-isotope SPECT/CT imaging studies were conducted using a nanoScan SPECT/CT system (Mediso Medical Imaging Systems, Budapest, Hungary) to analyze the biodistribution of ¹⁷⁷Lu and ¹⁶¹Tb-labeled tumor-targeting agents. Radiolabeled DOTATATE, DOTA-LM3, PSMA-617, and OxFol-1 were prepared at a molar activity of 20 MBq/nmol, ensuring >99% radiochemical purity. Tumor-bearing and immunocompetent mice received intravenous injections of either Ln-labeled biomolecules, lanthanide salts, or Ln-DTPA complexes, followed by biodistribution analysis at multiple time points using ICP-MS.

SPECT/CT imaging was performed at 1 h, 4 h, and 24 h post-injection, enabling the simultaneous detection of γ-ray emissions from ¹⁷⁷Lu  (112.9 keV and 208.4 keV) and ¹⁶¹Tb (47.7 keV and 74.6 keV). Data reconstruction utilized distinct energy windows for each radionuclide to obtain separate distribution profiles. The high-resolution images provided by the nanoScan SPECT/CT system facilitated precise in vivo analysis of radioconjugate localization.

Key findings from the nanoScan SPECT/CT imaging studies:

• Tumor-bearing mice showed nearly identical tissue distribution profiles for co-administered ¹⁷⁷Lu and ¹⁶¹Tb-labeled biomolecules, confirming their comparable in vivo behavior.
• Radiolanthanide salts displayed distinct uptake patterns, with ¹⁷⁷Lu accumulating significantly in bone, particularly in the epiphysis, while ¹⁶¹Tb exhibited less bone uptake but higher retention in the liver.
• When administered as colloids in a pH-neutral formulation, both ¹⁷⁷Lu and ¹⁶¹Tb showed similar accumulation in the liver and spleen, aligning with biodistribution studies using stable lanthanide isotopes.
• Increased radiolanthanide localization was observed in epiphyseal plates due to metal ion resorption, consistent with previous findings in rats and dogs.

Figure 4. a‒d Dual-isotope SPECT/CT images of tumor-bearing mice injected with a mixture of ¹⁷⁷Lu-labeled (10 MBq) and ¹⁶¹Tb-labeled (10 MBq) biomolecules at 4 h p.i. a AR42J tumor-bearing mouse injected with Ln-DOTATATE; b AR42J tumor-bearing mouse injected with Ln-DOTA-LM3; c PC-3 PIP/flu tumor-bearing mouse injected with Ln-PSMA-617; d KB tumor-bearing mouse injected with Ln-OxFol-1. (AR42J, SSTR-positive tumor xenograft; PC-3 PIP, PSMA-positive tumor xenograft; PC-3 flu, PSMA-negative tumor xenograft; KB, folate receptor-positive tumor xenograft; Ki, kidney)

Figure 5. a‒c Dual-isotope SPECT/CT images of an FVB mouse injected with a mixture of [¹⁷⁷Lu]LuCl₃ (10 MBq) and [¹⁶¹Tb]TbCl₃ (10 MBq) in acidic formulation. a Scan acquired at 1 h p.i.; b scan acquired at 4 h p.i. and c scan acquired at 24 h p.i. (Ki, kidney; Li, liver; Sp, spine; Ep, epiphysis (only indicated in knee joint))

These results validate the utility of dual-isotope nanoScan SPECT/CT imaging for visualizing whole-body and sub-organ distribution of radiopharmaceuticals. The nanoScan SPECT/CT system enabled accurate, high-resolution imaging, supporting the potential interchangeability of ¹⁷⁷Lu  and ¹⁶¹Tb in targeted radiotherapy applications. This approach also demonstrated the feasibility of simultaneous screening of multiple radiolanthanides, enhancing the development of novel radiopharmaceuticals.

Conclusion

Dual-isotope nanoScan SPECT/CT imaging confirmed the comparable in vivo distribution of ¹⁷⁷Lu and ¹⁶¹Tb-labeled biomolecules, supporting their potential interchangeability in radiopharmaceutical applications. While free lanthanides showed distinct biodistribution due to differences in ionic properties, chelator-complexed forms exhibited only minor variations. These findings suggest that radiolanthanides beyond ¹⁷⁷Lu and ¹⁶¹Tb could be used without altering biological behavior. The similar behavior of chelated lutetium, terbium, gadolinium, and europium enables the simultaneous screening of drug candidates for radiopharmaceutical development.

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