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 Ga, and for targeted therapy, such as Lu and Ac, 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 Ga, In, Lu and Ac. PSMA binding affinity was determined by competitive binding using LNCaP cells, while in vivo tumor targeting of the Ga-labeled constructs was examined by positron emission tomography (PET) in LNCaP xenograft tumor-bearing mice. RESULTS: PMSA affinities (IC 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 Ga, In, Lu and Ac at 95 °C, with EuK-107 also rapidly complexing In and Lu at 25 °C. The inability of EuK-106 to chelate Lu and Ac 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, Ga-EuK-107 proved to have similar uptake to Ga-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.