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

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 ([Ga-68] 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 (na)tgallium and lutetium complexes to PSMA and the internalization efficiency of the radiotracers were determined on PSMA-expressing LNCaP cells. The Ga-68- and Lu-177-labelled ligands were further investigated for lipophilicity, binding specificity, metabolic stability, as well as biodistribution and mu PET in LNCaP-tumour-bearing mice. Results: Radiochemical yields for Ga-68 (3 nmol, 5.0 M NaCl/2.7 M HEPES (approximately 5/1), pH 3.5 to 4.5, 5 min, 95 degrees C) and Lu-177 labelling (0.7 nmol, 0.1 M NH4OAc, pH 5.5, 30 min, 95 degrees C) were almost quantitative, resulting in specific activities of 250 to 300 GBq/mu mol for the Ga-68 analogues and 38 GBq/mu mol for Lu-177 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 Ga-68 and Lu-177, respectively) and improved affinity to PSMA resulting in an about twofold increased specific internalization of the Ga-68- and Lu-177-labelled DOTAGA analogue. Especially, [Ga-68] 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 [Ga-68/Lu-177] DOTAGA-ffk(Sub-KuE) possess remarkable potential for the management of prostate cancer.