Synthesis and preclinical evaluation of BOLD-100 radiolabeled with ruthenium-97 and ruthenium-103.

BOLD-100 (formerly IT-139, KP1339), a well-established chemotherapeutic agent, is currently being investigated in clinical trials for the treatment of gastric, pancreatic, colorectal, and bile duct cancer. Despite numerous studies, the exact mode of action is still the subject of discussions. Radiolabeled BOLD-100 could be a powerful tool to clarify pharmacokinetic pathways of the compound and to predict therapy responses in patients using nuclear molecular imaging prior to the therapy. In this study, the radiosyntheses of carrier-added (c.a.) [97/103Ru]BOLD-100 were performed with the two ruthenium isotopes ruthenium-103 (103Ru; ß-, γ) and ruthenium-97 (97Ru; EC, γ), of which in particular the latter isotope is suitable for imaging by single-photon emission computed tomography (SPECT). To identify the best tumor-to-background ratio for diagnostic imaging, biodistribution studies were performed with two different injected doses of c.a. [103Ru]BOLD-100 (3 and 30 mg kg-1) in Balb/c mice bearing CT26 allografts over a time period of 72 h. Additionally, ex vivo autoradiography of the tumors (24 h p.i.) was conducted. Our results indicate that the higher injected dose (30 mg kg-1) leads to more unspecific accumulation of the compound in non-targeted tissue, which is likely due to an overload of the albumin transport system. It was also shown that lower amounts of injected c.a. [103Ru]BOLD-100 resulted in a relatively higher tumor uptake and, therefore, a better tumor-to-background ratio, which are encouraging results for future imaging studies using c.a. [97Ru]BOLD-100.

Improved reaction conditions for the synthesis of new NKP-1339 derivatives and preliminary investigations on their anticancer potential.

The very promising results of Na-trans-[RuCl4(1H-indazole)2] (NKP-1339) in clinical studies have fuelled renewed interest in the research and development of ruthenium(III) coordination compounds for cancer therapy. By applying an improved synthetic approach to this class of coordination compounds, six new examples of the general formula (cation)-trans-[RuCl4(azole)2], where (cation) = tetrabutylammonium (Bu4N)(+) (1, 2), sodium (3, 4), azolium (5, 6), and azole = 1-methyl-indazole (1, 3, 5), 1-ethyl-indazole (2, 4, 6), have been prepared. All compounds have been characterized by elemental analysis, electrospray ionization (ESI) mass spectrometry, UV-vis-, and NMR-spectroscopy and, if possible, X-ray diffraction analysis. Furthermore, the influence of the alkyl substituent at the position N1 of the indazole backbone on the stability in aqueous media as well as on the biological activity in three human cancer cell lines (CH1, A549, and SW480) and on the cellular accumulation in SW480 cells is discussed.