Bivalent Inhibitors of Prostate-Specific Membrane Antigen Conjugated to Desferrioxamine B Squaramide Labeled with Zirconium-89 or Gallium-68 for Diagnostic Imaging of Prostate Cancer

Abstract

Prostate-specific membrane antigen (PSMA) is a carboxypeptidase that is overexpressed in prostate cancer and is an excellent candidate for targeted diagnostic imaging and therapy. Lysine-ureido-glutamate inhibitors of PSMA radiolabeled with positron-emitting radionuclides can be used for diagnostic imaging with positron emission tomography (PET). A squaramide ester derivative of desferrioxamine B (H 3 DFOSq) was used to prepare four new agents with either one or two lysine-ureido-glutamate pharmacophores. The H 3 DFOSq ligand can be used to form stable complexes with either of the positron-emitting radionuclides gallium-68 (t 1/2 = 68 min) or zirconium-89 (t 1/2 = 3.3 days). The complexes were evaluated in PSMA-positive xenograft mouse models. Bivalent inhibitors, where two pharmacophores are tethered to a single DFOSq ligand, have better tumor uptake than their monovalent analogues. The ligands presented here, which can be labeled with either gallium-68 or zirconium-89, have the potential to increase the number of clinical sites that can perform diagnostic PET imaging.

Imaging Somatostatin Positive Tumors with Tyr3-Octreotate/Octreotide Conjugated to Desferrioxamine B Squaramide Radiolabeled with either Zirconium-89 or Gallium-68

“…The conditions for radiolabeling with zirconium-89 were extrapolated from our previous work with H 3 DFOSq conjugated to lysine-ureido-glutamate. 27 Both peptides were labeled with zirconium-89 at a concentration of 2 μg/MBq (1.1 nmol/MBq). Analysis by radio-HPLC shows radiochemical yield of >95% in 30 min at room temperature.…”

“…Analysis of a zirconium(IV) complex of a DFOSq-conjugate by 13 C NMR spectroscopy suggested that the dione backbone does interact with the metal ion, whereas there are no such interactions in the analogous gallium(III) complex. 27,34 Predictive computational modeling of [Zr(DFOSqOCH 2 CH 3 )] + with density functional theory suggested that one of the oxygen atoms of the dicarbonyl functional group bound to the zirconium(IV) ion. 38 Both [ 89 Zr]ZrDFOsq-TIDE and [ 89 Zr]ZrDFOsq-TATE are stable in the presence of human serum albumin.…”

“…In recent work, aimed at preparing receptor targeting ligands that can be radiolabeled with either zirconium-89 or gallium-68, we used a version of the bacterial siderophore, desferrioxamine B (H 3 DFO) that has been modified by the addition of a squaramide ethyl ester functional group to give H 3 DFOSquaramide (H 3 DFOSq) to attach glutamate-ureido-lysine small molecules that target prostate-specific membrane antigen. 27 The potential of derivatives of H 3 DFO to coordinate gallium-67 and gallium-68 radionuclides has been demonstrated previously. 27−32 For example, a [ 67 Ga][Ga(DFO)] complex was demonstrated as being sufficiently stable in human serum for 2 days.…”

Enzyme mediated incorporation of zirconium-89 or copper-64 into a fragment antibody for same day imaging of epidermal growth factor receptor

“…The DFOSq chelator can also be used to coordinate to 68 Ga III . 63 The major advantage of the Fab528 conjugates presented is that high-quality PET images can be acquired three hours after administration and this could translate to same day imaging in humans improving the feasibility of diagnostic EGFR PET imaging.…”

Radiolabeled PSMA Inhibitors

“…Noor et al [ 251 ] conjugated the Lys-ureido-Glu binding motif to the desferrioxamine B squareamide ester derivative H 3 DFOSq, leading to two monovalent and two bivalent DFO-Sq-lysine-ureido-glutamate derivatives with different linker structures to be radiolabeled with 89 Zr and 68 Ga. The bivalent ligands performed superior in LNCaP tumor models compared to the monovalent ligands.…”