Improving the Imaging Contrast of 68Ga-PSMA-11 by Targeted Linker Design: Charged Spacer Moieties Enhance the Pharmacokinetic Properties

Abstract

⁶⁸Ga-Glu-urea-Lys-(Ahx)-HBED-CC (⁶⁸Ga-PSMA-11) represents a successful radiopharmaceutical for PET/CT imaging of prostate cancer. Further optimization of the tumor-to-background contrast might significantly enhance the sensitivity of PET/CT imaging and the probability of detecting recurrent prostate cancer at low PSA values. This study describes the advantage of histidine (H)/glutamic acid (E) and tryptophan (W)/glutamic acid (E) containing linkers on the pharmacokinetic properties of ⁶⁸Ga-PSMA-11. The tracers were obtained by a combination of standard Fmoc-based solid-phase synthesis and copper(I)-catalyzed azide-alkyne cycloaddition. Their ⁶⁸Ga complexes were compared to the clinical reference ⁶⁸Ga-PSMA-11 with respect to cell binding, effective internalization, and tumor targeting properties in LNCaP-bearing balb/c nu/nu mice. The introduction of (HE)_i (i = 1-3) or (WE)_i (i = 1-3) into PSMA-11 resulted in a significantly changed biodistribution profile. The uptake values in kidneys, spleen, liver, and other background organs were reduced for (HE)₃ while the tumor uptake was not affected. For (HE)₁ the tumor uptake was significantly increased. The introduction of tryptophan-containing linkers also modulated the organ distribution profile. The results clearly indicate that histidine is of essential impact in order to improve the tumor-to-organ contrast. Hence, the histidine/glutamic acid linker modifications considerably improved the pharmacokinetic properties of ⁶⁸Ga-PSMA-11 leading to a reduced uptake in dose limiting organs and a significantly enhanced tumor-to-background contrast. Glu-urea-Lys-(HE)₃-HBED-CC represents a promising ⁶⁸Ga complex ligand for PET/CT-imaging of prostate cancer.