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.

Optimization of reaction conditions for the radiolabeling of DOTA and DOTA-peptide with (44m/44)Sc and experimental evidence of the feasibility of an in vivo PET generator.

INTRODUCTION: Among the number of generator systems providing radionuclides with decay parameters promising for imaging and treatment applications, there is the (44)Ti (T1/2=60 years)/(44)Sc (T1/2=3.97 h) generator. This generator provides a longer-lived daughter for extended PET/CT measurements compared to the chemically similar system (68)Ge/(68)Ga. Scandium also exists as (47)Sc, a potential therapeutic radionuclide. It is possible to produce (44)Sc in a cyclotron using, for example, the (44)Ca (d, n) (44)Sc nuclear reaction. In that case, the isomeric state (44 m)Sc (T1/2=58.6h) is co-produced and may be used as an in vivo(44 m)Sc/(44)Sc generator. The aim of this study is to evaluate the feasibility of this in vivo(44 m)Sc/(44)Sc generator and to demonstrate that the daughter radionuclide stays inside the chelator after decay of the parent radionuclide. Indeed, the physico-chemical process occurring after the primary radioactive decay (EC, IT, Auger electron …) has prevented in many cases the use of in-vivo generator, because of the post-effect as described in the literature. METHODS: The DOTA macrocyclic ligand forms stable complexes with many cations and has been shown to be the most suitable chelating moiety for scandium. Initially, the radiolabeling of DOTA and a DOTA-peptide (DOTATATE) with Sc was performed and optimized as a function of time, pH, metal-to-ligand ratio and temperature. Next, the physico-chemical processes that could occur after the decay (post-effect) were studied. (44 m)Sc(III)-labeled DOTA-peptide was quantitatively adsorbed on a solid phase matrix through a hydrophobic interaction. Elutions were then performed at regular time intervals using a DTPA solution at various concentrations. Finally, the radiolabelled complex stability was studied in serum. RESULTS: Radiolabeling yields ranged from 90% to 99% for metal-to-ligand ratio ranging from 1:10 to 1:500 for DOTA or DOTATATE respectively. The optimum physico-chemical parameters were pH=4-6, t=20 min, T=70°C. Then, the (44 m)Sc-DOTATATE complex, radiolabeled at 98%, was adsorbed through a hydrophobic interaction to a solid phase. Unlabeled scandium was completely eluted from the column whereas the Sc-DOTATATE complex was 100% retained. The release of (44)Sc from the complex due to decay was less than 1% over 2 periods of (44 m)Sc, independent of the DTPA concentration used for elution. (44 m)Sc/(44)Sc-DOTATATE was stable in serum over 72 h. CONCLUSIONS: The results indicate that the decay of (44 m)Sc to (44)Sc does not affect the integrity of the radiolabeled compound. Thus the (44 m)Sc/(44)Sc generator is chemically valid and stable in serum. It could be used for PET imaging as an in-vivo generator increasing the life time of the scandium and allowing the use of antibody as labelled compound. Further in-vivo biological evaluations should complete this work.

82Sr purification procedure using Chelex-100 resin.

(82)Rb is a positron-emitting radionuclide widely used in nuclear cardiology. One great advantage is its availability through a generator loaded with (82)Sr. (82)Sr can be produced in a high energy cyclotron by irradiating rubidium chloride target with proton beam. In this paper, we present an extensive study (elution profiles, effect of the elution flow rate) on the use of Chelex-100 resin and ammonia buffer. No significant effect of flow rate was evidenced between 1 and 10mL/min leading us to propose a purification process which can be easily automated.