A dimerized urea-based inhibitor of the prostate-specific membrane antigen for 68Ga-PET imaging of prostate cancer

Abstract

BackgroundAlternative positron-emission tomography (PET) probes like labeled inhibitors of the prostate-specific membrane antigen (PSMA) are of emerging clinical impact as they show the ability to image small lesions of recurrent prostate cancer. Here, the dimerization of the pharmacophore Glu‐ureido‐Lys via the 68Ga chelator N,N′-bis[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N′-diacetic acid (HBED-CC) was investigated to further improve the binding characteristics and pharmacokinetics.MethodsThe peptidomimetic structures were synthesized by solid-phase chemistry, and the resulting products were coupled with the respective 2,3,5,6-tetrafluorophenol esters of HBED-CC to form the monomeric reference and the dimeric Glu‐ureido‐Lys derivative. The binding properties were analyzed in competitive binding, internalization, and cell surface retention experiments. PET images and biodistribution data were obtained 1 h after injection in BALB/c nu/nu mice bearing LNCaP tumor xenografts.ResultsCell binding data revealed significant better binding properties of the dimer (IC50 = 3.9 ± 1.8 nM; IC50 (monomer) = 12.1 ± 2.1 nM). The inhibition potency investigated by the enzyme-based NAALADase assay confirmed these results. Specific internalization in LNCaP cells was demonstrated for both, the monomer and dimer. As shown by efflux measurements, the dimeric compound was more effectively retained on the cell surface, resulting in advanced in vivo properties (T/BMonomer = 9.2; T/BDimer = 26.5).ConclusionsThe dimeric [68Ga]7 is a promising imaging agent for PSMA-expressing tumors as it shows higher tumor uptake while observing more favorable background clearance. As compared to the respective monomer, the higher affinity and prolonged tumor retention additionally represent promising features and warrant further evaluation regarding 68Ga-PET imaging of PSMA expression.

Evaluation of Hybrid 68Ga-PSMA Ligand PET/CT in 248 Patients with Biochemical Recurrence After Radical Prostatectomy

“…The ligand was labeled with 68 Ga 31 (half-life, 67.6 min) from a 68 Ge/ 68 Ga radionuclide generator (iThemba Labs) by means of a fully automated module (Scintomics) and good manufacturing practice-grade disposable cassettes and reagent kit (ABX) (16,22). The final product was dissolved in isotonic phosphate-buffered saline with subsequent sterile filtration.…”

68Ga-PSMA-HBED-CC PET for Differential Diagnosis of Suggestive Lung Lesions in Patients with Prostate Cancer

“…Images were obtained with HBED-CC (7) that was labeled with 68 Ga 31 (half-life, 67.6 min) from a 68 Ge/ 68 Ga radionuclide generator (iThemba Labs) by means of a fully automated module (Scintomics) and good manufacturing practice-grade disposable cassettes and reagent kit (ABX) as described previously (16). The final product was dissolved in isotonic phosphate-buffered saline with subsequent sterile filtration.…”

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

“…The monoactive tetrafluorophenyl (TFP) ester of N,N9-bis [2-hydroxy-5 (carboxyethyl)benzyl] ethylenediamine-N,N9-diacetic acid (HBED-CC) and the bis-activated ester (HBED-CC)TFP 2 were synthesized as previously described (12,13). The purified protected TATE-PEG 2 or Gluurea-Lys(Ahx) was reacted with 1.2 equivalents of HBED-CC-TFP-ester in the presence of 2 equivalents of N,N-diisopropylethylamine in N,Ndimethylformamide.…”