Assessment of PSMA targeting ligands bearing novel chelates with application to theranostics: Stability and complexation kinetics of 68Ga3 +, 111In3 +, 177Lu3 + and 225Ac3 +

James M. Kelly, Alejandro Amor-Coarasa, Anastasia Nikolopoulou, Dohyun Kim, Clarence Williams, Shankar Vallabhajosula, John W. Babich

Research output: Contribution to journalArticlepeer-review

22 Scopus citations


Introduction Recent successes in the treatment of metastatic castration-resistant prostate cancer (mCRPCa) by systemic endoradiotherapy has sparked renewed interest in developing small molecule ligands targeting prostate-specific membrane antigen (PSMA) and chelators capable of stable complexation of metal radionuclides for imaging and therapy. As the size and coordination number of metals for imaging, such as 68Ga3 +, and for targeted therapy, such as 177Lu3 + and 225Ac3 +, are substantially different, they may show a preference for macrocycles of different denticity. We have prepared three simple conjugates that target PSMA and form radiometal complexes through coordination by either octa-, deca-, or dodecadentate tetraazacyclododecane chelators. The complex formation and metal ion selectivity of these constructs were determined at two relevant temperatures, complex stability was examined in vitro, and tumor targeting was demonstrated in preclinical PCa models with a view towards identifying a candidate with potential value as a theranostic agent for the imaging and therapy of mCRPCa. Methods Three bifunctional chelates with high denticity, including the octadentate chelate DOTA, the decadentate 3p-C-DEPA and a novel dodecadentate analogue of DEPA, were synthesized and conjugated to a glutamate-urea-lysine (EuK) pharmacophore (EuK-DOTA, EuK-107 and EuK-106, respectively) to enable targeting of PSMA. The metal ion selectivity for each construct was determined by incubation at 25 °C and 95 °C with the trivalent radiometals 68Ga3 +, 111In3 +, 177Lu3 + and 225Ac3 +. PSMA binding affinity was determined by competitive binding using LNCaP cells, while in vivo tumor targeting of the 68Ga-labeled constructs was examined by positron emission tomography (PET) in LNCaP xenograft tumor-bearing mice. Results PMSA affinities (IC50 values) were 13.3 ± 0.9 nM for EuK-DOTA, 18.0 ± 3.7 nM for EuK-107 and 42.6 ± 6.6 nM for EuK-106. EuK-107 and EuK-DOTA proved to rapidly and near quantitatively complex 68Ga3 +, 111In3 +, 177Lu3 + and 225Ac3 + at 95 °C, with EuK-107 also rapidly complexing 111In3 + and 177Lu3 + at 25 °C. The inability of EuK-106 to chelate 177Lu3 + and 225Ac3 + suggests that size of the cavity of the macrocylic ring may be more critical than the number of donor groups for the chelation of larger radiometals. In vivo, 68Ga-EuK-107 proved to have similar uptake to 68Ga-DKFZ-PSMA-617, a theranostic ligand currently in clinical evaluation, in a PSMA positive xenograft tumor model. Conclusions The broad metal ion selectivity, good in vitro affinity for PSMA and good in vivo tumor targeting suggest that EuK-107, with the 3p-C-DEPA chelator, merits further evaluation as a theranostics construct in prostate cancer.

Original languageEnglish (US)
Pages (from-to)38-46
Number of pages9
JournalNuclear Medicine and Biology
StatePublished - Dec 2017
Externally publishedYes


  • 3p-C-DEPA
  • Bifunctional chelate
  • PET
  • PSMA
  • Prostate cancer
  • Targeted radiotherapy

ASJC Scopus subject areas

  • Molecular Medicine
  • Radiology Nuclear Medicine and imaging
  • Cancer Research


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