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

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 (H3DFOSq) was used to prepare four new agents with either one or two
lysine-ureido-glutamate pharmacophores. The H3DFOSq ligand
can be used to form stable complexes with either of the positron-emitting
radionuclides gallium-68 (t1/2 = 68 min)
or zirconium-89 (t1/2 = 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.

前列腺特异性膜抗原（Prostate-specific membrane antigen, PSMA）是一种羧肽酶，在前列腺癌中呈过表达状态，是靶向诊断成像与治疗的理想候选靶点。经正电子发射放射性核素标记的赖氨酸-脲基谷氨酸类PSMA抑制剂，可用于正电子发射断层显像（Positron Emission Tomography, PET）诊断成像。本研究采用去铁胺B（desferrioxamine B, H3DFOSq）的方酰胺酯衍生物，制备了四种分别携带一个或两个赖氨酸-脲基谷氨酸药效团的新型显像剂。H3DFOSq配体可与镓-68（半衰期t₁/₂=68 min）或锆-89（半衰期t₁/₂=3.3天）这两种正电子发射放射性核素形成稳定络合物。研究人员在PSMA阳性异种移植小鼠模型中对上述络合物进行了活性评价。结果显示，双价抑制剂——即两个药效团锚定至单个DFOSq配体——的肿瘤摄取量优于其单价类似物。本文所报道的配体可通过镓-68或锆-89进行标记，有望扩充可开展PET诊断成像的临床机构数量。