Pharmacokinetic Properties of Peptidic Radiopharmaceuticals: Reduced Uptake of (EH)₃-Conjugates in Important Organs

Abstract

The translation of radiolabeled tumor-targeting peptides into clinical routine is often hampered by an enhanced accumulation into the excreting organs. It has recently been reported that the (EH)₃ purification tag is able to improve the biodistribution of Affibody molecules. Therefore, the aim of this study was to prove the positive influence of (EH)₃ on the biodistribution of 2 peptidic radiopharmaceuticals, Glu-urea-Lys(Ahx)-HBED-CC and TATE-PEG₂-HBED-CC (HBED-CC is N,N′-bis [2-hydroxy-5(carboxyethyl)benzyl] ethylenediamine-N,N′- diacetic acid, TATE is octreotate, and PEG₂ is 8-amino-3,6-dioxaoctanoic acid spacer). Methods: Both compounds were compared with their respective (EH)₃-conjugated variants in cell-based in vitro assays and organ distribution. Results: The introduction of (EH)₃ to HBED-CC significantly changed the biodistribution profiles. In both cases, the uptake in several organs was reduced whereas tumor uptake was not affected. Most importantly, (EH)₃ lowered the kidney and liver uptake of the prostate-specific membrane antigen inhibitor each by a factor of 2.8 and, in the case of octreotate, the liver accumulation by a factor of 51. Conclusion: The biodistribution data suggest that (EH)₃ is able to improve the pharmacokinetic properties of peptidic radiopharmaceuticals, leading to reduced uptake in organs such as the liver, an important site of metastatic disease.