Clinical translation of a PSMA inhibitor for 99mTc-based SPECT

Background: Prostate-specific membrane antigen (PSMA) is highly over-expressed in advanced prostate cancers. Ga-68-labeled PSMA inhibitors (iPSMA) are currently used for prostate cancer detection by PET imaging. The availability of simple, efficient and reproducible radiolabeling procedures is essential for developing new SPELT radio pharmaceuticals for clinical translation. The aim of this research was to prepare Tc-99m-EDDA/HYNIC-Lys(Nal)Urea-Glu (Tc-99m-EDDA/HYNIC-iPSMA) obtained from lyophilized kit formulations and evaluate the in vitro and in vivo radiopharmaceutical binding to prostate cancer cells over-expressing PSMA, as well as the Tc-99m-EDDA/HYNIC-iPSMA normal biodistribution in humans and the preliminary uptake in patients with prostate cancer. Methods: Tc-99m labeling was performed by adding sodium pertechnetate solution and a 0.2 M phosphate buffer (pH 7.0) to a lyophilized formulation containing HYNIC-iPSMA, EDDA, tricine, mannitol and stannous chloride. The radiochemical purity was evaluated by reversed-phase HPLC and ITLC-SG analyses. Stability studies in human serum were performed by size-exclusion HPLC. In vitro cell uptake was tested using prostate cancer cells (LNCaP) with blocked and non-blocked receptors. Biodistribution and tumor uptake were determined in LNCaP tumor-bearing nude mice with blocked and non-blocked receptors, and images were obtained using a micro-SPECT/CT. Whole-body images from three healthy men and two patients with histologically-confirmed prostate cancer (one of them with a previous Ga-68-PSMA-617scan) were acquired at 1 h and 3 h after (99m)TcEDDA/HYNIC-iPSMA administration with radiochemical purities of >98%. Results: In vitro and in vivo studies showed high radiopharmaceutical stability in human serum, specific recognition for PSMA, high tumor uptake (10.22 +/- 2.96% ID/g at 1 h) with rapid blood clearance and mainly kidney elimination. Preliminary images in patients demonstrated the ability of Tc-99m-EDDA/HYNIC-iPSMA to detect tumors and metastases of prostate cancer as well as Ga-69-PSMA-617 does. Conclusions: The results obtained in this study warrant further dosimetry and clinical studies to determine the specificity and sensitivity of Tc-99m-EDDA/HYNIC-iPSMA. (C) 2017 Elsevier Inc. All rights reserved.