Synthesis and preclinical evaluation of DOTAGA-conjugated PSMA ligands for functional imaging and endoradiotherapy of prostate cancer

Martina Weineisen, Jakub Simecek, Margret Schottelius, Markus Schwaiger, Hans Jürgen Wester

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Background: Due to its high expression in prostate cancer, PSMA (prostate-specific membrane antigen) represents an ideal target for both diagnostic imaging and endoradiotherapeutic approaches. Based on a previously published highly specific PSMA ligand ([68Ga]DOTA-FFK(Sub-KuE)), we developed a corresponding metabolically stable 1,4,7,10-tetraazacyclododececane,1-(glutaric acid)-4,7,10-triacetic acid (DOTAGA) construct for theranostic treatment of prostate cancer.

Methods: All ligands were synthesized by a combined solid phase and solution phase synthesis strategy. The affinity of the natgallium and lutetium complexes to PSMA and the internalization efficiency of the radiotracers were determined on PSMA-expressing LNCaP cells. The 68Ga- and 177Lu-labelled ligands were further investigated for lipophilicity, binding specificity, metabolic stability, as well as biodistribution and μPET in LNCaP-tumour-bearing mice.

Results: Radiochemical yields for 68Ga (3 nmol, 5.0 M NaCl/2.7 M HEPES (approximately 5/1), pH 3.5 to 4.5, 5 min, 95°C) and 177Lu labelling (0.7 nmol, 0.1 M NH4OAc, pH 5.5, 30 min, 95°C) were almost quantitative, resulting in specific activities of 250 to 300 GBq/μmol for the 68Ga analogues and 38 GBq/μmol for 177Lu complexes. Due to metabolic instability of l-amino acid spacers, d-amino acids were implemented resulting in a metabolically stable DOTAGA ligand. Compared to the DOTA ligand, the DOTAGA derivatives showed higher hydrophilicity (logP = −3.6 ± 0.1 and −3.9 ± 0.1 for 68Ga and 177Lu, respectively) and improved affinity to PSMA resulting in an about twofold increased specific internalization of the 68Ga- and 177Lu-labelled DOTAGA analogue. Especially, [68Ga]DOTAGA-ffk(Sub-KuE) exhibits favourable pharmacokinetics, low unspecific uptake and high tumour accumulation in LNCaP-tumour-bearing mice.

Conclusions: The pair of diagnostic/therapeutic PSMA-ligands [68Ga/177Lu]DOTAGA-ffk(Sub-KuE) possess remarkable potential for the management of prostate cancer.

Original languageEnglish
Article number63
JournalEJNMMI Research
Issue number1
StatePublished - 2014


  • Endoradiotherapy
  • PET
  • PSMA
  • PSMA ligand
  • Prostate cancer
  • Prostate-specific membrane antigen
  • Theranostic
  • [Ga]DOTAGA-ffk(Sub-KuE)
  • [Lu]DOTAGA-ffk(Sub-KuE)


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