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Muller C.,Paul Scherrer Institute | Bunka M.,Paul Scherrer Institute | Bunka M.,University of Bern | Haller S.,Paul Scherrer Institute | And 9 more authors.
Journal of Nuclear Medicine | Year: 2014

Conclusion: With this study, we demonstrated the suitability of using 47Sc for therapeutic purposes. On the basis of our recent results obtained with 44Sc-folate, the present work confirms the applicability of 44Sc/47Sc as an excellent matched pair of nuclides for PET imaging and radionuclide therapy.Results: Irradiation of 46Ca resulted in approximately 1.8 GBq of 47Ca, which subsequently decayed to 47Sc. Separation of 47Sc from 47Ca was obtained with 80% yield in only 10 min. The 47Sc was then available in a small volume (∼500 μL) of an ammonium acetate/HCl (pH 4.5) solution suitable for direct radiolabeling. 47Sc-cm10 was prepared with a radiochemical yield of more than 96% at a specific activity of up to 13 MBq/nmol. In vitro 47Sccm10 showed folate receptor-specific binding and uptake into KB tumor cells. In vivo SPECT/CT images allowed the visualization of accumulated radioactivity in KB tumors and in the kidneys. The therapy study showed a significantly delayed tumor growth in mice, which received 47Sc-cm10 (10 MBq, 10 Gy) resulting in a more than 50% increase in survival time, compared with untreated control mice.In recent years, 47Sc has attracted attention because of its favorable decay characteristics (half-life, 3.35 d; average energy, 162 keV; Eγ, 159 keV) for therapeutic application and for SPECT imaging. The aim of the present study was to investigate the suitability of 47Sc for radionuclide therapy in a preclinical setting. For this purpose a novel DOTA-folate conjugate (cm10) with an albumin-binding entity was used.Methods: 47Sc was produced via the 46Ca(n,γ)47Caβ-→ 47Sc nuclear reaction at the high-flux reactor at the Institut Laue-Langevin. Separation of the 47Sc from the target material was performed by a semi-automated process using extraction chromatography and cation exchange chromatography. 47Sc-labeled cm10 was tested on folate receptor-positive KB tumor cells in vitro. Biodistribution and SPECT imaging experiments were performed in KB tumor-bearing mice. Radionuclide therapy was conducted with two groups of mice, which received either 47Sc-cm10 (10 MBq) or only saline. Tumor growth and survival time were compared between the two groups of mice. COPYRIGHT © 2014 by the Society of Nuclear Medicine and Molecular Imaging, Inc. Source

Haller S.,Paul Scherrer Institute | Reber J.,Paul Scherrer Institute | Brandt S.,University of Zurich | Bernhardt P.,Gothenburg University | And 4 more authors.
Nuclear Medicine and Biology | Year: 2015

Introduction: Application of therapeutic folate radioconjugates is a promising option for the treatment of folate receptor (FR)-positive tumors, although high uptake of radiofolates in the kidneys remains a critical issue. Recently, it was shown that enhancing the blood circulation of radiofolates results in increased tumor uptake and reduced retention of radioactivity in the kidneys. In this study, we investigated and compared the anti-tumor effects and potential long-term damage to the kidneys after application of an albumin-binding (177Lu-cm09), and a conventional (177Lu-EC0800) folate radioconjugate. Methods: In vivo studies were performed with KB tumor-bearing nude mice. 177Lu-EC0800 and 177Lu-cm09 were applied at variable quantities (10-30MBq/mouse), and the tumor growth was monitored over time. Mice without tumors were injected with the same radiofolates and investigated over eight months by determination of creatinine and blood urea nitrogen plasma levels and by measuring renal uptake of 99mTc-DMSA using SPECT. At the study end, the morphological changes were examined on renal tissue sections using variable staining methods. Results: Compared to untreated controls, dose-dependent tumor growth inhibition and prolonged survival was observed in all treated mice. In line with the resulting absorbed dose, the treatment was more effective with 177Lu-cm09 than with 177Lu-EC0800, enabling complete tumor remission after application of ≥20MBq (≥28Gy). Application of radiofolates with an absorbed renal dose ≥23Gy showed increased levels of renal plasma parameters and reduced renal uptake of 99mTc-DSMA. Morphological changes observed on tissue sections confirmed radionephropathy of variable stages. Conclusions: 177Lu-cm09 showed more favorable anti-tumor effects and significantly less damage to the kidneys compared to 177Lu-EC0800 as was expected based on improved tumor-to-kidney ratios. It was demonstrated that enhancing the blood circulation time of radiofolates was favorable regarding the risk-benefit profile of a therapeutic application. These results hold promise for future translation of the albumin-binder concept to the clinics, potentially enabling FR-targeted radionuclide therapy in patients. © 2015 Elsevier Inc. Source

Vakalopoulos A.,Bayer AG | Schmeck C.,Bayer AG | Thutewohl M.,Merck and Cie | Li V.,Bayer AG | And 5 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2011

Based on our former development candidate BAY 38-1315, optimization efforts led to the discovery of a novel chemical class of orally active cholesteryl ester transfer protein (CETP) inhibitors. The chromanol derivative 19b is a highly potent CETP inhibitor with favorable pharmacokinetic properties suitable for clinical studies. Chemical process optimization furnished a robust synthesis for a kilogram-scale process. © 2010 Elsevier Ltd. All rights reserved. Source

Ross T.L.,ETH Zurich | Honer M.,ETH Zurich | Muller C.,ETH Zurich | Groehn V.,Merck and Cie | And 2 more authors.
Journal of Nuclear Medicine | Year: 2010

The folate receptor is a proven target for folate-based diagnosis and treatment of cancer. Several folic acid conjugates have been developed as radiopharmaceuticals, but a suitable 18F-labeled folic acid derivative for routine clinical use is still lacking. The purpose of this study was to investigate the potential of 2′-18F-fluorofolic acid as a PET agent for folate receptor-positive tumors. Methods: The binding affinity of the cold reference compound 2′-fluorofolic acid was determined by in vitro displacement assays using human folate receptor-positive KB cells and 3H-folic acid. 18F labeling of 2′-fluorofolic acid was accomplished via a direct nucleophilic aromatic substitution of N 2-(N,N-dimethylamino-methylene)-2′-nitrofolic acid di-tertbutylester followed by acidic cleavage of the amino and carboxylic protecting groups. The new radiofolate was evaluated in nude mice bearing KB tumor xenografts under control and blocking conditions. Animals were either scanned from 75 to 105 min after injection of the radiotracer or sacrificed 75 min after injection for ex vivo biodistribution studies. Results: 2′-fluorofolic acid showed a high binding affinity (inhibition constant, 1.8 ± 0.1 nM) for the folate receptor. Direct aromatic 18F labeling of 2′-fluorofolic acid was achieved within 80 min via a convenient 2-step procedure in satisfactory radiochemical yields. The new radiotracer exhibited excellent pharmacokinetics with fast renal clearance and only moderate hepatobiliary elimination. Uptake of 29-18F-fluorofolic acid in folate receptor-positive KB tumors was high and specific, allowing a clear-cut visualization by PET. Conclusion: 2′-18F-fluorofolic acid, obtained via an integrated approach, is a promising PET agent for folate receptor-positive tumors and outperforms previously reported 18F-labeled folates. Copyright © 2010 by the Society of Nuclear Medicine, Inc. Source

Green T.J.,University of British Columbia | Liu Y.,University of British Columbia | Dadgar S.,University of British Columbia | Li W.,University of British Columbia | And 2 more authors.
Journal of Nutrition | Year: 2013

Mandatory folic acid fortification of grains such as wheat flour has been introduced in several countries to reduce the incidence of neural tube defects. There are concerns, however, that folic acid could mask the hematologic signs of vitamin B-12 deficiency and lead to other adverse health outcomes in the population. Calcium L-5-methyltetrahydrofolic acid (L-5-MTHF), a synthetic form of reduced folate, should not mask vitamin B-12 deficiency and may be safer than folic acid. Unfortunately, L-5-MTHF is not stable in most food matrices such as bread. Microencapsulation of L-5-MTHF with sodium ascorbate and a modified starch is effective at preventing loss of the vitamin during baking and storage. Our aim was to assess the efficacy of wheat rolls fortified with microencapsulated L-5-MTHF or equimolar folic acid compared with wheat rolls containing no added folate (placebo) at increasing blood folate concentrations during 16 wk. Healthy men and women aged 18-45 y (n = 45) were randomly assigned to consume wheat rolls that contained L-5-MTHF (452 μg/d), the molar equivalent of folic acid (400 μg/d), or placebo. At 16 wk, the mean (95% CI) erythrocyte folate was 0.48 (0.27, 0.71) and 0.37 (0.17, 0.57) μmol/L higher in the L-5-MTHF (P < 0.001) and folic acid wheat roll (P = 0.001) groups, respectively, than in the placebo group. Likewise, the mean plasma folate was 23 (12, 34) and 23 (12, 34) nmol/L higher in the L-5-MTHF (P < 0.001) and folic acid wheat roll (P < 0.001) groups, respectively, than in the placebo group. There were no significant differences in blood folate concentrations between the L-5-MTHF and folic acid wheat roll groups. Both microencapsulated L-5-MTHF and folic acid-fortified wheat rolls increased blood folate concentrations compared with placebo. © 2013 American Society for Nutrition. Source

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