A Cu-64/Cu-67 bifunctional PSMA ligand as a theranostic for prostate cancer

1215 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. A sarcophagine-based macrobicyclic cage amine conjugated to two glutamate-urea-lysine containing inhibitors of PSMA was prepared. The complex was radiolabelled with [64Cu]CuII or [67Cu]CuII and evaluated in a LNCaP xenograft prostate cancer mouse model. Methods: A sarcophagine ligand containing two glutamate-urea-lysine functional groups (SarbisPSMA) was synthesised. SarbisPSMA could be radiolabelled with [64Cu]CuII or [67Cu]CuII at room temperature in less than 20 minutes to give complexes with high radiochemical purity, without the need for further purification. Small animal PET/CT images and organ biodistribution data of LNCap tumour-bearing NSG mice were acquired at 1, 4, and 24 hours post-injections following intravenous administration of [64Cu]Cu(SarbisPSMA). Efficacy of a single administration at varying administered activity of [67Cu]Cu(SarbisPSMA) was compared to [177Lu]Lu(PSMAI&T) in LNCaP tumour-bearing NSG mice. Results: [64Cu]Cu(SarbisPSMA) displayed excellent tumour uptake and significant tumour retention at 24 hours post-injection (22% IA/g at 1 h and 26% IA/g at 24 h). Tumour, as well as kidney uptake could be blocked by over 90% by injection of excess non-radioactive peptide or 2-PMPA. The antitumour activity of [67Cu]Cu(SarbisPSMA) in the LNCaP prostate cancer model was equivalent to that of [177Lu]Lu(PSMAI&T), demonstrating the suitability of this novel agent for clinical assessment in the treatment of prostate cancer. Conclusions: [64/67Cu]Cu(SarbisPSMA) has excellent tumour uptake and retention, which was reflected in the promising antitumour activity that was equivalent to a Lu-177 based compound. This study warrants further investigation for the product as a theranostic agent for prostate cancer.