Molecular Targeting with Radionuclides: State of the Science*
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Landscape Analysis of Phase 2/3 Clinical Trials of Targeted
Journal of Nuclear Medicine, published on February 12, 2021 as doi:10.2967/jnumed.120.258103 Landscape analysis of Phase 2/3 clinical trials for Targeted Radionuclide Therapy Erik Mittra1, Amanda Abbott2, and Lisa Bodei3 Affiliations 1. Division of Nuclear Medicine & Molecular Imaging, Oregon Health & Science University, Portland, OR 2. Clinical Trials Network, Society of Nuclear Medicine & Molecular Imaging, Reston, VA 3. Molecular Imaging and Therapy Service, Memorial Sloan Kettering Cancer Center, New York, NY Word count without figure: 880 Word count with figure: 971 Key Words: radioisotope therapy, radiopharmaceutical therapy and radioligand therapy Text Within Nuclear Medicine, theranostics has revitalized the field of Targeted Radionuclide Therapy (TRT) and there is a growing number of investigator-initiated and industry-sponsored clinical trials of TRT. This article summarizes the current trials available in the NIH database, the largest trial repository, to provide both an overview of the current landscape and a glimpse towards an undeniably exciting future of theranostics. This landscape analysis was completed by searching the terms “radionuclide therapy”, “radioisotope therapy”, “radiopharmaceutical therapy” and “radioligand therapy” on ClinicalTrials.gov in November 2020. Other terms may provide different results. Phase 1/2, 2, and 3 trials that are currently recruiting and those not yet recruiting were included. Studies. Overall, the results showed 42 clinical trials including 13 Phase 1/2, 26 Phase 2, and three Phase 3. Given this range of phases, the planned enrollment varies widely from 10-813, with an average of 147 participants. Five different radioisotopes, 12 ligands or targets, and 11 different cancer types are represented (Figure 1). -
Effects of Stress-Induced Depression on Parkinson's Disease
Effects of stress-induced depression on Parkinson’s disease symptomatology A dissertation submitted to the Division of Research and Advanced Studies of the University of Cincinnati in partial fulfillment of the requirements for the degree of Doctor of Philosophy (Ph.D.) in the Graduate Program in Neuroscience of the College of Medicine 2011 By Ann Marie Hemmerle B.S., University of Dayton Advisor: Kim B. Seroogy, Ph.D. Committee Chair: Neil Richtand, M.D., Ph.D. James P. Herman, Ph.D. Kathy Steece-Collier, Ph.D. Aaron Johnson, Ph.D. Abstract Parkinson’s disease (PD) is a chronic neurodegenerative disorder that primarily affects dopaminergic neurons of the nigrostriatal pathway resulting in debilitating motor symptoms. Parkinson’s patients also have a high risk of comorbid depression, though this aspect of the disorder is less well studied. Understanding the underlying pathology of the comorbidity is important in improving clinical treatments and the quality of life for PD patients. To address this issue, we have developed a new model combining the unilateral striatal 6-hydroxydopamine lesion model of PD with the chronic variable stress model (CVS) of depression. Dysfunction of the hypothalamic-pituitary-adrenal axis and its relationship to depression symptomatology is well established. Stress dysfunction may also have a role in the etiology of preclinical PD non- motor symptoms, and later in the course of the disease, may worsen motor symptoms. The combined model allows us to test the hypothesis that experimental depression exacerbates PD symptoms and to ascertain the mechanisms behind the increased neuronal loss. In the first study, we examined several temporal paradigms of the combined model. -
RADIO PHARMACEUTICALS Production Control Safety Precautions Applications Storage
RADIO PHARMACEUTICALS Production control Safety precautions Applications Storage. Presented by: K. ARSHAD AHMED KHAN M.Pharm, (Ph.D) Department of Pharmaceutics, Raghavendra Institute of Pharmaceutical Education and Research [RIPER] Anantapur. 1 DEFINITION: Radiopharmaceuticals are the radioactive substances or radioactive drugs for diagnostic or therapeutic interventions. or Radiopharmaceuticals are medicinal formulations containing radioisotopes which are safe for administration in humans for diagnosis or for therapy. 2 COMPOSITION: • A radioactive isotope that can be injected safely into the body, and • A carrier molecule which delivers the isotope to the area to be treated or examined. 3 USAGE/WORKING: 4 BASICS Nuclide: This is a particular nuclear species characterized by its atomic number (No. of protons) and mass 12 23 number (No. of protons + neutrons). 6C , 11Na Isotopes: These are nuclides with same atomic number and different mass number. 1 2 3 Hydrogen has 3 isotopes --- 1H , 1H , 1H . 10 11 12 13 14 Carbon has 5 isotopes ------6C , 6C , 6C , 6C , 6C . 5 • ISOTOPES MAY BE STABLE OR UNSTABLE. • The nucleus is unstable if the number of neutrons is less or greater than the number of protons. • If they are unstable, they under go radioactive decay or disintegration and are known as radioactive isotopes/ radioactive nuclides. Radioactivity: The property of unstable nuclides of emitting radiation by spontaneous transformation of nuclei into other nuclides is called radioactivity. •Radioactive isotopes emit radiations or rays like α, β, γ rays. 6 PRODUCTION CONTROL 7 8 9 10 11 12 13 14 15 Radiopharmaceuticals production occurs in machines like 1. Cyclotron (low energy, high energy) 2. -
Brain Imaging
Publications · Brochures Brain Imaging A Technologist’s Guide Produced with the kind Support of Editors Fragoso Costa, Pedro (Oldenburg) Santos, Andrea (Lisbon) Vidovič, Borut (Munich) Contributors Arbizu Lostao, Javier Pagani, Marco Barthel, Henryk Payoux, Pierre Boehm, Torsten Pepe, Giovanna Calapaquí-Terán, Adriana Peștean, Claudiu Delgado-Bolton, Roberto Sabri, Osama Garibotto, Valentina Sočan, Aljaž Grmek, Marko Sousa, Eva Hackett, Elizabeth Testanera, Giorgio Hoffmann, Karl Titus Tiepolt, Solveig Law, Ian van de Giessen, Elsmarieke Lucena, Filipa Vaz, Tânia Morbelli, Silvia Werner, Peter Contents Foreword 4 Introduction 5 Andrea Santos, Pedro Fragoso Costa Chapter 1 Anatomy, Physiology and Pathology 6 Elsmarieke van de Giessen, Silvia Morbelli and Pierre Payoux Chapter 2 Tracers for Brain Imaging 12 Aljaz Socan Chapter 3 SPECT and SPECT/CT in Oncological Brain Imaging (*) 26 Elizabeth C. Hackett Chapter 4 Imaging in Oncological Brain Diseases: PET/CT 33 EANM Giorgio Testanera and Giovanna Pepe Chapter 5 Imaging in Neurological and Vascular Brain Diseases (SPECT and SPECT/CT) 54 Filipa Lucena, Eva Sousa and Tânia F. Vaz Chapter 6 Imaging in Neurological and Vascular Brain Diseases (PET/CT) 72 Ian Law, Valentina Garibotto and Marco Pagani Chapter 7 PET/CT in Radiotherapy Planning of Brain Tumours 92 Roberto Delgado-Bolton, Adriana K. Calapaquí-Terán and Javier Arbizu Chapter 8 PET/MRI for Brain Imaging 100 Peter Werner, Torsten Boehm, Solveig Tiepolt, Henryk Barthel, Karl T. Hoffmann and Osama Sabri Chapter 9 Brain Death 110 Marko Grmek Chapter 10 Health Care in Patients with Neurological Disorders 116 Claudiu Peștean Imprint 126 n accordance with the Austrian Eco-Label for printed matters. -
Personalized Treatment of Alcohol Dependence
Curr Psychiatry Rep DOI 10.1007/s11920-012-0296-5 SUBSTANCE USE AND RELATED DISORDERS (JR MCKAY, SECTION EDITOR) Personalized Treatment of Alcohol Dependence Henry R. Kranzler & James R. McKay # Springer Science+Business Media, LLC 2012 Abstract Pharmacogenetic and adaptive treatment approaches Ondansetron . Sertraline . Adaptive trial designs . can be used to personalize care for alcohol-dependent patients. Adaptive protocol . Stepped care . Treatment algorithm Preliminary evidence shows that variation in the gene encoding the μ-opioid receptor moderates the response to naltrexone when used to treat alcohol dependence. Studies have also shown moderating effects of variation in the gene encoding Introduction the serotonin transporter on response to serotonergic treatment of alcohol dependence. Adaptive algorithms that modify alco- Traditionally, diagnostic tests and medical treatments have hol treatment based on patients’ progress have also shown been developed and evaluated using group data, a “one-size promise. Initial response to outpatient treatment appears to be fits all” approach that leaves little room for individual variation a particularly important in the selection of optimal continuing [1]. Personalized medicine, which uses individual features to care interventions. In addition, stepped-care algorithms can diagnose and treat disease, is of growing interest, having reduce the cost and burden of treatment while maintaining good produced notable successes in oncology and cardiology [2•, outcomes. Finally, matching treatment to specific problems 3]. To date, there have been fewer advances in the personalized present at intake or that emerge during treatment can also diagnosis and treatment of addictive disorders. However, on- improve outcomes. Although all of these effects require repli- going developments in genetics and pharmacogenetics and in cation and further refinement, the future of personalized care for the use of adaptive trial designs offer great potential to extend alcohol dependence appears bright. -
Targeted Radiotherapeutics from 'Bench-To-Bedside'
RadiochemistRy in switzeRland CHIMIA 2020, 74, No. 12 939 doi:10.2533/chimia.2020.939 Chimia 74 (2020) 939–945 © C. Müller, M. Béhé, S. Geistlich, N. P. van der Meulen, R. Schibli Targeted Radiotherapeutics from ‘Bench-to-Bedside’ Cristina Müllera, Martin Béhéa, Susanne Geistlicha, Nicholas P. van der Meulenab, and Roger Schibli*ac Abstract: The concept of targeted radionuclide therapy (TRT) is the accurate and efficient delivery of radiation to disseminated cancer lesions while minimizing damage to healthy tissue and organs. Critical aspects for success- ful development of novel radiopharmaceuticals for TRT are: i) the identification and characterization of suitable targets expressed on cancer cells; ii) the selection of chemical or biological molecules which exhibit high affin- ity and selectivity for the cancer cell-associated target; iii) the selection of a radionuclide with decay properties that suit the properties of the targeting molecule and the clinical purpose. The Center for Radiopharmaceutical Sciences (CRS) at the Paul Scherrer Institute in Switzerland is privileged to be situated close to unique infrastruc- ture for radionuclide production (high energy accelerators and a neutron source) and access to C/B-type labora- tories including preclinical, nuclear imaging equipment and Swissmedic-certified laboratories for the preparation of drug samples for human use. These favorable circumstances allow production of non-standard radionuclides, exploring their biochemical and pharmacological features and effects for tumor therapy and diagnosis, while investigating and characterizing new targeting structures and optimizing these aspects for translational research on radiopharmaceuticals. In close collaboration with various clinical partners in Switzerland, the most promising candidates are translated to clinics for ‘first-in-human’ studies. -
A Nonlinear Relationship Between Cerebral Serotonin Transporter And
The Journal of Neuroscience, March 3, 2010 • 30(9):3391–3397 • 3391 Cellular/Molecular A Nonlinear Relationship between Cerebral Serotonin Transporter and 5-HT2A Receptor Binding: An In Vivo Molecular Imaging Study in Humans David Erritzoe,1,3 Klaus Holst,3,4 Vibe G. Frokjaer,1,3 Cecilie L. Licht,1,3 Jan Kalbitzer,1,3 Finn Å. Nielsen,3,5 Claus Svarer,1,3 Jacob Madsen,2 and Gitte M. Knudsen1,3 1Neurobiology Research Unit and 2PET and Cyclotron Unit, University Hospital Rigshospitalet, DK-2100 Copenhagen, Denmark, 3Center for Integrated Molecular Brain Imaging, DK-2100 Copenhagen, Denmark, 4Department of Biostatistics, University of Copenhagen, DK-2200 Copenhagen, Denmark, and 5DTU Informatics, Technical University of Denmark, DK-2800 Lyngby, Denmark Serotonergic neurotransmission is involved in the regulation of physiological functions such as mood, sleep, memory, and appetite. Withintheserotonintransmittersystem,boththepostsynapticallylocatedserotonin2A(5-HT2A )receptorandthepresynapticserotonin transporter (SERT) are sensitive to chronic changes in cerebral 5-HT levels. Additionally, experimental studies suggest that alterations in either the 5-HT2A receptor or SERT level can affect the protein level of the counterpart. The aim of this study was to explore the covariation betweencerebral5-HT2A receptorandSERT invivointhesamehealthyhumansubjects.Fifty-sixhealthyhumansubjectswithameanage of 36 Ϯ 19 years were investigated. The SERT binding was imaged with [ 11C]3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)- 18 benzonitrile (DASB) and 5-HT2A receptor binding with [ F]altanserin using positron emission tomography. Within each individual, a regionalintercorrelationforthevariousbrainregionswasseenwithbothmarkers,mostnotablyfor5-HT2A receptorbinding.Aninverted U-shaped relationship between the 5-HT2A receptor and the SERT binding was identified. The observed regional intercorrelation for both the 5-HT2A receptor and the SERT cerebral binding suggests that, within the single individual, each marker has a set point adjusted through a common regulator. -
Bispecific Antibody Pretargeting of Radionuclides for Immuno^ Single
Bispecific Antibody Pretargeting of Radionuclides for Immuno ^ Single-Photon Emission Computed Tomography and Immuno ^ Positron Emission Tomography Molecular Imaging:An Update Robert M. Sharkey,1Habibe Karacay,1William J. McBride,2 Edmund A. Rossi,3 Chien-Hsing Chang,3 and David M. Goldenberg1 Abstract Molecular imaging is intended to localize disease based on distinct molecular/functional characteristics. Much of today’s interest in molecular imaging is attributed to the increased acceptance and role of 18F-flurodeoxyglucose (18F-FDG) imaging in a variety of tumors. The clinical acceptance of 18F-FDG has stimulated research for other positron emission tomography (PET) agents with improved specificity to aid in tumor detection and assessment. In this regard, a number of highly specific antibodies have been described for different cancers. Although scintigraphic imaging with antibodies in the past was helpful in patient management, most antibody-based imaging products have not been able to compete successfully with the sensitivity afforded by 18F-FDG-PET, especially when used in combination with computed tomography. Recently, however, significant advances have been made in reengineering antibodies to improve their targeting properties. Herein, we describe progress being made in using a bispecific antibody pretargeting method for immuno ^ single-photon emission computed tomography and immunoPETapplications, as contrasted to directly radiolabeled antibodies.This approach not only significantly enhances tumor/nontumor ratios but also provides high signal intensity in the tumor, making it possible to visualize micrometastases of colonic cancer as small as 0.1to 0.2 mm in diameter using an anti ^ carcinoembryonic antigen bispecific antibody, whereas FDG failed to localize these lesions in a nude mouse model. -
The Evolving Landscape of Therapeutic and Diagnostic Radiopharmaceuticals
ARTICLE THE EVOLVING LANDSCAPE OF THERAPEUTIC AND DIAGNOSTIC RADIOPHARMACEUTICALS Therapeutic and diagnostic approaches involving the use of radiation and radioactive compounds have a long- standing history in the fields of science and medicine. Radiotherapy was first used in cancer treatments in 1896.1 Since then, the field of radiation has advanced to further understand how radioactive compounds interact with biological tissues and how they can be used in both diagnostic and therapeutic applications. Radiopharmaceuticals are compounds used for medicinal purposes that contain radioactive isotopes (also known as radionuclides) and can be diagnostic or therapeutic in nature, or both.2 They represent a unique category of pharmaceuticals due to their radioactive properties. As such, there are specific guidelines and regulations that impact and direct the study and use of these compounds. Radiopharmaceutical drug development has rapidly expanded over the last decade. Radiopharmaceuticals are widely used in the field of imaging for diagnosis, staging, and follow up; in the realm of therapeutics, their use has increased, most notably, in the area of oncology. In a recent webinar, experts from Medpace’s radiation oncology, imaging, regulatory, and operational teams discussed the growing space of radiopharmaceutical development with respect to their biological use and application, regulatory frameworks that govern their evaluation in support of approvals, operational manufacturing considerations, and associated imaging approaches. BIOLOGICAL MECHANISMS OF ACTION OF RADIONUCLIDES According to Dr. Jess Guarnaschelli, Medical Director, Radiation Oncology, the radioactivity of radionuclides can be employed for both diagnostic and therapeutic medical uses. While external beam ionizing radiation involves radiation emitted in the form of electromagnetic waves or particles, radiopharmaceuticals use radionuclides to deliver localized radiation to specific targets. -
Radiotoxicity After Iodine-131 Therapy for Thyroid Cancer Using the Micronucleus Assay
Radiotoxicity After Iodine-131 Therapy for Thyroid Cancer Using the Micronucleus Assay Naoto Watanabe, Kunihiko Yokoyama, Seigo Kinuya, Noriyuki Shuke, Masashi Shimizu, Ryusuke Futatsuya, Takatoshi Michigishi, Norihisa Tonami, Hikaru Seto and David A. Goodwin Departments of Radiology and Radiological Science, Toyama Medical and Pharmaceutical University, Toyama; Department of Nuclear Medicine, Kanazawa University, Kanazawa; Department of Radiology, Asahikawa Medical University, Asahikawa, Japan; Nuclear Medicine Service, Veterans Affairs Health Sciences, Palo Alto, California; and Department of Radiology, Stanford University School of Medicine, Stanford, California thrombocytopenia have been reported (6,7). Therefore, in most The purpose of the present study was to evaluate the degree of patients who are treated with a large amount of I3il, the limiting cytological radiation damage to lymphocytes after1311therapy using the cytokinesis-blocked micronucleus assay. The chromosomal factor is the radiation dose to the blood and the bone marrow damage to lymphocytes induced by 131I ¡nvivo should result in (8). Dosimetrie studies have estimated the radiation dose to the augmentation of the cells with micronuclei. Methods: We studied 25 blood and bone marrow with a large amount of radioiodine (3 ). patients with differentiated thyroid carcinoma who were treated with Previous work has been done on cytogenetic changes (9). 3.7 GBq of 131I.Isolated lymphocytes collected from patients 1 wk However, the cytological effects of radiation exposure on the after therapy were harvested and treated according to the cytoki lymphocytes in vivo with large therapeutic doses of radioiodine nesis-blocked method of Fenech and Morley. The micronucleus have not been extensively examined. number of micronuclei per 500 binucleated cells were scored by The purpose of our study was to evaluate the degree of visual inspection. -
EANM Procedure Guidelines for 131I-Meta-Iodobenzylguanidine (131I-Mibg) Therapy
Eur J Nucl Med Mol Imaging (2008) 35:1039–1047 DOI 10.1007/s00259-008-0715-3 GUIDELINES EANM procedure guidelines for 131I-meta-iodobenzylguanidine (131I-mIBG) therapy Francesco Giammarile & Arturo Chiti & Michael Lassmann & Boudewijn Brans & Glenn Flux Published online: 15 February 2008 # EANM 2008 Abstract Meta-iodobenzylguanidine, or Iobenguane, is an nervous system. The neuroendocrine system is derived from a aralkylguanidine resulting from the combination of the family of cells originating in the neural crest, characterized by benzyl group of bretylium and the guanidine group of an ability to incorporate amine precursors with subsequent guanethidine (an adrenergic neurone blocker). It is a decarboxylation. The purpose of this guideline is to assist noradrenaline (norepinephrine) analogue and so-called nuclear medicine practitioners to evaluate patients who might “false” neurotransmitter. This radiopharmaceutical, labeled be candidates for 131I-meta-iodobenzylguanidine to treat with 131I, could be used as a radiotherapeutic metabolic agent neuro-ectodermal tumours, to provide information for in neuroectodermal tumours, that are derived from the performing this treatment and to understand and evaluate primitive neural crest which develops to form the sympathetic the consequences of therapy. F. Giammarile (*) Keywords Guidelines . Therapy . mIBG CH Lyon Sud, EA 3738, HCL, UCBL, 165 Chemin du Grand Revoyet, Purpose 69495 Pierre Benite Cedex, France e-mail: [email protected] The purpose of this guideline is to assist nuclear medicine A. Chiti practitioners to U.O. di Medicina Nucleare, Istituto Clinico Humanitas, via Manzoni, 56, 1. Evaluate patients who might be candidates for 131I-meta- 20089 Rozzano (MI), Italy iodobenzylguanidine (mIBG) to treat neuro-ectodermal e-mail: [email protected] tumours M. -
Molecular Imaging and Radionuclide Therapy of Pheochromocytoma and Paraganglioma in the Era of Genomic Characterization of Disease Subgroups
26 11 Theranostics of D Taïeb et al. 26:11 R627–R656 Endocrine-Related pheochromocytoma and Cancer paraganglioma REVIEW Molecular imaging and radionuclide therapy of pheochromocytoma and paraganglioma in the era of genomic characterization of disease subgroups David Taïeb1,*, Abhishek Jha2,*, Giorgio Treglia3,4,5 and Karel Pacak2 1Department of Nuclear Medicine, La Timone University Hospital, CERIMED, Aix-Marseille University, Marseille, France 2Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA 3Clinic of Nuclear Medicine and PET/CT Center, Ente Ospedaliero Cantonale, Bellinzona, Switzerland 4Department of Nuclear Medicine and Molecular Imaging, Lausanne University Hospital, Lausanne, Switzerland 5Health Technology Assessment Unit, General Directorate, Ente Ospedaliero Cantonale, Bellinzona, Switzerland Correspondence should be addressed to K Pacak: [email protected] *(D Taïeb and A Jha contributed equally to this work) Abstract In recent years, advancement in genetics has profoundly helped to gain a more Key Words comprehensive molecular, pathogenic, and prognostic picture of pheochromocytomas f pheochromocytoma and paragangliomas (PPGLs). Newly discovered molecular targets, particularly those f paraganglioma that target cell membranes or signaling pathways have helped move nuclear medicine f PPGL in the forefront of PPGL precision medicine. This is mainly based on the introduction f succinate dehydrogenase and increasing experience of various PET radiopharmaceuticals across PPGL genotypes complex quickly followed by implementation of novel radiotherapies and revised imaging f SDHB algorithms. Particularly, 68Ga-labeled-SSAs have shown excellent results in the diagnosis f 18F-FDOPA and staging of PPGLs and in selecting patients for PRRT as a potential alternative to f 68Ga-DOTATATE 123/131I-MIBG theranostics.