First preclinical SPECT/CT imaging and biodistribution of [165Er]ErCl3 and [165Er]Er-PSMA-617

Background

¹⁶⁵Er (t_1/2 = 10.4 h, E_x-ray = 47.1 keV (59.4%) and 54.3 keV (14.3%)) is a promising radionuclide suitable for targeted Auger electron therapy of cancer. ¹⁶⁵Er can be produced at a relatively low cost, high yield, and high purity using small medical cyclotrons. As a late lanthanide, ¹⁶⁵Er is easy to label and can be used as a surrogate for other lanthanides or Ac in proof-of-concept studies. In this report, we explore the radiochemistry, in vitro, and in vivo behavior of [¹⁶⁵Er]ErCl₃ and [¹⁶⁵Er]Er-PSMA-617 to showcase the application of this radionuclide. Particularly, we report the first phantom and preclinical SPECT imaging of this radionuclide leveraging its characteristic X-ray photon emissions.

Results

The ¹⁶⁵Ho(p,n)¹⁶⁵Er nuclear reaction using a 13 MeV cyclotron demonstrated production yields of up to 25 ± 5 MBq. µA⁻¹ h⁻¹ at the end of the bombardment. After the purification (4.0 ± 0.5 h) using a sequential combination of cation exchange and extraction chromatography, 4-h irradiation produced up to 1.5 GBq of [¹⁶⁵Er]ErCl₃. High molar activity [¹⁶⁵Er]Er-PSMA-617 was prepared (~ 200 MBq/nmol). [¹⁶⁵Er]Er-PSMA-617 showed a LogD_7.4 value of -2.34 ± 0.24 meaning high hydrophilicity of the complex as expected. The stability of [¹⁶⁵Er]Er-PSMA-617 in saline, human, and mouse serum was studied and showed intact tracer after 12 h in all three cases. [¹⁶⁵Er]ErCl₃ and [¹⁶⁵Er]Er-PSMA-617 were both taken up by LNCaP cells. PSMA-617 has IC₅₀ at nanomolar range for [¹⁶⁵Er]Er-PSMA-617 in LNCaP cells. SPECT images with preclinical phantoms showed good uniformity, spatial resolution, and quantitative accuracy. SPECT/CT imaging in LNCaP tumor-bearing mice injected with [¹⁶⁵Er]Er-PSMA-617 showed high tumor uptake and quantitative accuracy when comparing the results to ex vivo biodistribution %IA/g values. Mice injected with [¹⁶⁵Er]ErCl₃ showed uptake in bone structures and excretion through both liver and kidneys.

Conclusions

This study demonstrated the preclinical use of ¹⁶⁵Er for the first time. Using [¹⁶⁵Er]ErCl₃ and [¹⁶⁵Er]Er-PSMA-617 as examples, the radiochemistry, cell, and animal studies showed that ¹⁶⁵Er can be used as a tool for evaluating targeted radiopharmaceuticals. The X-ray emission from ¹⁶⁵Er can be used for quantitative SPECT imaging in mice.