Development of a new bifunctional PSMA ligand as a theranostic for prostate cancer

1057 Background: The prostate-specific membrane antigen (PSMA) is a promising target for imaging and targeted radionuclide therapy of metastatic prostate cancer. Positron-emitting copper-64 has attractive physical characteristics for imaging and provides a diagnostic partner for the therapeutic radionuclide copper-67. New sarcophagine-based macrobicyclic cage amine ligands were prepared conjugated to either one or two glutamate-urea-lysine containing inhibitors of PSMA. The new complexes were radiolabelled with [64Cu]CuII and evaluated in a LNCaP xenograft prostate cancer mouse model. Methods: A sarcophagine ligand with a single glutamate-urea-lysine functional group (SarPSMA) was prepared as well as derivative containing two glutamate-urea-lysine functional groups (SarbisPSMA). Both ligands could be radiolabelled with [64Cu]CuII at room temperature in <20 min to give complexes with high radiochemical purity. Small animal PET/CT images and organ biodistribution data of LNCaP tumour-bearing NGS mice were acquired at 1, 4, and 24 hr post-injection following intravenous administration of either [64Cu]Cu(SarPSMA) or [64Cu]Cu(SarbisPSMA). Results: Tumour uptake of [64Cu]Cu(SarPSMA) peaked at 1 hr to 9% IA/g but tumour retention was low with 1% IA/g remaining at 24 hrs post-injection and rapid renal clearance. In comparison, [64Cu]Cu(SarbisPSMA) displayed significantly increased tumour uptake and retention (13% IA/g at 24 h post injection. Tumour as well as kidney uptake could be blocked by injection of excess non-radioactive peptide. Conclusions: [64Cu]Cu(SarbisPSMA) has superior tumour uptake and retention when compared to monomeric [64Cu]Cu(SarPSMA) and warrants further investigation.