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

Abstract

Ga-Glu-urea-Lys-(Ahx)-HBED-CC (Ga-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 Ga-PSMA-11. The tracers were obtained by a combination of standard Fmoc-based solid-phase synthesis and copper(I)-catalyzed azide-alkyne cycloaddition. TheirGa complexes were compared to the clinical reference Ga-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 = 1-3) or (WE) (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) while the tumor uptake was not affected. For (HE) 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 Ga-PSMA-11 leading to a reduced uptake in dose limiting organs and a significantly enhanced tumor-to-background contrast. Glu-urea-Lys-(HE)-HBED-CC represents a promising Ga complex ligand for PET/CT-imaging of prostate cancer.

PSMA-11–Derived Dual-Labeled PSMA Inhibitors for Preoperative PET Imaging and Precise Fluorescence-Guided Surgery of Prostate Cancer

“…The lipophilicity of the 68 Ga-labeled compounds was investigated by log D determination in comparison to 68 Ga-PSMA-11 (22.91 6 0.06) and ranged from 22.01 to 22.98 (Supplemental Table 1). All dye conjugates showed a high, complexation-independent PSMA-binding affinity in the same nanomolar range as the reference PSMA-11 (25,27). In contrast to the slightly reduced specific cell surface binding, the specific internalization was improved for the 68 Ga-and dye-labeled compounds, with a strong, significant enhancement for 68 Ga-Glu-urea-Lys-HBED-CC-IRDye800CW by a factor of 3.9 (P , 0.05).…”

“…2A; Supplemental Table 3). Compared with the reference 68 Ga-PSMA-11 (4.89 6 1.34 percentage injected dose [%ID]/g) (27), tumor uptake was significantly increased for the 68 Ga-labeled conjugates with fluorescein isothiocyanate (10.86 6 0.94 %ID/g, factor of 2.2, P , 0.05), IRDye800CW (13.66 6 3.73 %ID/g, factor of 2.8, P , 0.05), and DyLight800 (15.62 6 5.52 %ID/g, factor of 3.2, P , 0.05), whereas 68 Ga-Glu-urea-Lys-HBED-CC-AlexaFluor488 showed a similar tumor uptake (9.12 6 5.47 %ID/g, factor of 1.9, P . 0.05).…”

“…(A) Organ distribution of 60 pmol of 68 Ga-labeled Glu-urea-Lys-HBED-CC dye conjugates at 1 h after injection compared with reference 68 Ga-PSMA-11(27). (B) Organ distribution of 60 pmol of 68 Ga-Glu-urea-Lys-HBED-CC-IRDye800CW at 1, 2, and 6 h after injection.…”

Bispecific radioligands targeting prostate‐specific membrane antigen and gastrin‐releasing peptide receptors on the surface of prostate cancer cells

“…44 This observations were repeated in another study of the same group where the combinations of histidine-glutamic acid and tryptophan/glutamic acid were included as spacers between the HBED-CC chelator and the Glu-urea-Lys pharmacophore. 59 For the GRPr side of the heterodimers, the inclusion of (HE) n spacers resulted either did not change the binding affinity, as in the case of 3 (n = 1, 7.28nM) and 5 (n = 3, 7.09nM), or improved it, as in the case of 4 (n = 2, 4.40nM). 44 For the ligands 1-5, maximal cell uptake was achieved in a similar rate within a relative short time (between 20-40 min) for both PC-3 and for LNCaP cells, which corresponds ideally with the half-life T 1/2 = 68 minutes of the positron emitter 68 Ga.…”

“…44 The same results were also observed for PSMA monomers with the (HE) n spacers. 59 However, the lack of clinical data at this point could not provide information whether this is also true for the salivary glands. Salivary glands uptake is considered a major side effect of theranostic PSMA ligands at the moment.…”