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Shankar Vallabhajosula - One of the best experts on this subject based on the ideXlab platform.
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a broad overview of positron emission tomography Radiopharmaceuticals and clinical applications what is new
Seminars in Nuclear Medicine, 2011Co-Authors: Shankar Vallabhajosula, Lilja Solnes, Brigitte VallabhajosulaAbstract:Positron emission tomography (PET)/computed tomography (CT) is a rapidly expanding imaging modality, thanks to the availability of compact medical cyclotrons and automated chemistry synthesis modules for the production of PET Radiopharmaceuticals. Despite the availability of many radiotracers, [(18)F]fluorodeoxyglucose (FDG) is currently the most widely used Radiopharmaceutical in PET, and the field of molecular imaging is anxiously awaiting the introduction of new PET Radiopharmaceuticals for routine clinical use. During the last five years, several proprietary PET Radiopharmaceuticals have been developed by major companies, and these new agents are in different stages of clinical evaluation. These new PET drugs are designed for imaging brain beta amyloid, myocardial perfusion, amino acid transport, angiogenesis, and tumor antigen expression. In addition, the National Cancer Institute, Society of Nuclear Medicine Clinical Trials Network, and the American College of Radiology Imaging Network have been conducting multicenter clinical trials with several nonproprietary PET drugs such as sodium [(18)F]fluoride, [(18)F]fluorothymidine, [(18)F]fluoromisonidazole, and (64)Cu-labeled diacetyl-bis (N(4)-methylthiosemicarbazone. All new PET Radiopharmaceuticals, like any other drugs, must be manufactured under current good manufacturing practices as required by the Food and Drug Administration before clinical evaluation (phases I, II, and III) and submission of new drug application. This review briefly describes the chemistry, mechanisms(s) of localization, and clinical application of both proprietary and nonproprietary new PET drugs under multicenter clinical evaluation.
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altered biodistribution of Radiopharmaceuticals role of radiochemical pharmaceutical purity physiological and pharmacologic factors
Seminars in Nuclear Medicine, 2010Co-Authors: Shankar Vallabhajosula, Ronan P Killeen, Joseph R OsborneAbstract:One of the most common problems associated with Radiopharmaceuticals is an unanticipated or altered biodistribution, which can have a significant clinical impact on safety, scan interpretation, and diagnostic imaging accuracy. In their most extreme manifestations, unanticipated imaging results may even compromise the utility and or accuracy of nuclear medicine studies. We present here an overall summary of altered biodistribution of Radiopharmaceuticals with a special emphasis on the molecular mechanisms involved. Important factors affecting the biodistribution of Radiopharmaceuticals can be described in 5 major categories and include (1) Radiopharmaceutical preparation and formulation problems; (2) problems caused by Radiopharmaceutical administration techniques and procedures; (3) by changes in biochemical and pathophysiology; (4) previous medical procedures, such as surgery, radiation therapy and dialysis; and finally (5) by drug interactions. The altered biodistribution of 99m Tc Radiopharmaceuticals are generally associated with increased amounts of 99m Tc radiochemical impurities, such as free 99m TcO 4 − and particulate impurities, such as 99m Tc colloids or 99m Tc-reduced hydrolyzed species. Faulty injection, such as dose infiltration or contamination with antiseptics and aluminum during dose administration, may cause significant artifacts. The patient's own medical problems, such as abnormalities in the regulation of hormone levels; failure in the function of excretory organs and systems, such as hepatobiliary and genitourinary systems; and even simple conditions, such as excessive talking may contribute to altered biodistribution of Radiopharmaceuticals. Previous medical procedures (chemotherapy, radiation therapy, dialysis) and drug interaction are the some of the nontechnical factors responsible for unanticipated biodistribution of radiotracers. This review provides a comprehensive summary of various factors and specific examples to illustrate the significance of altered biodistribution of Radiopharmaceuticals.
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18 f labeled positron emission tomographic Radiopharmaceuticals in oncology an overview of radiochemistry and mechanisms of tumor localization
Seminars in Nuclear Medicine, 2007Co-Authors: Shankar VallabhajosulaAbstract:Molecular imaging is the visualization, characterization, and measurement of biological processes at the molecular and cellular levels in a living system. At present, positron emission tomography/computed tomography (PET/CT) is one the most rapidly growing areas of medical imaging, with many applications in the clinical management of patients with cancer. Although [(18)F]fluorodeoxyglucose (FDG)-PET/CT imaging provides high specificity and sensitivity in several kinds of cancer and has many applications, it is important to recognize that FDG is not a "specific" radiotracer for imaging malignant disease. Highly "tumor-specific" and "tumor cell signal-specific" PET Radiopharmaceuticals are essential to meet the growing demand of radioisotope-based molecular imaging technology. In the last 15 years, many alternative PET tracers have been proposed and evaluated in preclinical and clinical studies to characterize the tumor biology more appropriately. The potential clinical utility of several (18)F-labeled radiotracers (eg, fluoride, FDOPA, FLT, FMISO, FES, and FCH) is being reviewed by several investigators in this issue. An overview of design and development of (18)F-labeled PET Radiopharmaceuticals, radiochemistry, and mechanism(s) of tumor cell uptake and localization of radiotracers are presented here. The approval of clinical indications for FDG-PET in the year 2000 by the Food and Drug Administration, based on a review of literature, was a major breakthrough to the rapid incorporation of PET into nuclear medicine practice, particularly in oncology. Approval of a Radiopharmaceutical typically involves submission of a "New Drug Application" by a manufacturer or a company clearly documenting 2 major aspects of the drug: (1) manufacturing of PET drug using current good manufacturing practices and (2) the safety and effectiveness of a drug with specific indications. The potential routine clinical utility of (18)F-labeled PET Radiopharmaceuticals depends also on regulatory compliance in addition to documentation of potential safety and efficacy by various investigators.
Neil Vasdev - One of the best experts on this subject based on the ideXlab platform.
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iodonium ylide mediated radiofluorination of 18f fpeb and validation for human use
The Journal of Nuclear Medicine, 2015Co-Authors: Nickeisha A Stephenson, Jason P Holland, Alina Kassenbrock, Daniel Yokell, Eli Livni, Steven H Liang, Neil VasdevAbstract:Translation of new methodologies for labeling nonactivated aromatic molecules with 18F remains a challenge. Here, we report a one-step, regioselective, metal-free 18F-labeling method that uses a hypervalent iodonium(III) ylide precursor, to prepare the Radiopharmaceutical 18F-3-fluoro-5-[(pyridin-3-yl)ethynyl]benzonitrile (18F-FPEB). Methods: Automated radiosynthesis of 18F-FPEB was achieved by reaction of the ylide precursor (4 mg) with 18F-Et4NF in dimethylformamide at 80°C for 5 min and formulated for injection within 1 h. Results:18F-FPEB was synthesized in 20% ± 5% (n = 3) uncorrected radiochemical yields relative to 18F-fluoride, with specific activities of 666 ± 51.8 GBq (18 ± 1.4 Ci)/μmol at the end of synthesis and was validated for human use. Conclusion: Radiofluorination of iodonium (III) ylides proved to be an efficient radiosynthetic strategy for synthesis of 18F-labeled Radiopharmaceuticals.
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iodonium ylide mediated radiofluorination of 18f fpeb and validation for human use
The Journal of Nuclear Medicine, 2015Co-Authors: Nickeisha A Stephenson, Jason P Holland, Alina Kassenbrock, Daniel Yokell, Eli Livni, Steven H Liang, Neil VasdevAbstract:UNLABELLED: Translation of new methodologies for labeling nonactivated aromatic molecules with (18)F remains a challenge. Here, we report a one-step, regioselective, metal-free (18)F-labeling method that uses a hypervalent iodonium(III) ylide precursor, to prepare the Radiopharmaceutical (18)F-3-fluoro-5-[(pyridin-3-yl)ethynyl]benzonitrile ((18)F-FPEB). METHODS: Automated radiosynthesis of (18)F-FPEB was achieved by reaction of the ylide precursor (4 mg) with (18)F-Et4NF in dimethylformamide at 80°C for 5 min and formulated for injection within 1 h. RESULTS: (18)F-FPEB was synthesized in 20% ± 5% (n = 3) uncorrected radiochemical yields relative to (18)F-fluoride, with specific activities of 666 ± 51.8 GBq (18 ± 1.4 Ci)/μmol at the end of synthesis and was validated for human use. CONCLUSION: Radiofluorination of iodonium (III) ylides proved to be an efficient radiosynthetic strategy for synthesis of (18)F-labeled Radiopharmaceuticals.
Richard L. Wahl - One of the best experts on this subject based on the ideXlab platform.
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radiation dose does matter mechanistic insights into dna damage and repair support the linear no threshold model of low dose radiation health risks
The Journal of Nuclear Medicine, 2018Co-Authors: James R Duncan, Michael R Lieber, Noritaka Adachi, Richard L. WahlAbstract:1014 Objectives: Human internal dosimetry of new Radiopharmaceuticals should have presumed by the animal data. Cu-64 labeled Radiopharmaceuticals has possibly can use PET imaging and therapeutic effect assuming of convergence Radiopharmaceutical. The aim of this study has evaluated the Cu-64 labeled Radiopharmaceutical projected human internal dosimetry using small animal biodistribution and image data. Methods: Cu-64 labeled Radiopharmaceutical PET image was acquired using small animal PET/CT system (Inveon, Siemens Healthcare.) in mouse (n = 3) at 1, 2, 6, 24, 48 and 72 hour after intravenous injection of Cu-64 labeled Radiopharmaceutical. Each organ region was defined by contrast mouse CT image (Exitron nano 12000, Miltenyi Biotec). In this study, three internal dosimetry method which are animal derived, human extrapolated, and object specific dosimetry. Animal derived dosimetry method was estimated by estimated biodistribution in mouse and human S-value. Human extrapolate dosimetry method was calculated extrapolated human biodistribution and human S-value. Object specific dosimetry method was calculated using image based residence time and object specific S-value. Object specific S-value was calculated based on individual small animal CT image using Monte Carlo simulation. Results: Animal derived absorbed dose in heart, lung, liver, spleen were 0.048 ± 0.006, 0.028 ± 0.012, 0.079 ± 0.002, 0.047 ± 0.005 mGy/MBq, respectively. Human extrapolated absorbed dose were 0.054 ± 0.007 for heart, 0.102 ± 0.017 for lung, 0.118 ± 0.012 for liver, and 0.100 ± 0.013 mGy/MBq for spleen. Object specific absorbed dose were 0.053 ± 0.006 for heart, 0.027 ± 0.005 for lung, 0.035 ± 0.005 for liver, 0.025 ± 0.003 mGy/MBq for spleen. According to the absorbed dose, extrapolate dosimetry method has more higher estimated Cu-64 absorbed dose in lung, liver, spleen region than animal derived and object specific dosimetry Methods: Conclusion: We evaluated the human projected internal dosimetry using Cu-64 small animal data. Human extrapolated dose was overestimated in lung, liver, and spleen. Object specific dosimetry will be applied for diagnostic and therapeutic human dose calculation.
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reply radiation dose does matter mechanistic insights into dna damage and repair support the linear no threshold model of low dose radiation health risks
The Journal of Nuclear Medicine, 2018Co-Authors: James R Duncan, Michael R Lieber, Noritaka Adachi, Richard L. WahlAbstract:1014 Objectives: Human internal dosimetry of new Radiopharmaceuticals should have presumed by the animal data. Cu-64 labeled Radiopharmaceuticals has possibly can use PET imaging and therapeutic effect assuming of convergence Radiopharmaceutical. The aim of this study has evaluated the Cu-64 labeled Radiopharmaceutical projected human internal dosimetry using small animal biodistribution and image data. Methods: Cu-64 labeled Radiopharmaceutical PET image was acquired using small animal PET/CT system (Inveon, Siemens Healthcare.) in mouse (n = 3) at 1, 2, 6, 24, 48 and 72 hour after intravenous injection of Cu-64 labeled Radiopharmaceutical. Each organ region was defined by contrast mouse CT image (Exitron nano 12000, Miltenyi Biotec). In this study, three internal dosimetry method which are animal derived, human extrapolated, and object specific dosimetry. Animal derived dosimetry method was estimated by estimated biodistribution in mouse and human S-value. Human extrapolate dosimetry method was calculated extrapolated human biodistribution and human S-value. Object specific dosimetry method was calculated using image based residence time and object specific S-value. Object specific S-value was calculated based on individual small animal CT image using Monte Carlo simulation. Results: Animal derived absorbed dose in heart, lung, liver, spleen were 0.048 ± 0.006, 0.028 ± 0.012, 0.079 ± 0.002, 0.047 ± 0.005 mGy/MBq, respectively. Human extrapolated absorbed dose were 0.054 ± 0.007 for heart, 0.102 ± 0.017 for lung, 0.118 ± 0.012 for liver, and 0.100 ± 0.013 mGy/MBq for spleen. Object specific absorbed dose were 0.053 ± 0.006 for heart, 0.027 ± 0.005 for lung, 0.035 ± 0.005 for liver, 0.025 ± 0.003 mGy/MBq for spleen. According to the absorbed dose, extrapolate dosimetry method has more higher estimated Cu-64 absorbed dose in lung, liver, spleen region than animal derived and object specific dosimetry Methods: Conclusion: We evaluated the human projected internal dosimetry using Cu-64 small animal data. Human extrapolated dose was overestimated in lung, liver, and spleen. Object specific dosimetry will be applied for diagnostic and therapeutic human dose calculation.
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Radiobiologic Optimization of Combination Radiopharmaceutical Therapy Applied to Myeloablative Treatment of Non-Hodgkin Lymphoma
2016Co-Authors: Robert F. Hobbs, Richard L. Wahl, Eric C. Frey, Yvette Kasamon, Hong Song, Peng Huang, Richard J. Jones, George SgourosAbstract:Combination treatment is a hallmark of cancer therapy. Although the rationale for combination Radiopharmaceutical therapy was de-scribed in the mid-1990s, such treatment strategies have only been implemented clinically recently and without a rigorous methodology for treatment optimization. Radiobiologic and quantitative imaging-based dosimetry tools are now available that enable rational im-plementation of combined targeted Radiopharmaceutical therapy. Optimal implementation should simultaneously account for radiobi-ologic normal-organ tolerance while optimizing the ratio of 2 dif-ferent Radiopharmaceuticals required to maximize tumor control. We have developed such a methodology and applied it to hypoth-etical myeloablative treatment of non-Hodgkin lymphoma (NHL) patients using 131I-tositumomab and 90Y-ibritumomab tiuxetan. Methods: The range of potential administered activities (AAs) is limited by the normal-organ maximum-tolerated biologic effectiv
Jie Tian - One of the best experts on this subject based on the ideXlab platform.
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Radiopharmaceutical and eu3 doped gadolinium oxide nanoparticles mediated triple excited fluorescence imaging and image guided surgery
Journal of Nanobiotechnology, 2021Co-Authors: Xiaojing Shi, Zeyu Zhang, Jie Tian, Caiguang CaoAbstract:Cerenkov luminescence imaging (CLI) is a novel optical imaging technique that has been applied in clinic using various radionuclides and Radiopharmaceuticals. However, clinical application of CLI has been limited by weak optical signal and restricted tissue penetration depth. Various fluorescent probes have been combined with Radiopharmaceuticals for improved imaging performances. However, as most of these probes only interact with Cerenkov luminescence (CL), the low photon fluence of CL greatly restricted it’s interaction with fluorescent probes for in vivo imaging. Therefore, it is important to develop probes that can effectively convert energy beyond CL such as β and γ to the low energy optical signals. In this study, a Eu3+ doped gadolinium oxide (Gd2O3:Eu) was synthesized and combined with Radiopharmaceuticals to achieve a red-shifted optical spectrum with less tissue scattering and enhanced optical signal intensity in this study. The interaction between Gd2O3:Eu and Radiopharmaceutical were investigated using 18F-fluorodeoxyglucose (18F-FDG). The ex vivo optical signal intensity of the mixture of Gd2O3:Eu and 18F-FDG reached 369 times as high as that of CLI using 18F-FDG alone. To achieve improved biocompatibility, the Gd2O3:Eu nanoparticles were then modified with polyvinyl alcohol (PVA), and the resulted nanoprobe PVA modified Gd2O3:Eu (Gd2O3:Eu@PVA) was applied in intraoperative tumor imaging. Compared with 18F-FDG alone, intraoperative administration of Gd2O3:Eu@PVA and 18F-FDG combination achieved a much higher tumor-to-normal tissue ratio (TNR, 10.24 ± 2.24 vs. 1.87 ± 0.73, P = 0.0030). The use of Gd2O3:Eu@PVA and 18F-FDG also assisted intraoperative detection of tumors that were omitted by preoperative positron emission tomography (PET) imaging. Further experiment of image-guided surgery demonstrated feasibility of image-guided tumor resection using Gd2O3:Eu@PVA and 18F-FDG. In summary, Gd2O3:Eu can achieve significantly optimized imaging property when combined with 18F-FDG in intraoperative tumor imaging and image-guided tumor resection surgery. It is expected that the development of the Gd2O3:Eu nanoparticle will promote investigation and application of novel nanoparticles that can interact with Radiopharmaceuticals for improved imaging properties. This work highlighted the impact of the nanoprobe that can be excited by Radiopharmaceuticals emitting CL, β, and γ radiation for precisely imaging of tumor and intraoperatively guide tumor resection.
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in vivo 3 dimensional Radiopharmaceutical excited fluorescence tomography
The Journal of Nuclear Medicine, 2017Co-Authors: Mingxuan Zhao, Xiaojun Zhang, Mingru Zhang, Muhan Liu, Hongbo Guo, Zeyu Zhang, Jing Wang, Weidong Yang, Jie TianAbstract:Cerenkov luminescence imaging (CLI) can image Radiopharmaceuticals using high-sensitivity charge coupled device (CCD) camera. However, Cerenkov luminescence (CL) emitted from the Radiopharmaceuticals is weak and has low penetration depth in biological tissues, which severely limits the sensitivity and accuracy of CLI. This study presents the three-dimensional (3D) Radiopharmaceutical excited fluorescence tomography (REFT) using europium oxide (EO) nanoparticles, which enhances the CL signal intensity, improves the penetration depth, and obtains more accurate 3D distribution of Radiopharmaceuticals. Methods: The enhanced optical signals of various Radiopharmaceuticals (including Na131I, 18F-FDG, 68GaCl3, Na99mTcO4) by EO nanoparticles were detected in vitro. The location and 3D distribution of the Radiopharmaceuticals of REFT were then reconstructed and compared with those of Cerenkov luminescence tomography (CLT) through the experiments of the phantom, artificial source-implanted mouse models, and mice bearing hepatocellular carcinomas (HCCs). Results: The mixture of 68GaCl3 and EO nanoparticles possessed the strongest optical signals compared with the other mixtures. The in vitro phantom and implanted mouse studies showed that REFT revealed more accurate 3D distribution of 68GaCl3. REFT can detected more tumors than small animal positron emission tomography (PET) in HCC bearing mice and achieved more accurate 3D distribution information compared with CLT. Conclusion: REFT with EO nanoparticles significantly improves accuracy of localization of Radiopharmaceuticals and can precisely localize the tumor in vivo.
Aldo N Serafini - One of the best experts on this subject based on the ideXlab platform.
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systemic metabolic Radiopharmaceutical therapy in the treatment of metastatic bone pain
Seminars in Nuclear Medicine, 2010Co-Authors: Fabio M Paes, Aldo N SerafiniAbstract:Bone pain due to skeletal metastases constitutes the most common type of chronic pain among patients with cancer. It significantly decreases the patient's quality of life and is associated with comorbidities, such as hypercalcemia, pathologic fractures and spinal cord compression. Approximately 65% of patients with prostate or breast cancer and 35% of those with advanced lung, thyroid, and kidney cancers will have symptomatic skeletal metastases. The management of bone pain is extremely difficult and involves a multidisciplinary approach, which usually includes analgesics, hormone therapies, bisphosphonates, external beam radiation, and systemic Radiopharmaceuticals. In patients with extensive osseous metastases, systemic Radiopharmaceuticals should be the preferred adjunctive therapy for pain palliation. In this article, we review the current approved Radiopharmaceutical armamentarium for bone pain palliation, focusing on indications, patient selection, efficacy, and different biochemical characteristics and toxicity of strontium-89 chloride, samarium-153 lexidronam, and rhenium-186 etidronate. A brief discussion on the available data on rhenium-188 is presented focusing on its major advantages and disadvantages. We also perform a concise appraisal of the other available treatment options, including pharmacologic and hormonal treatment modalities, external beam radiation, and bisphosphonates. Finally, the available data on combination therapy of Radiopharmaceuticals with bisphosphonates or chemotherapy are discussed.
