RT Journal Article SR Electronic T1 A Next Generation Theranostic PSMA Ligand for 64Cu and67Cu-Based Prostate Cancer Imaging and Therapy JF Journal of Nuclear Medicine JO J Nucl Med FD Society of Nuclear Medicine SP 1005 OP 1005 VO 60 IS supplement 1 A1 Shashikanth Ponnala A1 Alejandro Amor-Coarasa A1 James Kelly A1 Nicholas Zia A1 Williams Clarence A1 Anastasia Nikolopoulou A1 Paul Donnelly A1 John Babich YR 2019 UL http://jnm.snmjournals.org/content/60/supplement_1/1005.abstract AB 1005Objectives: The concept of theranostics describes the use of a matched pair of radioisotopes to enable quantification of the distribution of radioactivity in the body, followed by radioligand therapy using the same delivery vector [1]. 64Cu (t1/2 = 12.7 h, β+ = 17.5%) and 67Cu (t1/2 = 2.58 d, β- = 100%) form a unique theranostic pair of radioisotopes suitable for this purpose. We have recently introduced a number of trifunctional PSMA-targeting ligands bearing the DOTA macrocycle for chelation of trivalent metals [2]. The in vivo tissue distribution of these ligands is highly promising, but the complexation of copper by DOTA is suboptimal. Sarcophagine chelators such as MeCOSar complex copper ions efficiently and with high stability [3,4]. Our aim was develop a 64Cu/67Cu theranostic ligand with high stability and optimal in vivo properties for PSMA-targeted imaging and therapy of prostate cancer. Methods: RPS-085 was synthesized by conjugation of a PSMA-targeting triazolylphenylurea-derivatized glutamate-urea-lysine moiety, an Nε-(2-(4-iodophenyl)acetyl)lysine albumin binding group, and a bifunctionalized MeCOSar chelator via a PEG3 spacer. The PSMA affinity of the metal-free ligand was determined in a competition binding assay against [99mTc]MIP-1427 in LNCaP cells. [64Cu]RPS-085 was synthesized in 20 min at 25 °C in either 10X PBS, 0.5 M NH4OAc, pH 5-6, or 3 N NaOAc, pH 5. Imaging by microPET/CT was performed up to 48 h post injection (p.i.) of 21.5 ± 0.5 MBq [64Cu]RPS-085in nu/nu mice bearing LNCaP tumor xenografts. Results: The PSMA affinity of RPS-085 was high (IC50 <30 nM). The radiosynthesis of [64Cu]RPS-085 was nearly quantitative in both 10X PBS and 0.5 M NH4OAc. When the latter buffer was used, radiochemical yield was 98.3%, radiochemical purity exceeded 99%, and the molar activity was 117 GBq/µmol. The radioligand was reformulated in 10% v/v EtOH/saline, and was >99% stable over 24 h at 25 °C. The tumor uptake of [64Cu]RPS-085 reached a maximum at 3 h p.i. (28.1 ± 8.5 %ID/cm3), and was persistent out to 48 h p.i. (23.3 ± 8.2 %ID/cm3). Kidney uptake was high initially, but cleared rapidly. As a result, the tumor-to-kidney ratio was 3.3 ± 1.3 at 6 h, and 45.6 ± 17.2 at 48 h p.i. No accumulation of activity was observed in other tissues, including liver. Conclusions: Complexation of 64Cu2+ by the MeCOSar chelator is rapid and efficient, and complex stability is excellent both in vitro and in vivo. Furthermore, the in vivo tissue profile of [64Cu]RPS-085, including high and sustained tumor uptake, and excellent tumor-to-background ratios even at early time points, is promising. The ligand shows great potential for PET imaging using 64Cu, and its tissue distribution projects favorably for therapeutic applications. Further studies will evaluate the efficacy of [67Cu]RPS-085. References: [1] Rösch F, et al. The Beginning and Development of the Theranostic Approach in Nuclear Medicine, as Exemplified by the Radionuclide Pair 86Y and 90Y. Pharmaceuticals (Basel). 2017;10:56. [2] Kelly JM, et al. Trifunctional PSMA-targeting constructs for prostate cancer with unprecedented localization to LNCaP tumors. Eur J Nucl Med Mol Imaging. 2018;45:1841-1851. [3] Paterson BM, et al. PET imaging of tumours with a 64Cu labeled macrobicyclic cage amine ligand tethered to Tyr3-octreotate. Dalton Trans. 2014;43:1386-1396. [4] Gourni E, et al. Copper-64 Labeled Macrobicyclic Sarcophagine Coupled to a GRP Receptor Antagonist Shows Great Promise for PET Imaging of Prostate Cancer. Mol Pharm. 2015;12:2781-2790.