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.

Production of scandium radionuclides for theranostic applications: towards standardization of quality requirements.

In the frame of "precision medicine", the scandium radionuclides have recently received considerable interest, providing personalised adjustment of radiation characteristics to optimize the efficiency of medical care or therapeutic benefit for particular groups of patients. Radionuclides of scandium, namely scandium-43 and scandium-44 (43/44Sc) as positron emitters and scandium-47 (47Sc), beta-radiation emitter, seem to fit ideally into the concept of theranostic pair. This paper aims to review the work on scandium isotopes production, coordination chemistry, radiolabeling, preclinical studies and the very first clinical studies. Finally, standardized procedures for scandium-based radiopharmaceuticals have been proposed as a basis to pave the way for elaboration of the Ph.Eur. monographs for perspective scandium radionuclides.

Bifunctional aryliodonium salts for highly efficient radioiodination and astatination of antibodies.

In this report we describe the development of an alternative approach to arylstannane chemistry for radiolabeling antibodies with radioiodine or astatine based on aryliodonium salts precursors. Bifunctional aryliodonium salts were designed and tested for the synthesis of 125I and 211At labeled prosthetic groups for bioconjugation. The nature of the electron rich aryl group was varied and its impact on the regioselectivity of radiohalogenation was evaluated. Unexpectedly, whereas the 2-thienyl group provided the best regioselectivity towards the radioiodination of the aryl moiety of interest (98:2), it was less selective for astatination (87:13); the anisyl group providing the best regioselectivity of astatination (94:6). Under optimized conditions, both radioiodination and astatination could be performed very efficiently in mild conditions (radiochemical yields>85%). The ionic nature of the precursors was exploited to develop an efficient purification approach: the HPLC step that is usually necessary in conventionnal approaches to optimize removal of organotin toxic precursors and side products was replaced by a filtration through a silica cartridge with a significantly reduced loss of radiolabeled product. The purified radioiodinated and astatinated prosthetic groups were then conjugated efficiently to an anti-CD138 monoclonal antibody (75-80% conjugation yield). By using this novel and simple radiohalogenation procedure, higher overall radiochemical yields of astatination were obtained in comparison with the use of an arylstannane precursor and procedures of the litterature for labeling the same antibody. Overall, due to their simplicity of use and high robustness, these new precursors should simplify the labeling of proteins of interest with iodine and astatine radioisotopes for imaging and therapeutic applications.

Scandium(III) complexes of monophosphorus acid DOTA analogues: a thermodynamic and radiolabelling study with (44)Sc from cyclotron and from a (44)Ti/(44)Sc generator.

The complexation ability of DOTA analogs bearing one methylenephosphonic (DO3AP) or methylenephosphinic (DO3AP(PrA) and DO3AP(ABn)) acid pendant arm toward scandium was evaluated. Stability constants of their scandium(iii) complexes were determined by potentiometry combined with (45)Sc NMR spectroscopy. The stability constants of the monophosphinate analogues are somewhat lower than that of the Sc-DOTA complex. The phosphorus acid moiety interacts with trivalent scandium even in very acidic solutions forming out-of-cage complexes; the strong affinity of the phosphonate group to Sc(iii) precludes stability constant determination of the Sc-DO3AP complex. These results were compared with those obtained by the free-ion selective radiotracer extraction (FISRE) method which is suitable for trace concentrations. FISRE underestimated the stability constants but their relative order was preserved. Nonetheless, as this method is experimentally simple, it is suitable for a quick relative comparison of stability constant values under trace concentrations. Radiolabelling of the ligands with (44)Sc was performed using the radioisotope from two sources, a (44)Ti/(44)Sc generator and (44m)Sc/(44)Sc from a cyclotron. The best radiolabelling conditions for the ligands were pH = 4, 70 °C and 20 min which were, however, not superior to those of the parent DOTA. Nonetheless, in vitro behaviour of the Sc(iii) complexes in the presence of hydroxyapatite and rat serum showed sufficient stability of (44)Sc complexes of these ligands for in vivo applications. PET images and ex vivo biodistribution of the (44)Sc-DO3AP complex performed on healthy Wistar male rats showed no specific bone uptake and rapid clearance through urine.

Cyclotron production of high purity (44m,44)Sc with deuterons from (44)CaCO3 targets.

INTRODUCTION: Due to its longer half-life, (44)Sc (T1/2 = 3.97 h) as a positron emitter can be an interesting alternative to (68)Ga (T1/2 = 67.71 min). It has been already proposed as a PET radionuclide for scouting bone disease and is already available as a (44)Ti/(44)Sc generator. (44)Sc has an isomeric state, (44 m)Sc (T1/2 = 58.6 h), which can be co-produced with (44)Sc and that has been proved to be considered as an in-vivo PET generator (44 m)Sc/(44)Sc. This work presents the production route of (44 m)Sc/(44)Sc generator from (44)Ca(d,2n), its extraction/purification process and the evaluation of its performances. METHODS: Irradiation was performed in a low activity target station using a deuteron beam of 16 MeV, which favors the number of (44 m)Sc atoms produced simultaneously to (44)Sc. Typical irradiation conditions were 60 min at 0.2 µA producing 44 MBq of (44)Sc with a (44)Sc/(44 m)Sc activity ratio of 50 at end of irradiation. Separations of the radionuclides were performed by means of cation exchange chromatography using a DGA® resin (Triskem). Then, the developed process was applied with bigger targets, and could be used for preclinical studies. RESULTS: The extraction/purification process leads to a radionucleidic purity higher than 99.99% ((43)Sc, (46)Sc, (48)Sc < DL). (44 m)Sc/(44)Sc labeling towards DOTA moiety was performed in order to get an evaluation of the specific activities that could be reached with regard to all metallic impurities from the resulting source. Reaction parameters of radiolabeling were optimized, reaching yields over 95%, and leading to a specific activity of about 10-20 MBq/nmol for DOTA. A recycling process for the enriched (44)Ca target was developed and optimized. CONCLUSION: The quality of the final batch with regard to radionucleidic purity, specific activity and metal impurities allowed a right away use for further radiopharmaceutical evaluation. This radionucleidic pair of (44 m)Sc/(44)Sc offers a quite interesting PET radionuclide for being further evaluated as an in-vivo generator.

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.

Astatine standard redox potentials and speciation in acidic medium.

A combined experimental and theoretical approach is used to define astatine (At) speciation in acidic aqueous solution and to answer the two main questions raised from literature data: does At(0) exist in aqueous solution and what is the chemical form of At(+III), if it exists. The experimental approach considers that a given species is characterized by its distribution coefficient (D) experimentally determined in a biphasic system. The change in speciation arising from a change in experimental conditions is observed by a change in D value. The theoretical approach involves quasi-relativistic quantum chemistry calculations. The results show that At at the oxidation state 0 cannot exist in aqueous solution. The three oxidation states present in the range of water stability are At(-I), At(+I), and At(+III) and exist as At(-), At(+), and AtO(+), respectively, in the 1-2 pH range. The standard redox potentials of the At(+)/At(-) and AtO(+)/At(+) couples have been determined, the respective values being 0.36 +/- 0.01 and 0.74 +/- 0.01 V vs NHE.

Febrile pancytopenia and psychosis revealing pernicious anemia.

The rare case of a 42-year-old woman of African origin presenting with persecution mania leading to admission to a psychiatric hospital is reported. The outcome was rapidly marked by febrile pancytopenia and ataxia leading to the diagnosis of pernicious anemia. Although the hematologic abnormalities and mania were corrected within 2 weeks under vitamin therapy, neural improvement was slower as observed classically. The literature regarding pancytopenia and psychiatric presentations is briefly reviewed, suggesting that vitamin B(12) deficiency may induce paranoid delusion.

Multisystem sarcoidosis and carcinoma of the uterine cervix: an unusual association.

Sarcoidosis malignancy syndrome is a rare phenomenon which remains controversial. We report here the case of a 46-year-old woman presenting with multisystem sarcoidosis 12 months after the completion of combined treatment for stage III squamous cell carcinoma of the uterine cervix; at the time she was still in complete remission of the tumor. The outcome was rapidly favorable under oral corticosteroid therapy. The time interval between the two illnesses as well as patient's age strongly suggest a relationship. Possible pathophysiologic mechanisms and the literature regarding uterine tumors are briefly reviewed.