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Simon M. Ametamey - One of the best experts on this subject based on the ideXlab platform.
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Investigation of the chick embryo as a potential alternative to the mouse for evaluation of radiopharmaceuticals.
Nuclear medicine and biology, 2014Co-Authors: Stephanie Haller, Roger Schibli, Simon M. Ametamey, Cristina MüllerAbstract:The chick embryo is an emerging in vivo model in several areas of pre-clinical research including radiopharmaceutical sciences. Herein, it was evaluated as a potential test system for assessing the biodistribution and in vivo stability of radiopharmaceuticals. For this purpose, a number of radiopharmaceuticals labeled with (18)F, (125)I, (99m)Tc, and (177)Lu were investigated in the chick embryo and compared with the data obtained in mice. Chick embryos were cultivated ex ovo for 17-19 days before application of the radiopharmaceutical directly into the peritoneum or intravenously using a vein of the chorioallantoic membrane (CAM). At a defined time point after application of radioactivity, the embryos were euthanized by shock-freezing using liquid nitrogen. Afterwards they were separated from residual egg components for post mortem imaging purposes using positron emission tomography (PET) or single photon emission computed tomography (SPECT). SPECT images revealed uptake of [(99m)Tc]pertechnetate and [(125)I]iodide in the thyroid of chick embryos and mice, whereas [(177)Lu]lutetium, [(18)F]fluoride and [(99m)Tc]-methylene diphosphonate ([(99m)Tc]-MDP) were accumulated in the bones. [(99m)Tc]-dimercaptosuccinic Acid ((99m)Tc-DMSA) and the somatostatin analog [(177)Lu]-DOTATOC, as well as the Folic Acid Derivative [(177)Lu]-DOTA-folate showed accumulation in the renal tissue whereas [(99m)Tc]-mebrofenin accumulated in the gall bladder and intestine of both species. In vivo dehalogenation of [(18)F]fallypride and of the Folic Acid Derivative [(125)I]iodo-tyrosine-folate was observed in both species. In contrast, the 3'-aza-2'-[(18)F]fluoroFolic Acid ([(18)F]-AzaFol) was stable in the chick embryo as well as in the mouse. Our results revealed the same tissue distribution profile and in vivo stability of radiopharmaceuticals in the chick embryo and the mouse. This observation is promising with regard to a potential use of the chick embryo as an inexpensive and simple test model for preclinical screening of novel radiopharmaceuticals. Copyright © 2014 Elsevier Inc. All rights reserved.
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A New 18F-Labeled Folic Acid Derivative with Improved Properties for the PET Imaging of Folate Receptor–Positive Tumors
Journal of nuclear medicine : official publication Society of Nuclear Medicine, 2010Co-Authors: Tobias L. Ross, Michael Honer, Viola Groehn, Roger Schibli, Cristina Müller, Simon M. AmetameyAbstract: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 N2-(N,N-dimethylamino-methylene)-2′-nitroFolic Acid di-tert-butylester 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 2′-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.
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Fluorine-18 Click Radiosynthesis and Preclinical Evaluation of a New 18F-Labeled Folic Acid Derivative
Bioconjugate chemistry, 2008Co-Authors: Tobias L. Ross, Michael Honer, Lam Phoebe, Thomas L. Mindt, Viola Groehn, Roger Schibli, P. August Schubiger, Simon M. AmetameyAbstract:The folate receptor (FR) is highly expressed on most epithelial cancer cells, while normal cells show only restricted expression of FR. As a result, the FR is an ideal target for receptor-based molecular imaging and therapy of cancer and has become a promising target in oncology. To date, several folate-based chemotherapeutics and imaging probes such as radiopharmaceuticals for single photon emission computed tomography (SPECT) have been developed. However, an (18)F-labeled Folic Acid Derivative suitable for positron emission tomography (PET) imaging that can be routinely applied is still lacking. In this study, a new fluorinated and radiofluorinated Folic Acid Derivative, (18/19)F-click folate, was synthesized using click chemistry. In a convenient and very efficient two-step radiosynthesis, the isolated (18)F-click folate was obtained in good radiochemical yields of 25-35% with a specific activity of 160+/-70 GBq/micromol after
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fluorine 18 click radiosynthesis and preclinical evaluation of a new 18f labeled Folic Acid Derivative
Bioconjugate Chemistry, 2008Co-Authors: Tobias L. Ross, Michael Honer, Thomas L. Mindt, Viola Groehn, Roger Schibli, Phoebe Lam, August P Schubiger, Simon M. AmetameyAbstract:The folate receptor (FR) is highly expressed on most epithelial cancer cells, while normal cells show only restricted expression of FR. As a result, the FR is an ideal target for receptor-based molecular imaging and therapy of cancer and has become a promising target in oncology. To date, several folate-based chemotherapeutics and imaging probes such as radiopharmaceuticals for single photon emission computed tomography (SPECT) have been developed. However, an 18F-labeled Folic Acid Derivative suitable for positron emission tomography (PET) imaging that can be routinely applied is still lacking. In this study, a new fluorinated and radiofluorinated Folic Acid Derivative, 18/19F-click folate, was synthesized using click chemistry. In a convenient and very efficient two-step radiosynthesis, the isolated 18F-click folate was obtained in good radiochemical yields of 25−35% with a specific activity of 160 ± 70 GBq/μmol after ≤90 min synthesis time. The new compound was pharmacologically evaluated in vitro and ...
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synthesis and preclinical evaluation of a Folic Acid Derivative labeled with 18f for pet imaging of folate receptor positive tumors
The Journal of Nuclear Medicine, 2006Co-Authors: Andrea Bettio, Michael Honer, Viola Groehn, Roger Schibli, August P Schubiger, Cristina Müller, Matthias Brühlmeier, Ursina Müller, Simon M. AmetameyAbstract:Folic Acid was linked regioselectively through its α- and γ-carboxyl groups to 4-fluorobenzylamine (FBA), and the α- and γ-FBA-folate regioisomers were evaluated for their ability to bind to folate receptor–positive cells. The 18F-labeled α/γ-FBA-folate counterpart was examined for in vivo tumor targeting efficiency in nude mice bearing folate receptor–positive tumor cells. Methods:18F-α/γ-FBA-folate was prepared in a 4-step reaction sequence starting from Folic Acid. The relative binding affinities of the α- and γ-FBA-folates to the folate receptor with respect to parent Folic Acid were determined in cultured KB-31 cells (nasopharyngeal epidermal carcinoma cell line) overexpressing the folate receptor using 3H-Folic Acid. Tumor accumulation of the 18F-labeled α/γ-FBA-folate and 18F-FDG was analyzed in vivo by high-resolution PET. Biodistribution and PET studies were performed under baseline and blockage conditions. Results: The radiochemical yield of the coupling step ranged from 15% to 44%, and the maximum specific radioactivity was 24 GBq/μmol. The in vitro binding affinities of the α- and γ-isomers and Folic Acid were 71, 62, and 41 nmol/L, respectively. PET revealed heterogeneous uptake of the radioligand, with the highest activity concentrations found in the tumor rim. In contrast, 18F-FDG uptake in a nude mouse bearing KB-31 folate receptor–positive tumors was negligible. Radioligand uptake in tumors at 125 min after injection amounted to 6.56% of the injected dose per gram of tissue (%ID/g) in control animals, whereas radioactivity accumulation in the tumors of Folic Acid–treated animals was significantly reduced by more than 80%—to 1.07 %ID/g (P = 0.001). Conclusion: This new 18F-labeled Folic Acid Derivative is a promising tool for PET imaging of folate receptor–positive tumors.
Roger Schibli - One of the best experts on this subject based on the ideXlab platform.
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Investigation of the chick embryo as a potential alternative to the mouse for evaluation of radiopharmaceuticals.
Nuclear medicine and biology, 2014Co-Authors: Stephanie Haller, Roger Schibli, Simon M. Ametamey, Cristina MüllerAbstract:The chick embryo is an emerging in vivo model in several areas of pre-clinical research including radiopharmaceutical sciences. Herein, it was evaluated as a potential test system for assessing the biodistribution and in vivo stability of radiopharmaceuticals. For this purpose, a number of radiopharmaceuticals labeled with (18)F, (125)I, (99m)Tc, and (177)Lu were investigated in the chick embryo and compared with the data obtained in mice. Chick embryos were cultivated ex ovo for 17-19 days before application of the radiopharmaceutical directly into the peritoneum or intravenously using a vein of the chorioallantoic membrane (CAM). At a defined time point after application of radioactivity, the embryos were euthanized by shock-freezing using liquid nitrogen. Afterwards they were separated from residual egg components for post mortem imaging purposes using positron emission tomography (PET) or single photon emission computed tomography (SPECT). SPECT images revealed uptake of [(99m)Tc]pertechnetate and [(125)I]iodide in the thyroid of chick embryos and mice, whereas [(177)Lu]lutetium, [(18)F]fluoride and [(99m)Tc]-methylene diphosphonate ([(99m)Tc]-MDP) were accumulated in the bones. [(99m)Tc]-dimercaptosuccinic Acid ((99m)Tc-DMSA) and the somatostatin analog [(177)Lu]-DOTATOC, as well as the Folic Acid Derivative [(177)Lu]-DOTA-folate showed accumulation in the renal tissue whereas [(99m)Tc]-mebrofenin accumulated in the gall bladder and intestine of both species. In vivo dehalogenation of [(18)F]fallypride and of the Folic Acid Derivative [(125)I]iodo-tyrosine-folate was observed in both species. In contrast, the 3'-aza-2'-[(18)F]fluoroFolic Acid ([(18)F]-AzaFol) was stable in the chick embryo as well as in the mouse. Our results revealed the same tissue distribution profile and in vivo stability of radiopharmaceuticals in the chick embryo and the mouse. This observation is promising with regard to a potential use of the chick embryo as an inexpensive and simple test model for preclinical screening of novel radiopharmaceuticals. Copyright © 2014 Elsevier Inc. All rights reserved.
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A New 18F-Labeled Folic Acid Derivative with Improved Properties for the PET Imaging of Folate Receptor–Positive Tumors
Journal of nuclear medicine : official publication Society of Nuclear Medicine, 2010Co-Authors: Tobias L. Ross, Michael Honer, Viola Groehn, Roger Schibli, Cristina Müller, Simon M. AmetameyAbstract: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 N2-(N,N-dimethylamino-methylene)-2′-nitroFolic Acid di-tert-butylester 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 2′-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.
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Fluorine-18 Click Radiosynthesis and Preclinical Evaluation of a New 18F-Labeled Folic Acid Derivative
Bioconjugate chemistry, 2008Co-Authors: Tobias L. Ross, Michael Honer, Lam Phoebe, Thomas L. Mindt, Viola Groehn, Roger Schibli, P. August Schubiger, Simon M. AmetameyAbstract:The folate receptor (FR) is highly expressed on most epithelial cancer cells, while normal cells show only restricted expression of FR. As a result, the FR is an ideal target for receptor-based molecular imaging and therapy of cancer and has become a promising target in oncology. To date, several folate-based chemotherapeutics and imaging probes such as radiopharmaceuticals for single photon emission computed tomography (SPECT) have been developed. However, an (18)F-labeled Folic Acid Derivative suitable for positron emission tomography (PET) imaging that can be routinely applied is still lacking. In this study, a new fluorinated and radiofluorinated Folic Acid Derivative, (18/19)F-click folate, was synthesized using click chemistry. In a convenient and very efficient two-step radiosynthesis, the isolated (18)F-click folate was obtained in good radiochemical yields of 25-35% with a specific activity of 160+/-70 GBq/micromol after
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fluorine 18 click radiosynthesis and preclinical evaluation of a new 18f labeled Folic Acid Derivative
Bioconjugate Chemistry, 2008Co-Authors: Tobias L. Ross, Michael Honer, Thomas L. Mindt, Viola Groehn, Roger Schibli, Phoebe Lam, August P Schubiger, Simon M. AmetameyAbstract:The folate receptor (FR) is highly expressed on most epithelial cancer cells, while normal cells show only restricted expression of FR. As a result, the FR is an ideal target for receptor-based molecular imaging and therapy of cancer and has become a promising target in oncology. To date, several folate-based chemotherapeutics and imaging probes such as radiopharmaceuticals for single photon emission computed tomography (SPECT) have been developed. However, an 18F-labeled Folic Acid Derivative suitable for positron emission tomography (PET) imaging that can be routinely applied is still lacking. In this study, a new fluorinated and radiofluorinated Folic Acid Derivative, 18/19F-click folate, was synthesized using click chemistry. In a convenient and very efficient two-step radiosynthesis, the isolated 18F-click folate was obtained in good radiochemical yields of 25−35% with a specific activity of 160 ± 70 GBq/μmol after ≤90 min synthesis time. The new compound was pharmacologically evaluated in vitro and ...
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“Click-to-Chelate”: In Vitro and In Vivo Comparison of a 99mTc(CO)3-Labeled N(τ)-Histidine Folate Derivative with Its Isostructural, Clicked 1,2,3-Triazole Analogue
Bioconjugate chemistry, 2008Co-Authors: Thomas L. Mindt, Cristina Müller, Marleen Melis, Marion De Jong, Roger SchibliAbstract:A side-by-side comparison of the synthesis, radiolabeling, and in vitro and in vivo characterization of two new and isostructural 99mTc-tricarbonyl Folic Acid radiotracers comprising either a N(τ)-functionalized histidine (His) chelator or a 1,4-bifunctionalized 1,2,3-triazole His analogue is described. The 1,2,3-triazole-containing Folic Acid Derivative was synthesized in approximately 80% yield by a short reaction sequence including application of click chemistry (the Cu(I)-catalyzed cycloaddition of azides and terminal alkynes). The synthesis of the ligand system and the functionalization of the Folic Acid Derivative were accomplished simultaneously, which prompted us to call this approach “click-to-chelate”. In comparison, the reported regioselective synthesis of the N(τ)-His compound provided the final product in only very low yields (
Enrico L Filonzi - One of the best experts on this subject based on the ideXlab platform.
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Direct optical biosensor analysis of folate-binding protein in milk.
Journal of agricultural and food chemistry, 2004Co-Authors: Harvey E. Indyk, Enrico L FilonziAbstract:An automated, rapid, sensitive, and label-free biosensor-based assay for folate-binding protein (FBP) in bovine milk utilizing surface plasmon resonance optical detection is described. The active concentration of FBP is estimated from its specific interaction with a pteroyl-l-glutamic (Folic) Acid Derivative immobilized on the sensor surface in a direct binding assay format. Milk, colostrum, and milk powders are prepared for analysis by dilution into buffer. Analysis conditions, including ligand immobilization, flow rate, contact time, and regeneration, have been defined, and nonspecific binding considerations were evaluated. Performance parameters include a working range for FBP in buffer of 0−200ng/mL, a method detection limit of 0.13 μg/mL in fluid milk, overall instrument response RSDR of 0.64%, a mean interassay RSDR of 7.3% for skim milk powder, and surface stability over ca. 200 samples. The technique was applied to the measurement of active FBP content of consumer milks, the heat classification of...
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Direct optical biosensor analysis of folate-binding protein in milk.
Journal of agricultural and food chemistry, 2004Co-Authors: Harvey E. Indyk, Enrico L FilonziAbstract:An automated, rapid, sensitive, and label-free biosensor-based assay for folate-binding protein (FBP) in bovine milk utilizing surface plasmon resonance optical detection is described. The active concentration of FBP is estimated from its specific interaction with a pteroyl-l-glutamic (Folic) Acid Derivative immobilized on the sensor surface in a direct binding assay format. Milk, colostrum, and milk powders are prepared for analysis by dilution into buffer. Analysis conditions, including ligand immobilization, flow rate, contact time, and regeneration, have been defined, and nonspecific binding considerations were evaluated. Performance parameters include a working range for FBP in buffer of 0-200 ng/mL, a method detection limit of 0.13 microg/mL in fluid milk, overall instrument response RSD(R) of 0.64%, a mean interassay RSD(R) of 7.3% for skim milk powder, and surface stability over ca. 200 samples. The technique was applied to the measurement of active FBP content of consumer milks, the heat classification of skim milk powders manufactured under a wide range of thermal processing protocols, and change during early bovine lactation.
Cristina Müller - One of the best experts on this subject based on the ideXlab platform.
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Investigation of the chick embryo as a potential alternative to the mouse for evaluation of radiopharmaceuticals.
Nuclear medicine and biology, 2014Co-Authors: Stephanie Haller, Roger Schibli, Simon M. Ametamey, Cristina MüllerAbstract:The chick embryo is an emerging in vivo model in several areas of pre-clinical research including radiopharmaceutical sciences. Herein, it was evaluated as a potential test system for assessing the biodistribution and in vivo stability of radiopharmaceuticals. For this purpose, a number of radiopharmaceuticals labeled with (18)F, (125)I, (99m)Tc, and (177)Lu were investigated in the chick embryo and compared with the data obtained in mice. Chick embryos were cultivated ex ovo for 17-19 days before application of the radiopharmaceutical directly into the peritoneum or intravenously using a vein of the chorioallantoic membrane (CAM). At a defined time point after application of radioactivity, the embryos were euthanized by shock-freezing using liquid nitrogen. Afterwards they were separated from residual egg components for post mortem imaging purposes using positron emission tomography (PET) or single photon emission computed tomography (SPECT). SPECT images revealed uptake of [(99m)Tc]pertechnetate and [(125)I]iodide in the thyroid of chick embryos and mice, whereas [(177)Lu]lutetium, [(18)F]fluoride and [(99m)Tc]-methylene diphosphonate ([(99m)Tc]-MDP) were accumulated in the bones. [(99m)Tc]-dimercaptosuccinic Acid ((99m)Tc-DMSA) and the somatostatin analog [(177)Lu]-DOTATOC, as well as the Folic Acid Derivative [(177)Lu]-DOTA-folate showed accumulation in the renal tissue whereas [(99m)Tc]-mebrofenin accumulated in the gall bladder and intestine of both species. In vivo dehalogenation of [(18)F]fallypride and of the Folic Acid Derivative [(125)I]iodo-tyrosine-folate was observed in both species. In contrast, the 3'-aza-2'-[(18)F]fluoroFolic Acid ([(18)F]-AzaFol) was stable in the chick embryo as well as in the mouse. Our results revealed the same tissue distribution profile and in vivo stability of radiopharmaceuticals in the chick embryo and the mouse. This observation is promising with regard to a potential use of the chick embryo as an inexpensive and simple test model for preclinical screening of novel radiopharmaceuticals. Copyright © 2014 Elsevier Inc. All rights reserved.
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A New 18F-Labeled Folic Acid Derivative with Improved Properties for the PET Imaging of Folate Receptor–Positive Tumors
Journal of nuclear medicine : official publication Society of Nuclear Medicine, 2010Co-Authors: Tobias L. Ross, Michael Honer, Viola Groehn, Roger Schibli, Cristina Müller, Simon M. AmetameyAbstract: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 N2-(N,N-dimethylamino-methylene)-2′-nitroFolic Acid di-tert-butylester 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 2′-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.
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“Click-to-Chelate”: In Vitro and In Vivo Comparison of a 99mTc(CO)3-Labeled N(τ)-Histidine Folate Derivative with Its Isostructural, Clicked 1,2,3-Triazole Analogue
Bioconjugate chemistry, 2008Co-Authors: Thomas L. Mindt, Cristina Müller, Marleen Melis, Marion De Jong, Roger SchibliAbstract:A side-by-side comparison of the synthesis, radiolabeling, and in vitro and in vivo characterization of two new and isostructural 99mTc-tricarbonyl Folic Acid radiotracers comprising either a N(τ)-functionalized histidine (His) chelator or a 1,4-bifunctionalized 1,2,3-triazole His analogue is described. The 1,2,3-triazole-containing Folic Acid Derivative was synthesized in approximately 80% yield by a short reaction sequence including application of click chemistry (the Cu(I)-catalyzed cycloaddition of azides and terminal alkynes). The synthesis of the ligand system and the functionalization of the Folic Acid Derivative were accomplished simultaneously, which prompted us to call this approach “click-to-chelate”. In comparison, the reported regioselective synthesis of the N(τ)-His compound provided the final product in only very low yields (
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synthesis and preclinical evaluation of a Folic Acid Derivative labeled with 18f for pet imaging of folate receptor positive tumors
The Journal of Nuclear Medicine, 2006Co-Authors: Andrea Bettio, Michael Honer, Viola Groehn, Roger Schibli, August P Schubiger, Cristina Müller, Matthias Brühlmeier, Ursina Müller, Simon M. AmetameyAbstract:Folic Acid was linked regioselectively through its α- and γ-carboxyl groups to 4-fluorobenzylamine (FBA), and the α- and γ-FBA-folate regioisomers were evaluated for their ability to bind to folate receptor–positive cells. The 18F-labeled α/γ-FBA-folate counterpart was examined for in vivo tumor targeting efficiency in nude mice bearing folate receptor–positive tumor cells. Methods:18F-α/γ-FBA-folate was prepared in a 4-step reaction sequence starting from Folic Acid. The relative binding affinities of the α- and γ-FBA-folates to the folate receptor with respect to parent Folic Acid were determined in cultured KB-31 cells (nasopharyngeal epidermal carcinoma cell line) overexpressing the folate receptor using 3H-Folic Acid. Tumor accumulation of the 18F-labeled α/γ-FBA-folate and 18F-FDG was analyzed in vivo by high-resolution PET. Biodistribution and PET studies were performed under baseline and blockage conditions. Results: The radiochemical yield of the coupling step ranged from 15% to 44%, and the maximum specific radioactivity was 24 GBq/μmol. The in vitro binding affinities of the α- and γ-isomers and Folic Acid were 71, 62, and 41 nmol/L, respectively. PET revealed heterogeneous uptake of the radioligand, with the highest activity concentrations found in the tumor rim. In contrast, 18F-FDG uptake in a nude mouse bearing KB-31 folate receptor–positive tumors was negligible. Radioligand uptake in tumors at 125 min after injection amounted to 6.56% of the injected dose per gram of tissue (%ID/g) in control animals, whereas radioactivity accumulation in the tumors of Folic Acid–treated animals was significantly reduced by more than 80%—to 1.07 %ID/g (P = 0.001). Conclusion: This new 18F-labeled Folic Acid Derivative is a promising tool for PET imaging of folate receptor–positive tumors.
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Synthesis and Preclinical Evaluation of a Folic Acid Derivative Labeled with 18F for PET Imaging of Folate Receptor–Positive Tumors
Journal of nuclear medicine : official publication Society of Nuclear Medicine, 2006Co-Authors: Andrea Bettio, Michael Honer, Viola Groehn, Roger Schibli, August P Schubiger, Cristina Müller, Matthias Brühlmeier, Ursina Müller, Simon M. AmetameyAbstract:Folic Acid was linked regioselectively through its alpha- and gamma-carboxyl groups to 4-fluorobenzylamine (FBA), and the alpha- and gamma-FBA-folate regioisomers were evaluated for their ability to bind to folate receptor-positive cells. The 18F-labeled alpha/gamma-FBA-folate counterpart was examined for in vivo tumor targeting efficiency in nude mice bearing folate receptor-positive tumor cells. 18F-alpha/gamma-FBA-folate was prepared in a 4-step reaction sequence starting from Folic Acid. The relative binding affinities of the alpha- and gamma-FBA-folates to the folate receptor with respect to parent Folic Acid were determined in cultured KB-31 cells (nasopharyngeal epidermal carcinoma cell line) overexpressing the folate receptor using 3H-Folic Acid. Tumor accumulation of the 18F-labeled alpha/gamma-FBA-folate and 18F-FDG was analyzed in vivo by high-resolution PET. Biodistribution and PET studies were performed under baseline and blockage conditions. The radiochemical yield of the coupling step ranged from 15% to 44%, and the maximum specific radioactivity was 24 GBq/micromol. The in vitro binding affinities of the alpha- and gamma-isomers and Folic Acid were 71, 62, and 41 nmol/L, respectively. PET revealed heterogeneous uptake of the radioligand, with the highest activity concentrations found in the tumor rim. In contrast, 18F-FDG uptake in a nude mouse bearing KB-31 folate receptor-positive tumors was negligible. Radioligand uptake in tumors at 125 min after injection amounted to 6.56% of the injected dose per gram of tissue (%ID/g) in control animals, whereas radioactivity accumulation in the tumors of Folic Acid-treated animals was significantly reduced by more than 80%-to 1.07 %ID/g (P = 0.001). This new 18F-labeled Folic Acid Derivative is a promising tool for PET imaging of folate receptor-positive tumors.
Mohammad-reza Rashidi - One of the best experts on this subject based on the ideXlab platform.
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Methotrexate-conjugated quantum dots: synthesis, characterisation and cytotoxicity in drug resistant cancer cells
2016Co-Authors: Mohammad Johari-ahar, Jaleh Barar, Ali Mohammad Alizadeh, Soodabeh Davaran, Yadollah Omidi, Mohammad-reza RashidiAbstract:Methotrexate (MTX), a Folic Acid Derivative, is a potent anticancer used for treatment of different malignancies, but possible initiation of drug resistance to MTX by cancer cells has limited its applications. Nanoconjugates (NCs) of MTX to quantum dots (QDs) may favour the cellular uptake via folate receptors (FRs)-mediated endocytosis that circumvents the efflux functions of cancer cells. We synthesised MTX-conjugated l-cysteine capped CdSe QDs (MTX-QD nanoconjugates) and evaluated their internalisation and cytotoxicity in the KB cells with/without resistancy to MTX. The NCs were fully characterised by high resolution transmission electron microscopy (HR-TEM), atomic force microscopy (AFM), dynamic light scattering (DLS) and optical spectroscopy. Upon conjugation with MTX, the photoluminescence (PL) properties of QDs altered, while an obvious quenching in PL of QDs was observed after physical mixing. The MTX-QD nanoconjugates efficiently internalised into the cancer cells, and induced markedly high cytotoxicity (IC50, 12.0 µg/mL) in the MTX-resistant KB cells as compared to the free MTX molecules (IC50,105.0 µg/mL), whereas, these values were respectively about 7.0 and 0.6 µg/mL in the MTX-sensitive KB cells. Based on these findings, the MTX-QD nanoconjugates are proposed for the targeted therapy of MTX-resistant cancers, which may provide an improved outcome in the relapsed FR-overexpressing cancers.
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Methotrexate-conjugated quantum dots: synthesis, characterisation and cytotoxicity in drug resistant cancer cells
Journal of drug targeting, 2015Co-Authors: Mohammad Johari-ahar, Jaleh Barar, Ali Mohammad Alizadeh, Soodabeh Davaran, Yadollah Omidi, Mohammad-reza RashidiAbstract:AbstractMethotrexate (MTX), a Folic Acid Derivative, is a potent anticancer used for treatment of different malignancies, but possible initiation of drug resistance to MTX by cancer cells has limited its applications. Nanoconjugates (NCs) of MTX to quantum dots (QDs) may favour the cellular uptake via folate receptors (FRs)-mediated endocytosis that circumvents the efflux functions of cancer cells. We synthesised MTX-conjugated l-cysteine capped CdSe QDs (MTX-QD nanoconjugates) and evaluated their internalisation and cytotoxicity in the KB cells with/without resistancy to MTX. The NCs were fully characterised by high resolution transmission electron microscopy (HR-TEM), atomic force microscopy (AFM), dynamic light scattering (DLS) and optical spectroscopy. Upon conjugation with MTX, the photoluminescence (PL) properties of QDs altered, while an obvious quenching in PL of QDs was observed after physical mixing. The MTX-QD nanoconjugates efficiently internalised into the cancer cells, and induced markedly h...