Publisher: Elsevier   (Total: 3161 journals)

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Showing 1 - 200 of 3161 Journals sorted alphabetically
Academic Pediatrics     Hybrid Journal   (Followers: 39, SJR: 1.655, CiteScore: 2)
Academic Radiology     Hybrid Journal   (Followers: 26, SJR: 1.015, CiteScore: 2)
Accident Analysis & Prevention     Partially Free   (Followers: 106, SJR: 1.462, CiteScore: 3)
Accounting Forum     Hybrid Journal   (Followers: 28, SJR: 0.932, CiteScore: 2)
Accounting, Organizations and Society     Hybrid Journal   (Followers: 43, SJR: 1.771, CiteScore: 3)
Achievements in the Life Sciences     Open Access   (Followers: 7)
Acta Anaesthesiologica Taiwanica     Open Access   (Followers: 6)
Acta Astronautica     Hybrid Journal   (Followers: 446, SJR: 0.758, CiteScore: 2)
Acta Automatica Sinica     Full-text available via subscription   (Followers: 2)
Acta Biomaterialia     Hybrid Journal   (Followers: 30, SJR: 1.967, CiteScore: 7)
Acta Colombiana de Cuidado Intensivo     Full-text available via subscription   (Followers: 3)
Acta de Investigación Psicológica     Open Access   (Followers: 2)
Acta Ecologica Sinica     Open Access   (Followers: 11, SJR: 0.18, CiteScore: 1)
Acta Histochemica     Hybrid Journal   (Followers: 5, SJR: 0.661, CiteScore: 2)
Acta Materialia     Hybrid Journal   (Followers: 322, SJR: 3.263, CiteScore: 6)
Acta Mathematica Scientia     Full-text available via subscription   (Followers: 5, SJR: 0.504, CiteScore: 1)
Acta Mechanica Solida Sinica     Full-text available via subscription   (Followers: 9, SJR: 0.542, CiteScore: 1)
Acta Oecologica     Hybrid Journal   (Followers: 12, SJR: 0.834, CiteScore: 2)
Acta Otorrinolaringologica (English Edition)     Full-text available via subscription  
Acta Otorrinolaringológica Española     Full-text available via subscription   (Followers: 2, SJR: 0.307, CiteScore: 0)
Acta Pharmaceutica Sinica B     Open Access   (Followers: 2, SJR: 1.793, CiteScore: 6)
Acta Psychologica     Hybrid Journal   (Followers: 26, SJR: 1.331, CiteScore: 2)
Acta Sociológica     Open Access   (Followers: 1)
Acta Tropica     Hybrid Journal   (Followers: 6, SJR: 1.052, CiteScore: 2)
Acta Urológica Portuguesa     Open Access   (Followers: 1)
Actas Dermo-Sifiliograficas     Full-text available via subscription   (Followers: 3, SJR: 0.374, CiteScore: 1)
Actas Dermo-Sifiliográficas (English Edition)     Full-text available via subscription   (Followers: 2)
Actas Urológicas Españolas     Full-text available via subscription   (Followers: 3, SJR: 0.344, CiteScore: 1)
Actas Urológicas Españolas (English Edition)     Full-text available via subscription   (Followers: 1)
Actualites Pharmaceutiques     Full-text available via subscription   (Followers: 7, SJR: 0.19, CiteScore: 0)
Actualites Pharmaceutiques Hospitalieres     Full-text available via subscription   (Followers: 3)
Acupuncture and Related Therapies     Hybrid Journal   (Followers: 8)
Acute Pain     Full-text available via subscription   (Followers: 15, SJR: 2.671, CiteScore: 5)
Ad Hoc Networks     Hybrid Journal   (Followers: 11, SJR: 0.53, CiteScore: 4)
Addictive Behaviors     Hybrid Journal   (Followers: 18, SJR: 1.29, CiteScore: 3)
Addictive Behaviors Reports     Open Access   (Followers: 9, SJR: 0.755, CiteScore: 2)
Additive Manufacturing     Hybrid Journal   (Followers: 13, SJR: 2.611, CiteScore: 8)
Additives for Polymers     Full-text available via subscription   (Followers: 22)
Advanced Drug Delivery Reviews     Hybrid Journal   (Followers: 188, SJR: 4.09, CiteScore: 13)
Advanced Engineering Informatics     Hybrid Journal   (Followers: 13, SJR: 1.167, CiteScore: 4)
Advanced Powder Technology     Hybrid Journal   (Followers: 17, SJR: 0.694, CiteScore: 3)
Advances in Accounting     Hybrid Journal   (Followers: 9, SJR: 0.277, CiteScore: 1)
Advances in Agronomy     Full-text available via subscription   (Followers: 17, SJR: 2.384, CiteScore: 5)
Advances in Anesthesia     Full-text available via subscription   (Followers: 30, SJR: 0.126, CiteScore: 0)
Advances in Antiviral Drug Design     Full-text available via subscription   (Followers: 2)
Advances in Applied Mathematics     Full-text available via subscription   (Followers: 12, SJR: 0.992, CiteScore: 1)
Advances in Applied Mechanics     Full-text available via subscription   (Followers: 12, SJR: 1.551, CiteScore: 4)
Advances in Applied Microbiology     Full-text available via subscription   (Followers: 24, SJR: 2.089, CiteScore: 5)
Advances In Atomic, Molecular, and Optical Physics     Full-text available via subscription   (Followers: 15, SJR: 0.572, CiteScore: 2)
Advances in Biological Regulation     Hybrid Journal   (Followers: 4, SJR: 2.61, CiteScore: 7)
Advances in Botanical Research     Full-text available via subscription   (Followers: 1, SJR: 0.686, CiteScore: 2)
Advances in Cancer Research     Full-text available via subscription   (Followers: 35, SJR: 3.043, CiteScore: 6)
Advances in Carbohydrate Chemistry and Biochemistry     Full-text available via subscription   (Followers: 9, SJR: 1.453, CiteScore: 2)
Advances in Catalysis     Full-text available via subscription   (Followers: 5, SJR: 1.992, CiteScore: 5)
Advances in Cell Aging and Gerontology     Full-text available via subscription   (Followers: 5)
Advances in Cellular and Molecular Biology of Membranes and Organelles     Full-text available via subscription   (Followers: 14)
Advances in Chemical Engineering     Full-text available via subscription   (Followers: 29, SJR: 0.156, CiteScore: 1)
Advances in Child Development and Behavior     Full-text available via subscription   (Followers: 11, SJR: 0.713, CiteScore: 1)
Advances in Chronic Kidney Disease     Full-text available via subscription   (Followers: 11, SJR: 1.316, CiteScore: 2)
Advances in Clinical Chemistry     Full-text available via subscription   (Followers: 26, SJR: 1.562, CiteScore: 3)
Advances in Colloid and Interface Science     Full-text available via subscription   (Followers: 21, SJR: 1.977, CiteScore: 8)
Advances in Computers     Full-text available via subscription   (Followers: 14, SJR: 0.205, CiteScore: 1)
Advances in Dermatology     Full-text available via subscription   (Followers: 16)
Advances in Developmental Biology     Full-text available via subscription   (Followers: 14)
Advances in Digestive Medicine     Open Access   (Followers: 13)
Advances in DNA Sequence-Specific Agents     Full-text available via subscription   (Followers: 7)
Advances in Drug Research     Full-text available via subscription   (Followers: 26)
Advances in Ecological Research     Full-text available via subscription   (Followers: 45, SJR: 2.524, CiteScore: 4)
Advances in Engineering Software     Hybrid Journal   (Followers: 30, SJR: 1.159, CiteScore: 4)
Advances in Experimental Biology     Full-text available via subscription   (Followers: 9)
Advances in Experimental Social Psychology     Full-text available via subscription   (Followers: 52, SJR: 5.39, CiteScore: 8)
Advances in Exploration Geophysics     Full-text available via subscription   (Followers: 2)
Advances in Fluorine Science     Full-text available via subscription   (Followers: 9)
Advances in Food and Nutrition Research     Full-text available via subscription   (Followers: 68, SJR: 0.591, CiteScore: 2)
Advances in Fuel Cells     Full-text available via subscription   (Followers: 17)
Advances in Genetics     Full-text available via subscription   (Followers: 21, SJR: 1.354, CiteScore: 4)
Advances in Genome Biology     Full-text available via subscription   (Followers: 12, SJR: 12.74, CiteScore: 13)
Advances in Geophysics     Full-text available via subscription   (Followers: 8, SJR: 1.193, CiteScore: 3)
Advances in Heat Transfer     Full-text available via subscription   (Followers: 26, SJR: 0.368, CiteScore: 1)
Advances in Heterocyclic Chemistry     Full-text available via subscription   (Followers: 11, SJR: 0.749, CiteScore: 3)
Advances in Human Factors/Ergonomics     Full-text available via subscription   (Followers: 26)
Advances in Imaging and Electron Physics     Full-text available via subscription   (Followers: 3, SJR: 0.193, CiteScore: 0)
Advances in Immunology     Full-text available via subscription   (Followers: 37, SJR: 4.433, CiteScore: 6)
Advances in Inorganic Chemistry     Full-text available via subscription   (Followers: 10, SJR: 1.163, CiteScore: 2)
Advances in Insect Physiology     Full-text available via subscription   (Followers: 2, SJR: 1.938, CiteScore: 3)
Advances in Integrative Medicine     Hybrid Journal   (Followers: 6, SJR: 0.176, CiteScore: 0)
Advances in Intl. Accounting     Full-text available via subscription   (Followers: 3)
Advances in Life Course Research     Hybrid Journal   (Followers: 9, SJR: 0.682, CiteScore: 2)
Advances in Lipobiology     Full-text available via subscription   (Followers: 1)
Advances in Magnetic and Optical Resonance     Full-text available via subscription   (Followers: 8)
Advances in Marine Biology     Full-text available via subscription   (Followers: 21, SJR: 0.88, CiteScore: 2)
Advances in Mathematics     Full-text available via subscription   (Followers: 17, SJR: 3.027, CiteScore: 2)
Advances in Medical Sciences     Hybrid Journal   (Followers: 9, SJR: 0.694, CiteScore: 2)
Advances in Medicinal Chemistry     Full-text available via subscription   (Followers: 6)
Advances in Microbial Physiology     Full-text available via subscription   (Followers: 5, SJR: 1.158, CiteScore: 3)
Advances in Molecular and Cell Biology     Full-text available via subscription   (Followers: 26)
Advances in Molecular and Cellular Endocrinology     Full-text available via subscription   (Followers: 8)
Advances in Molecular Toxicology     Full-text available via subscription   (Followers: 7, SJR: 0.182, CiteScore: 0)
Advances in Nanoporous Materials     Full-text available via subscription   (Followers: 5)
Advances in Oncobiology     Full-text available via subscription   (Followers: 2)
Advances in Organ Biology     Full-text available via subscription   (Followers: 2)
Advances in Organometallic Chemistry     Full-text available via subscription   (Followers: 18, SJR: 1.875, CiteScore: 4)
Advances in Parallel Computing     Full-text available via subscription   (Followers: 7, SJR: 0.174, CiteScore: 0)
Advances in Parasitology     Full-text available via subscription   (Followers: 6, SJR: 1.579, CiteScore: 4)
Advances in Pediatrics     Full-text available via subscription   (Followers: 27, SJR: 0.461, CiteScore: 1)
Advances in Pharmaceutical Sciences     Full-text available via subscription   (Followers: 19)
Advances in Pharmacology     Full-text available via subscription   (Followers: 17, SJR: 1.536, CiteScore: 3)
Advances in Physical Organic Chemistry     Full-text available via subscription   (Followers: 10, SJR: 0.574, CiteScore: 1)
Advances in Phytomedicine     Full-text available via subscription  
Advances in Planar Lipid Bilayers and Liposomes     Full-text available via subscription   (Followers: 3, SJR: 0.109, CiteScore: 1)
Advances in Plant Biochemistry and Molecular Biology     Full-text available via subscription   (Followers: 11)
Advances in Plant Pathology     Full-text available via subscription   (Followers: 6)
Advances in Porous Media     Full-text available via subscription   (Followers: 5)
Advances in Protein Chemistry     Full-text available via subscription   (Followers: 19)
Advances in Protein Chemistry and Structural Biology     Full-text available via subscription   (Followers: 20, SJR: 0.791, CiteScore: 2)
Advances in Psychology     Full-text available via subscription   (Followers: 69)
Advances in Quantum Chemistry     Full-text available via subscription   (Followers: 7, SJR: 0.371, CiteScore: 1)
Advances in Radiation Oncology     Open Access   (Followers: 3, SJR: 0.263, CiteScore: 1)
Advances in Small Animal Medicine and Surgery     Hybrid Journal   (Followers: 3, SJR: 0.101, CiteScore: 0)
Advances in Space Biology and Medicine     Full-text available via subscription   (Followers: 7)
Advances in Space Research     Full-text available via subscription   (Followers: 430, SJR: 0.569, CiteScore: 2)
Advances in Structural Biology     Full-text available via subscription   (Followers: 6)
Advances in Surgery     Full-text available via subscription   (Followers: 13, SJR: 0.555, CiteScore: 2)
Advances in the Study of Behavior     Full-text available via subscription   (Followers: 37, SJR: 2.208, CiteScore: 4)
Advances in Veterinary Medicine     Full-text available via subscription   (Followers: 20)
Advances in Veterinary Science and Comparative Medicine     Full-text available via subscription   (Followers: 15)
Advances in Virus Research     Full-text available via subscription   (Followers: 6, SJR: 2.262, CiteScore: 5)
Advances in Water Resources     Hybrid Journal   (Followers: 56, SJR: 1.551, CiteScore: 3)
Aeolian Research     Hybrid Journal   (Followers: 6, SJR: 1.117, CiteScore: 3)
Aerospace Science and Technology     Hybrid Journal   (Followers: 394, SJR: 0.796, CiteScore: 3)
AEU - Intl. J. of Electronics and Communications     Hybrid Journal   (Followers: 8, SJR: 0.42, CiteScore: 2)
African J. of Emergency Medicine     Open Access   (Followers: 6, SJR: 0.296, CiteScore: 0)
Ageing Research Reviews     Hybrid Journal   (Followers: 12, SJR: 3.671, CiteScore: 9)
Aggression and Violent Behavior     Hybrid Journal   (Followers: 487, SJR: 1.238, CiteScore: 3)
Agri Gene     Hybrid Journal   (Followers: 1, SJR: 0.13, CiteScore: 0)
Agricultural and Forest Meteorology     Hybrid Journal   (Followers: 18, SJR: 1.818, CiteScore: 5)
Agricultural Systems     Hybrid Journal   (Followers: 32, SJR: 1.156, CiteScore: 4)
Agricultural Water Management     Hybrid Journal   (Followers: 46, SJR: 1.272, CiteScore: 3)
Agriculture and Agricultural Science Procedia     Open Access   (Followers: 4)
Agriculture and Natural Resources     Open Access   (Followers: 3)
Agriculture, Ecosystems & Environment     Hybrid Journal   (Followers: 58, SJR: 1.747, CiteScore: 4)
Ain Shams Engineering J.     Open Access   (Followers: 5, SJR: 0.589, CiteScore: 3)
Air Medical J.     Hybrid Journal   (Followers: 8, SJR: 0.26, CiteScore: 0)
AKCE Intl. J. of Graphs and Combinatorics     Open Access   (SJR: 0.19, CiteScore: 0)
Alcohol     Hybrid Journal   (Followers: 12, SJR: 1.153, CiteScore: 3)
Alcoholism and Drug Addiction     Open Access   (Followers: 12)
Alergologia Polska : Polish J. of Allergology     Full-text available via subscription   (Followers: 1)
Alexandria Engineering J.     Open Access   (Followers: 2, SJR: 0.604, CiteScore: 3)
Alexandria J. of Medicine     Open Access   (Followers: 1, SJR: 0.191, CiteScore: 1)
Algal Research     Partially Free   (Followers: 11, SJR: 1.142, CiteScore: 4)
Alkaloids: Chemical and Biological Perspectives     Full-text available via subscription   (Followers: 2)
Allergologia et Immunopathologia     Full-text available via subscription   (Followers: 1, SJR: 0.504, CiteScore: 1)
Allergology Intl.     Open Access   (Followers: 5, SJR: 1.148, CiteScore: 2)
Alpha Omegan     Full-text available via subscription   (SJR: 3.521, CiteScore: 6)
ALTER - European J. of Disability Research / Revue Européenne de Recherche sur le Handicap     Full-text available via subscription   (Followers: 11, SJR: 0.201, CiteScore: 1)
Alzheimer's & Dementia     Hybrid Journal   (Followers: 55, SJR: 4.66, CiteScore: 10)
Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring     Open Access   (Followers: 6, SJR: 1.796, CiteScore: 4)
Alzheimer's & Dementia: Translational Research & Clinical Interventions     Open Access   (Followers: 6, SJR: 1.108, CiteScore: 3)
Ambulatory Pediatrics     Hybrid Journal   (Followers: 5)
American Heart J.     Hybrid Journal   (Followers: 58, SJR: 3.267, CiteScore: 4)
American J. of Cardiology     Hybrid Journal   (Followers: 67, SJR: 1.93, CiteScore: 3)
American J. of Emergency Medicine     Hybrid Journal   (Followers: 48, SJR: 0.604, CiteScore: 1)
American J. of Geriatric Pharmacotherapy     Full-text available via subscription   (Followers: 13)
American J. of Geriatric Psychiatry     Hybrid Journal   (Followers: 15, SJR: 1.524, CiteScore: 3)
American J. of Human Genetics     Hybrid Journal   (Followers: 39, SJR: 7.45, CiteScore: 8)
American J. of Infection Control     Hybrid Journal   (Followers: 29, SJR: 1.062, CiteScore: 2)
American J. of Kidney Diseases     Hybrid Journal   (Followers: 37, SJR: 2.973, CiteScore: 4)
American J. of Medicine     Hybrid Journal   (Followers: 50)
American J. of Medicine Supplements     Full-text available via subscription   (Followers: 3, SJR: 1.967, CiteScore: 2)
American J. of Obstetrics and Gynecology     Hybrid Journal   (Followers: 264, SJR: 2.7, CiteScore: 4)
American J. of Ophthalmology     Hybrid Journal   (Followers: 67, SJR: 3.184, CiteScore: 4)
American J. of Ophthalmology Case Reports     Open Access   (Followers: 5, SJR: 0.265, CiteScore: 0)
American J. of Orthodontics and Dentofacial Orthopedics     Full-text available via subscription   (Followers: 6, SJR: 1.289, CiteScore: 1)
American J. of Otolaryngology     Hybrid Journal   (Followers: 25, SJR: 0.59, CiteScore: 1)
American J. of Pathology     Hybrid Journal   (Followers: 32, SJR: 2.139, CiteScore: 4)
American J. of Preventive Medicine     Hybrid Journal   (Followers: 30, SJR: 2.164, CiteScore: 4)
American J. of Surgery     Hybrid Journal   (Followers: 39, SJR: 1.141, CiteScore: 2)
American J. of the Medical Sciences     Hybrid Journal   (Followers: 12, SJR: 0.767, CiteScore: 1)
Ampersand : An Intl. J. of General and Applied Linguistics     Open Access   (Followers: 7)
Anaerobe     Hybrid Journal   (Followers: 4, SJR: 1.144, CiteScore: 3)
Anaesthesia & Intensive Care Medicine     Full-text available via subscription   (Followers: 67, SJR: 0.138, CiteScore: 0)
Anaesthesia Critical Care & Pain Medicine     Full-text available via subscription   (Followers: 25, SJR: 0.411, CiteScore: 1)
Anales de Cirugia Vascular     Full-text available via subscription   (Followers: 1)
Anales de Pediatría     Full-text available via subscription   (Followers: 3, SJR: 0.277, CiteScore: 0)
Anales de Pediatría (English Edition)     Full-text available via subscription  
Anales de Pediatría Continuada     Full-text available via subscription  
Analytic Methods in Accident Research     Hybrid Journal   (Followers: 6, SJR: 4.849, CiteScore: 10)
Analytica Chimica Acta     Hybrid Journal   (Followers: 44, SJR: 1.512, CiteScore: 5)
Analytica Chimica Acta : X     Open Access  
Analytical Biochemistry     Hybrid Journal   (Followers: 214, SJR: 0.633, CiteScore: 2)
Analytical Chemistry Research     Open Access   (Followers: 13, SJR: 0.411, CiteScore: 2)
Analytical Spectroscopy Library     Full-text available via subscription   (Followers: 14)
Anesthésie & Réanimation     Full-text available via subscription   (Followers: 2)
Anesthesiology Clinics     Full-text available via subscription   (Followers: 25, SJR: 0.683, CiteScore: 2)
Angiología     Full-text available via subscription   (SJR: 0.121, CiteScore: 0)
Angiologia e Cirurgia Vascular     Open Access   (Followers: 1, SJR: 0.111, CiteScore: 0)
Animal Behaviour     Hybrid Journal   (Followers: 236, SJR: 1.58, CiteScore: 3)
Animal Feed Science and Technology     Hybrid Journal   (Followers: 7, SJR: 0.937, CiteScore: 2)
Animal Reproduction Science     Hybrid Journal   (Followers: 7, SJR: 0.704, CiteScore: 2)
Annales d'Endocrinologie     Full-text available via subscription   (Followers: 3, SJR: 0.451, CiteScore: 1)

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Similar Journals
Journal Cover
Nuclear Medicine and Biology
Journal Prestige (SJR): 0.696
Citation Impact (citeScore): 2
Number of Followers: 5  
 
  Hybrid Journal Hybrid journal (It can contain Open Access articles)
ISSN (Print) 0969-8051
Published by Elsevier Homepage  [3161 journals]
  • Plasma pharmacokinetic and metabolism of [18F]THK-5317 are
           dependent on sex
    • Abstract: Publication date: Available online 13 January 2020Source: Nuclear Medicine and BiologyAuthor(s): Severin Mairinger, Thomas Filip, Michael Sauberer, Stefanie Flunkert, Thomas Wanek, Johann Stanek, Sara Furtner, Birgit Hutter-Paier, Nobuyuki Okamura, Claudia KuntnerAbstractIntroductionTau deposition is one of the hallmarks of Alzheimer's disease (AD) and can be visualized and quantified using [18F]THK-5317 together with kinetic modeling. To determine the feasibility of this approach, we measured blood/plasma pharmacokinetics and radiotracer metabolism in female and male rats.MethodsFemale and male rats (n = 11–12) were cannulated via the femoral artery for continuous blood sampling. Blood sampling was performed at regular intervals after intravenous injection of [18F]THK-5317. After collection of the last blood sample, animals were sacrificed, and organs were excised. Blood from minute 5, 20 and 60 was centrifuged to obtain plasma. Radiolabeled metabolites in plasma, brain, liver and urine were analyzed by radio-thin-layer chromatography (radio-TLC).ResultsPlasma pharmacokinetics and metabolism were significantly different between female and male rats. [18F]THK-5317 plasma clearance was faster in female (0.66 ± 0.08 mL/h/kg BW) than in male (0.52 ± 0.11 mL/h/kg BW) rats (p = .005). The percentage of unmetabolized parent was significantly different between both sexes at 20 min and 60 min p.i. In the liver, a 1.6-fold higher radioactivity concentration was found in male versus female animals and in addition also the percentage of unmetabolized parent was different.ConclusionOur results show pronounced sex differences in blood/plasma pharmacokinetics and metabolism of [18F]THK-5317 in rats. Female animals showed a faster plasma clearance compared to males. These results underline the importance of investigating both sexes and also support the notion that individual input functions or sex-specific population-based input functions are needed for kinetic modeling analyses.Advances in knowledgeFirst preclinical study in rats showing pronounced sex differences in blood/plasma pharmacokinetics and metabolism of [18F]THK-5317.Implications for patient careSex-specific differences might also be present in humans and thus clinical trials should have adequate sample size to account for effects in men and women separately.
       
  • Automated two-step manufacturing of [11C]glyburide radiopharmaceutical for
           PET imaging in humans
    • Abstract: Publication date: Available online 7 January 2020Source: Nuclear Medicine and BiologyAuthor(s): Fabien Caillé, Philippe Gervais, Sylvain Auvity, Christine Coulon, Solène Marie, Nicolas Tournier, Bertrand KuhnastAbstractIntroductionGlyburide is an approved anti-diabetes drug binding to the sulfonylurea receptors-1 (SUR-1) and substrate of solute carrier (SLC) transporters, which can be isotopically radiolabelled with carbon-11 for PET imaging. The aim of this work is to present an original and reproducible automated radiosynthesis of [11C]glyburide and a full European Pharmacopeia 9.7 compliant quality control to use [11C]glyburide in PET imaging clinical trials.MethodsDifferent conditions were explored to afford non-radioactive glyburide by one or two-step methylation. These experiments were monitored by UPLC-MS. The optimized process was applied to the automated radiosynthesis of [11C]glyburide using a TRACERlab® FX C Pro. A complete quality control according to Pharmacopeia guidelines was realized.ResultsOne-step methylation revealed regioselectivity issues as methylation occurred preferentially on the sulfonylurea moiety. Two-step approach by methylation followed by reaction with cyclohexyl isocyanate afforded glyburide without formation of methylated side products. Ready-to-inject [11C]glyburide was obtained in 5% non-decay corrected radiochemical yield and 110 ± 20 GBq/μmol molar activity within 40 min (n = 8). [11C]Glyburide quality control was compliant with the Pharmacopeia requirements.ConclusionsWe have described a highly reproducible and automated two-step radiosynthesis of [11C]glyburide which was qualified as a radiopharmaceutical for human injection. This whole manufacturing process is currently being used to conduct a clinical trial to elucidate the hepatic transport of drugs.Advances in knowledgeCompared to previously reported radiosynthesis of [11C]glyburide, this work provides an original and reproducible approach which can be transferred to any PET centre interested in using this radiotracer for preclinical or clinical imaging.Implication for patient careThis work provides a method to manufacture [11C]glyburide for human PET imaging. This radiopharmaceutical could be used to elucidate the role of transporters in drug exposure of different organs or to monitor brain recovery after central nervous system (CNS) injuries.
       
  • High-throughput radio-TLC analysis
    • Abstract: Publication date: March–April 2020Source: Nuclear Medicine and Biology, Volumes 82–83Author(s): Jia Wang, Alejandra Rios, Ksenia Lisova, Roger Slavik, Arion F. Chatziioannou, R. Michael van DamAbstractIntroductionRadio thin layer chromatography (radio-TLC) is commonly used to analyze purity of radiopharmaceuticals or to determine the reaction conversion when optimizing radiosynthesis processes. In applications where there are few radioactive species, radio-TLC is preferred over radio-high-performance liquid chromatography due to its simplicity and relatively quick analysis time. However, with current radio-TLC methods, it remains cumbersome to analyze a large number of samples during reaction optimization. In a couple of studies, Cerenkov luminescence imaging (CLI) has been used for reading radio-TLC plates spotted with a variety of isotopes. We show that this approach can be extended to develop a high-throughput approach for radio-TLC analysis of many samples.MethodsThe high-throughput radio-TLC analysis was carried out by performing parallel development of multiple radioactive samples spotted on a single TLC plate, followed by simultaneous readout of the separated samples using Cerenkov imaging. Using custom-written MATLAB software, images were processed and regions of interest (ROIs) were drawn to enclose the radioactive regions/spots. For each sample, the proportion of integrated signal in each ROI was computed. Various crude samples of [18F]fallypride, [18F]FET and [177Lu]Lu-PSMA-617 were prepared for demonstration of this new method.ResultsBenefiting from a parallel developing process and high resolution of CLI-based readout, total analysis time for eight [18F]fallypride samples was 7.5 min (2.5 min for parallel developing, 5 min for parallel readout), which was significantly shorter than the 48 min needed using conventional approaches (24 min for sequential developing, 24 min for sequential readout on a radio-TLC scanner). The greater separation resolution of CLI enabled the discovery of a low-abundance side product from a crude [18F]FET sample that was not discernable using the radio-TLC scanner. Using the CLI-based readout method, we also observed that high labeling efficiency (99%) of [177Lu]Lu-PSMA-617 can be achieved in just 10 min, rather than the typical 30 min timeframe used.ConclusionsCerenkov imaging in combination with parallel developing of multiple samples on a single TLC plate proved to be a practical method for rapid, high-throughput radio-TLC analysis.
       
  • Preclinical investigation of potential use of thymidine
           phosphorylase-targeting tracer for diagnosis of nonalcoholic
           steatohepatitis
    • Abstract: Publication date: March–April 2020Source: Nuclear Medicine and Biology, Volumes 82–83Author(s): Kei Higashikawa, Sawako Horiguchi, Makoto Tarisawa, Yuki Shibata, Kazue Ohkura, Hironobu Yasui, Hiroshi Takeda, Yuji KugeAbstractIntroductionAlthough liver biopsy is the gold standard for the diagnosis of nonalcoholic steatohepatitis (NASH), it has several problems including high invasiveness and sampling errors. Therefore, the development of alternative methods to overcome these disadvantages is strongly required. In this study, we evaluated the potential use of our tracer targeting thymidine phosphorylase (TYMP), 5-[123I]iodo-6-[(2-iminoimidazolidinyl)methyl]uracil ([123I]IIMU) for the diagnosis of NASH.MethodsThe mice used as the NASH model (hereafter, NASH mice) were prepared by feeding a methionine- and choline-deficient diet for 4 weeks. A control group was similarly given a control diet. The expression levels of the TYMP gene and protein in the liver were examined by real-time reverse-transcription polymerase chain reaction and western blot analyses. The localizations of [125I]IIMU and the TYMP protein in the liver were examined by autoradiography and immunohistochemical staining, respectively. Finally, the mice were injected with [123I]IIMU and single-photon emission tomography (SPECT) imaging was conducted.ResultsThe hepatic expression levels of TYMP were significantly lower in the NASH mice than in the control mice at both mRNA and protein levels, suggesting that a decrease in TYMP level could be an indicator of NASH. [125I]IIMU was uniformly distributed in the liver of the control mice, whereas it showed a patchy distribution in that of the NASH mice. The localization of [125I]IIMU was visually consistent with that of the TYMP protein in the liver of the control and NASH mice. SPECT analysis indicated that the hepatic accumulation of [123I]IIMU in the NASH mice was significantly lower than that in the control mice [SUV (g/ml): 4.14 ± 0.87 (Control) vs 2.31 ± 0.29 (NASH)].Conclusions[123I]IIMU may provide a noninvasive means for imaging TYMP expression in the liver and may be applicable to the diagnosis of NASH.
       
  • [68Ga]Ga-HBED-CC-DiAsp: A new renal function imaging agent
    • Abstract: Publication date: March–April 2020Source: Nuclear Medicine and Biology, Volumes 82–83Author(s): Shengyu Shi, Lifang Zhang, Zehui Wu, Aili Zhang, Haiyan Hong, Seok Rye Choi, Lin Zhu, Hank F. KungIntroduction[68Ga]Ga-EDTA ([68Ga]Ga-ethylenediaminetetraacetic acid) was previously reported as a renal imaging agent for measuring GFR (glomerular filtration rate). In an effort to provide new agents with better in vivo characteristics for renal imaging, [68Ga]Ga-HBED-CC-DiAsp (Di-Aspartic acid derivative of N,N′-bis [2-hydroxy-5-(carboxyethyl)benzyl]-ethylenediamine-N,N′-diacetic acid) was prepared and tested.MethodHBED-CC-DiAsp was synthesized and labeled with [68Ga]GaCl4− at room temperature. Plasma protein and red blood cells (RBC) binding were also evaluated. Biodistribution and dynamic PET imaging studies were performed in mice and rats, respectively.Results[68Ga]Ga-HBED-CC-DiAsp was radiolabeled at room temperature by a one-step kit formulation in high purity without any purification (radiochemical purity>98%). Previous reports suggested that Ga-HBED-CC exhibited a higher stability constant and rapid chelating formation rate than that of Ga-EDTA (logKGaL = 38.5 vs 22.1, respectively). In vitro stability studies indicated that it was stable up to 120 min. The log DOW value, partition coefficient between n-octanol and water, was found to be −2.52 ± 0.08. Plasma protein and RBC binding was similar to that observed for [68Ga]Ga-EDTA. Biodistribution and dynamic PET/CT imaging studies in rats revealed a rapid clearance primarily through the renal–urinary pathway. The PET-derived [68Ga]Ga-HBED-CC-DiAsp renograms in rats showed an average time-to-peak of 3.6 ± 0.7 min which was similar to that observed for [68Ga]Ga-EDTA (3.1 ± 0.5 min). The time-to-half-maximal activity was also comparable to that of [68Ga]Ga-EDTA (8.8 vs 8.2 min, respectively). Pretreatment of probenecid, a renal tubular excretion inhibitor, showed no significant effect on renal excretion.Conclusions[68Ga]Ga-HBED-CC-DiAsp could be prepared quickly at room temperature in high yield and purity. Results of in vitro studies and in vivo biodistribution in mice and rats suggested that [68Ga]Ga-HBED-CC-DiAsp might be useful as a PET imaging agent for measurement of GFR.Graphical abstractUnlabelled Image
       
  • 2-[18F]FELP, a novel LAT1-specific PET tracer, for the discrimination
           between glioblastoma, radiation necrosis and inflammation
    • Abstract: Publication date: March–April 2020Source: Nuclear Medicine and Biology, Volumes 82–83Author(s): Jeroen Verhoeven, Tristan Baguet, Sarah Piron, Glenn Pauwelyn, Charlotte Bouckaert, Benedicte Descamps, Robrecht Raedt, Christian Vanhove, Filip De Vos, Ingeborg GoethalsAbstractIntroductionConsidering the need for rapid change of treatment in recurrent glioblastoma (GB), it is of utmost importance to characterize PET radiopharmaceuticals that allow early discrimination of tumor from therapy-related effects. In this study, we examined the value of 2-[18F]FELP as a LAT1 tumor-specific PET tracer in comparison with [18F]FDG and [18F]FET in a combined orthotopic rat radiation necrosis and glioblastoma model. A second experiment compared 2-[18F]FELP to [18F]FDG in a mouse glioblastoma - inflammation model.MethodsUsing the small animal radiation research platform (SARRP), radiation necrosis (RN) was induced in the left frontal lobe of the rat brain. When radiation-induced changes were visible on MRI, F98 rat glioblastoma cells were stereotactically inoculated in the contralateral right frontal lobe. When tumor growth was confirmed on MRI, 2-[18F]FELP, [18F]FET and [18F]FDG PET scans were acquired on three consecutive days. In an inflammation experiment, mice were inoculated in the left thigh with U87 human glioblastoma cells. After heterotopic tumor growth was confirmed macroscopically, inflammation was induced by injection of turpentine subcutaneously in the right thigh. Subsequently, 2-[18F]FELP and [18F]FDG scans were acquired on two consecutive days.ResultsThe in vivo PET images demonstrated that 2-[18F]FELP could differentiate glioblastoma and radiation necrosis using SUVmean (p = 0.0016) and LNRmean (p = 0.009), while [18F]FET was only able to differentiate both lesions by means of the SUVmean. (p = 0.047) Delayed [18F]FDGlate PET (4 h postinjection) was also able to distinguish glioblastoma from radiation necrosis, but smaller lesion-to-normal brain ratios were observed (SUVmean: p = 0.009; LNRmean: p = 0.028). In the inflammation study, 2-[18F]FELP showed no significant uptake in the inflammation lesion when compared to the control group (SUVmean: p = 0.149; LNRmean: p = 0.083). In contrast, both conventional and delayed [18F]FDG displayed significant uptake in the turpentine-invoked lesion (SUVmean: p = 0.021; LNRmean: p = 0.021).ConclusionThis study suggests that the 2-[18F]FELP PET is able to differentiate glioblastoma from radiation necrosis and that the 2-[18F]FELP uptake is less likely to be contaminated by the presence of inflammation than the [18F]FDG signal.Advances in knowledgeThese results are clinically relevant for the differential diagnosis between tumor and radiation necrosis because radiation necrosis always contains a certain amount of inflammatory cells. Hence, 2-[18F]FELP is preferred to discriminate tumor from radiation necrosis.
       
  • A comparison of DFO and DFO* conjugated to trastuzumab-DM1 for complexing
           89Zr – In vitro stability and in vivo microPET/CT imaging studies in
           NOD/SCID mice with HER2-positive SK-OV-3 human ovarian cancer xenografts
    • Abstract: Publication date: Available online 30 December 2019Source: Nuclear Medicine and BiologyAuthor(s): Hyungjun Cho, Noor Al-saden, Heather Lam, Juri Möbus, Raymond M. Reilly, Mitchell A. WinnikAbstractIntroductionDesferrioxamine (DFO) is conjugated to antibodies to chelate 89Zr for PET, but DFO forms a hexadentate complex with Zr4+ that exhibits instability contributing to bone uptake of 89Zr, while the cationic charge of the Zr4+-DFO complex may promote normal tissue uptake of the radioimmunoconjugates (RICs). DFO* is a novel chelator that forms a more stable octadentate and neutral complex with 89Zr. Our aim was to compare the in vitro stability of [89Zr]Zr-DFO*-human IgG (hIgG) and [89Zr]Zr-DFO-hIgG RICs, and the in vivo PET imaging properties of the antibody-drug conjugate (ADC), trastuzumab-DM1 (T-DM1), labeled with 89Zr by conjugation to DFO or DFO*.MethodsSCN-pPhe-DFO and SCN-pPhe-DFO* were reacted with hIgG at a 14.6-fold excess or with T-DM1 at a 4.1-fold or 10-fold excess, respectively, purified and labeled with 89Zr. The number of DFO* introduced was determined by measuring the absorbance at 245/252 nm and the protein concentration was measured at 280 nm. The stability of [89Zr]Zr-DFO*-hIgG was studied in vitro in human plasma, and by challenge with a 385-fold excess (0.1 mM) DFO or EDTA. An inverse stability study was performed with [89Zr]Zr-DFO-hIgG challenged with 0.1 mM DFO*. The HER2 binding affinity of [89Zr]Zr-DFO*-T-DM1 was measured in a direct (saturation) binding assay using SK-BR-3 human breast cancer cells or SK-OV-3 cells. The biodistribution of [89Zr]Zr-DFO*-T-DM1 and [89Zr]Zr-DFO-T-DM1 were compared in non-tumor bearing Balb/c mice and in NOD/SCID mice with s.c. SK-OV-3 xenografts at 96 h post-intravenous injection (p.i.). MicroPET/CT images were obtained at 96 h p.i. of the RICs.ResultshIgG and T-DM1 were conjugated to 4.5–5.3 and 3.1 chelators (DFO or DFO*), respectively, and labeled with 89Zr to a final radiochemical purity of 91–99%. [89Zr]Zr-DFO*-hIgG was stable in vitro in human plasma or to challenge with 0.1 mM EDTA, but incubation with 0.1 mM DFO caused 26.0 ± 2.1% loss of 89Zr after 5 days. In contrast, incubation of [89Zr]Zr-DFO-hIgG with 0.1 mM DFO* resulted in 77.0 ± 3.9% loss of 89Zr after 5 days. [89Zr]Zr-DFO*-T-DM1 retained high affinity binding to HER2 on SK-BR-3 and SK-OV-3 cells with a Kd = 2.2 ± 0.3 nM and 1.9 ± 0.3 nM, respectively, and Bmax = 3.4 ± 0.1 × 105 and 1.1 ± 0.04 × 105 receptors/cell, respectively. Biodistribution studies of [89Zr]Zr-DFO-T-DM1 and [89Zr]Zr-DFO*-T-DM1 in Balb/c and NOD/SCID mice revealed significantly lower uptake in bone, liver, kidneys, and spleen for [89Zr]Zr-DFO*-T-DM1 than [89Zr]Zr-DFO-T-DM1. Uptake of [89Zr]Zr-DFO*-T-DM1 and [89Zr]Zr-DFO-T-DM1 in SK-OV-3 tumors was moderate [5.0 ± 1.8% injected dose/g (%ID/g) and 6.3 ± 0.6%ID/g, respectively; P = 0.18]. Tumors were imaged with both RICs.ConclusionWe conclude that DFO* conjugated to T-DM1 provides more stable complexation of 89Zr and therefore, [89Zr]Zr-DFO*-T-DM1 would be more useful than [89Zr]Zr-DFO-T-DM1 to probe the delivery of T-DM1 to tumors by PET, which we previously found is correlated with response to treatment with T-DM1 in mouse tumor xenograft models.Advances in knowledge and implication for patient careThis study is the first to directly compare the PET imaging properties of [89Zr]Zr-DFO*-T-DM1 and [89Zr]Zr-DFO-T-DM1 in a HER2-overexpressing tumor xenograft mouse model. Our results indicate that [89Zr]Zr-DFO*-T-DM1 provides superior imaging properties due to the greater stability of the [89Zr]Zr-DFO* than [89Zr]Zr-DFO complex.
       
  • Synthesis and evaluation of 6-[18F]fluoro-3-(pyridin-3-yl)-1H-indole as
           potential PET tracer for targeting tryptophan 2, 3-dioxygenase (TDO)
    • Abstract: Publication date: Available online 20 December 2019Source: Nuclear Medicine and BiologyAuthor(s): Zheng Qiao, Karine Mardon, Damion Stimson, Mary-anne Migotto, David C. Reutens, Rajiv BhallaAbstractIntroductionThe increase in expression of tryptophan 2, 3-dioxygenases (TDO) and indoleamine 2,3-dioxygenase (IDO) have been reported as potential tumor biomarkers. TDO and IDO are enzymes that catalyze the first and rate-limiting step of the kynurenine pathway. Positron emitting tomography (PET) tracers investigating the kynurenine pathway may allow for the detection of different disease pathologies in vivo including cancer. However, current PET tracers being developed for TDO and IDO have suffered from either multi-step low yielding syntheses or de-fluorination of the tracer in vivo.ResultsTDO inhibitors based on 6-fluoroindole with C3 substituents are a class of small molecules that have been shown to bind to TDO effectively, restore tryptophan concentration and decrease the production of immunosuppressive metabolites. The compound 6-fluoro-3-(pyridine-3-yl)-1H-indole has been reported to have high in vitro affinity for TDO. Herein we report the fully automated radiosynthesis of 6-[18F]fluoro-3-(pyridine-3-yl)-1H-indole [18F]4 using a copper-mediated nucleophilic 18F-fluorination resulting in a non-corrected yield of 5 to 6% of the tracer with a radiochemical purity of>99% after 4 h. Small animal dynamic PET/CT imaging of [18F]4 intravenously injected into normal C57BL/6 mice revealed rapid accumulation in heart and brain, reaching maximum occupancy in heart (10.9% ID/g) and brain (8.1% ID/g) at 1.75 min and 2.25 min, respectively. Furthermore, these in vivo studies revealed no de-fluorination of the tracer, as evidence by the absence of [18F]fluoride accumulation in bone.ConclusionIn vitro studies demonstrate that 4 has good affinity for hTDO and the radiolabeled analogue [18F]4 can be synthesized with suitable radiochemical yields. [18F]4 demonstrates good uptake in the brain and the radiolabeled compound shows no de-fluorination in vivo in C57BL/6 mice.
       
  • In vitro cytotoxicity of Auger electron-emitting
           [67Ga]Ga-trastuzumab
    • Abstract: Publication date: Available online 13 December 2019Source: Nuclear Medicine and BiologyAuthor(s): Muhamad Faiz bin Othman, Elise Verger, Ines Costa, Meena Tanapirakgul, Margaret S. Cooper, Cinzia Imberti, Valerie J. Lewington, Philip J. Blower, Samantha Y.A. TerryAbstractIntroductionMolecular radiotherapy exploiting short-range Auger electron-emitting radionuclides has potential for targeted cancer treatment and, in particular, is an attractive option for managing micrometastatic disease. Here, an approach using chelator-trastuzumab conjugates to target radioactivity to breast cancer cells was evaluated as a proof-of-concept to assess the suitability of 67Ga as a therapeutic radionuclide.MethodsTHP-trastuzumab and DOTA-trastuzumab were synthesised and radiolabelled with Auger electron-emitters 67Ga and 111In, respectively. Radiopharmaceuticals were tested for HER2-specific binding and internalisation, and their effects on viability (dye exclusion) and clonogenicity of HER2-positive HCC1954 and HER2–negative MDA-MB-231 cell lines was measured. Labelled cell populations were studied by microautoradiography.ResultsLabelling efficiencies for [67Ga]Ga-THP-trastuzumab and [111In]In-DOTA-trastuzumab were 90% and 98%, respectively, giving specific activities 0.52 ± 0.16 and 0.61 ± 0.11 MBq/μg (78–92 GBq/μmol). At 4 nM total antibody concentration and 200 × 103 cells/mL, [67Ga]Ga-THP-trastuzumab showed higher percentage of cell association (10.7 ± 1.3%) than [111In]In-DOTA-trastuzumab (6.2 ± 1.6%; p = 0.01). The proportion of bound activity that was internalised did not differ significantly for the two tracers (62.1 ± 1.4% and 60.8 ± 15.5%, respectively). At 100 nM, percentage cell binding of both radiopharmaceuticals was greatly reduced compared to 4 nM and did not differ significantly between the two (1.2 ± 1.0% [67Ga]Ga-THP-trastuzumab and 0.8 ± 0.9% for [111In]In-DOTA-trastuzumab). Viability and clonogenicity of HER2-positive cells decreased when each radionuclide was incorporated into cells by conjugation with trastuzumab, but not when the same level of radioactivity was confined to the medium by omitting the antibody conjugation, suggesting that 67Ga needs to be cell-bound or internalised for a therapeutic effect. Microautoradiography showed that radioactivity bound to individual cells varied considerably within the population.Conclusions[67Ga]Ga-THP-trastuzumab reduced cell viability and clonogenicity only when cell-bound, suggesting 67Ga holds promise as a therapeutic radionuclide as part of a targeted radiopharmaceutical. The causes and consequences of non-homogeneous uptake among the cell population should be explored.
       
  • Synthesis and evaluation of zirconium-89 labelled and long-lived GLP-1
           receptor agonists for PET imaging
    • Abstract: Publication date: Available online 4 December 2019Source: Nuclear Medicine and BiologyAuthor(s): Christian Borch Jacobsen, René Raavé, Marie Østergaard Pedersen, Pierre Adumeau, Mathieu Moreau, Ibai E. Valverde, Inga Bjørnsdottir, Jesper Bøggild Kristensen, Mette Finderup Grove, Kirsten Raun, James McGuire, Victor Goncalves, Sandra Heskamp, Franck Denat, Magnus GustafssonAbstractIntroductionLately, zirconium-89 has shown great promise as a radionuclide for PET applications of long circulating biomolecules. Here, the design and synthesis of protracted and long-lived GLP-1 receptor agonists conjugated to desferrioxamine and labelled with zirconium-89 is presented with the purpose of studying their in vivo distribution by PET imaging. The labelled conjugates were evaluated and compared to a non-labelled GLP-1 receptor agonist in both in vitro and in vivo assays to certify that the modification did not significantly alter the peptides' structure or function. Finally, the zirconium-89 labelled peptides were employed in PET imaging, providing visual verification of their in vivo biodistribution.MethodsThe evaluation of the radiolabelled peptides and comparison to their non-labelled parent peptide was performed by in vitro assays measuring binding and agonistic potency to the GLP-1 receptor, physicochemical studies aiming at elucidating change in peptide structure upon bioconjugation and labelling as well as an in vivo food in-take study illustrating the compounds' pharmacodynamic properties. The biodistribution of the labelled GLP-1 analogues was determined by ex vivo biodistribution and in vivo PET imaging.ResultsThe results indicate that it is surprisingly feasible to design and synthesize a protracted, zirconium-89 labelled GLP-1 receptor agonist without losing in vitro potency or affinity as compared to a non-labelled parent peptide. Physicochemical properties as well as pharmacodynamic properties are also maintained. The biodistribution in rats show high accumulation of radiolabelled peptide in well-perfused organs such as the liver, kidney, heart and lungs. The PET imaging study confirmed the findings from the biodistribution study with a significant high uptake in kidneys and presence of activity in liver, heart and larger blood vessels.Conclusions and advances in knowledgeThis initial study indicates the potential to monitor the in vivo distribution of long-circulating incretin hormones using zirconium-89 based PET.
       
  • Influence of binding affinity and blood plasma level on cerebral
           pharmacokinetics and PET imaging characteristics of two novel xanthine PET
           radioligands for the A1 adenosine receptor
    • Abstract: Publication date: Available online 2 December 2019Source: Nuclear Medicine and BiologyAuthor(s): Daniela Schneider, Angela Oskamp, Marcus Holschbach, Bernd Neumaier, Dirk Bier, Andreas BauerAbstractIntroductionThe suitability of novel positron emission tomography (PET) radioligands for quantitative in vivo imaging is affected by various physicochemical and pharmacological parameters. In this study, the combined effect of binding affinity, lipophilicity, protein binding and blood plasma level on cerebral pharmacokinetics and PET imaging characteristics of three xanthine-derived A1 adenosine receptor (A1AR) radioligands was investigated in rats.MethodsA comparative evaluation of two novel cyclobutyl-substituted xanthine derivatives, 8-cyclobutyl-3-(3-[18F]fluoropropyl)-1-propylxanthine ([18F]CBX) and 3-(3-[18F]fluoropropyl)-8-(1-methylcyclobutyl)-1-propylxanthine ([18F]MCBX), with the reference A1AR radioligand 8-cyclopentyl-3-(3-[18F]fluoropropyl)-1-propylxanthine ([18F]CPFPX) was conducted. This evaluation included in vitro competition binding assays, in vitro autoradiography and in vivo PET imaging. Differences in cerebral pharmacokinetics and minimal scan duration required for quantification of cerebral distribution volume (VT) were assessed.ResultsMeasured Ki values of non-labeled CBX, MCBX and CPFPX were 10.0 ± 0.52 nM, 3.3 ± 0.30 nM and 1.4 ± 0.15 nM, respectively (n = 3–4). In vitro autoradiographic binding patterns in rat brain were comparable between the radioligands, as well as the fraction of non-specific binding (1.0–1.9%). In vivo cerebral pharmacokinetics of the novel cyclobutyl-substituted xanthines differed considerably from that of [18F]CPFPX. Brain uptake and VT of [18F]CBX were substantially lower despite the higher concentration of radiotracer in plasma. [18F]MCBX showed comparable uptake and VT, but faster cerebral kinetics than [18F]CPFPX. However, the faster kinetics of [18F]MCBX did not enable the quantification of cerebral VT in a shorter scan time.ConclusionsThe combined effect of individual physicochemical and pharmacological properties of a radiotracer on its PET imaging characteristics cannot be readily predicted. In vivo performance of the xanthine A1AR radioligands was mainly influenced by binding affinity; plasma concentrations and cerebral kinetics were of secondary importance.
       
  • Delivery systems exploiting natural cell transport processes of
           macromolecules for intracellular targeting of Auger electron emitters
    • Abstract: Publication date: Available online 27 November 2019Source: Nuclear Medicine and BiologyAuthor(s): Andrey A. Rosenkranz, Tatiana A. Slastnikova, Georgii P. Georgiev, Michael R. Zalutsky, Alexander S. SobolevAbstractThe presence of Auger electrons (AE) among the decay products of a number of radionuclides makes these radionuclides an attractive means for treating cancer because these short-range electrons can cause significant damage in the immediate vicinity of the decomposition site. Moreover, the extreme locality of the effect provides a potential for selective eradication of cancer cells with minimal damage to adjacent normal cells provided that the delivery of the AE emitter to the most vulnerable parts of the cell can be achieved. Few cellular compartments have been regarded as the desired target site for AE emitters, with the cell nucleus generally recognized as the preferred site for AE decay due to the extreme sensitivity of nuclear DNA to direct damage by radiation of high linear energy transfer. Thus, the advantages of AE emitters for cancer therapy are most likely to be realized by their selective delivery into the nucleus of the malignant cells. To achieve this goal, delivery systems must combine a challenging complex of properties that not only provide cancer cell preferential recognition but also cell entry followed by transport into the cell nucleus. A promising strategy for achieving this is the recruitment of natural cell transport processes of macromolecules, involved in each of the aforementioned steps. To date, a number of constructs exploiting intracellular transport systems have been proposed for AE emitter delivery to the nucleus of a targeted cell. An example of such a multifunctional vehicle that provides smart step-by-step delivery is the so-called modular nanotransporter, which accomplishes selective recognition, binding, internalization, and endosomal escape followed by nuclear import of the delivered radionuclide. The current review will focus on delivery systems utilizing various intracellular transport pathways and their combinations in order to provide efficient targeting of AE to the cancer cell nucleus.
       
  • Effectiveness and normal tissue toxicity of Auger electron (AE)
           radioimmunotherapy (RIT) with [111In]In-Bn-DTPA-nimotuzumab in mice with
           triple-negative or trastuzumab-resistant human breast cancer xenografts
           that overexpress EGFR
    • Abstract: Publication date: Available online 22 October 2019Source: Nuclear Medicine and BiologyAuthor(s): Conrad Chan, Humphrey Fonge, Karen Lam, Raymond M. ReillyAbstractIntroductionOur objective was to evaluate the effectiveness and normal tissue toxicity of nimotuzumab labeled with the Auger electron (AE)-emitter, 111In ([111In]In-Bn-DTPA-nimotuzumab) for radioimmunotherapy (RIT) of human triple-negative breast cancer (TNBC) or trastuzumab-resistant HER2-positive BC tumors overexpressing epidermal growth factor receptors (EGFR) in athymic mice.MethodsNormal tissue toxicity was studied in non-tumor-bearing Balb/c mice i.v. administered 9.0 or 28.6 MBq (3 mg/kg) of [111In]In-Bn-DTPA-nimotuzumab, unlabeled nimotuzumab (3 mg/kg) or normal saline. A complete blood cell count (CBC) and serum alanine aminotransferase (ALT) and creatinine (Cr) were measured at 14 days. Body weight was monitored. RIT studies were performed in CD-1 athymic mice engrafted s.c. with MDA-MB-468 human TNBC tumors or TrR1 HER2-positive but trastuzumab-resistant BC tumors. Mice were i.v. administered two amounts (15.5 MBq; 3 mg/kg) of [111In]In-Bn-DTPA-nimotuzumab separated by 14 days. Control mice received unlabeled Bn-DTPA-nimotuzumab (3 mg/kg) or anti-HER2 [111In]In-Bn-DTPA-trastuzumab or normal saline. Tumor growth and body weight were measured for 6 weeks. A tumor growth index (TGI) and body weight index (BWI) were calculated to compare the tumor size and body weight post-treatment with the pre-treatment values. A tumor doubling ratio (TDR) was calculated for each treatment group compared to control mice receiving normal saline.ResultsThere was no loss of body weight or decreased red blood cells (RBC) or platelets (PLT) or increased serum ALT or Cr in Balb/c mice administered 9.0 or 28.6 MBq (3 mg/kg) of [111In]In-Bn-DTPA-nimotuzumab compared to mice treated with unlabeled Bn-DTPA-nimotuzumab (3 mg/kg) or normal saline. There was a significant decrease in white blood cell (WBC) counts in Balb/c mice receiving 28.6 MBq but not 9.0 MBq of [111In]In-Bn-DTPA-nimotuzumab. Based on these results, an administered amount of 15.5 MBq (3 mg/kg) was selected for RIT studies. Administration of two amounts (15.5 MBq; 3 mg/kg) separated by 14 days to CD-1 athymic mice with s.c. MDA-MB-468 xenografts strongly inhibited tumor growth. The TDR for mice treated with [111In]In-Bn-DTPA-nimotuzumab treatment was 2.15-fold compared to control mice receiving normal saline. In contrast, treatment with unlabeled Bn-DTPA-nimotuzumab or [111In]In-Bn-DTPA-trastuzumab had no significant effect on tumor growth (TDR = 0.96-fold and 1.08-fold, respectively). RIT with [111In]In-Bn-DTPA-nimotuzumab also strongly inhibited the growth of TrR1 tumors in athymic mice (TDR = 2.13-fold) compared to unlabeled Bn-DTPA-nimotuzumab (TDR = 0.91-fold). There were no losses in body weight over 6 weeks in tumor bearing mice receiving [111In]In-Bn-DTPA-nimotuzumab, unlabeled Bn-DTPA-nimotuzumab, [111In]In-Bn-DTPA-trastuzumab or normal saline.Conclusions[111In]In-Bn-DTPA-nimotuzumab was effective for treatment of TNBC or trastuzumab-resistant HER2-positive human BC tumors in mice that overexpress EGFR at administered amounts that caused no decrease in body weight or normal tissue toxicity in non-tumor-bearing Balb/c mice.Advances in knowledge and implications for patient careOur results suggest that Auger electron RIT with [111In]In-Bn-DTPA-nimotuzumab may provide a novel therapeutic option for patients with TNBC or trastuzumab-resistant HER2-positive BC that overexpresses EGFR. The low normal tissue toxicity of this approach may allow combination with other targeted therapies such as antibody-drug conjugates (ADCs).
       
  • Fluselenamyl: Evaluation of radiation dosimetry in mice and
           pharmacokinetics in brains of non-human primate
    • Abstract: Publication date: Available online 22 October 2019Source: Nuclear Medicine and BiologyAuthor(s): G.S.M. Sundaram, Lynne Jones, Yun Zhou, Richard Laforest, Vijay SharmaAbstractIntroductionTo allow quantitative assessment of therapeutic efficacy for therapeutic interventions (either approved or undergoing FDA approvals) for either inhibiting or reducing development of Aβ pathophysiology in vivo, 18F-labelled tracers, such as Florbetapir, Florbetaben, and Flutemetamol have been approved. Previously, we have reported on development and preclinical validation of 18F-Fluselenamyl, comprising traits of translatable Aβ imaging agents. Herein, we report the dosimetry data for 18F-Fluselenamyl to provide radiation dose deposited within organs and determine effective dose (ED) for human studies, while also evaluating its pharmacokinetics in the nonhuman primate brains.MethodsTo evaluate safety profiles of 18F-Fluselenamyl for enabling its deployment as a PET imaging agent for monitoring Aβ pathophysiology in vivo, we estimated the human radiation dosimetry extrapolated from rodent biodistribution data obtained by standard method of organ dissection. Animal biodistribution studies were performed in FVB/NCR mice (20 males, 20 females), following tail-vein injection of the tracer. Following euthanasia of mice, organs were harvested, counted, radiation dose to each organ and whole body was determined using the standard MIRD methodology. For evaluation of pharmacokinetics in non-human primates, following intravenous injection of the tracer, dynamic PET scan of rhesus monkey brains were performed, and co-registered with MR for anatomical reference. Parametric images of tracer transport rate constant and distribution volume relative to cerebellum were generated using a simplified reference tissue model and a spatially-constraint linear regression algorithm.ResultsThe critical organ in humans has been determined to be the gall bladder with a gender average radiation absorbed dose of 0.079 mGy/MBq with an effective dose of 0.017 mSv/MBq and 0.020 mSv/MBq, in males and females, respectively. Therefore, these data provide preliminary projections on human dosimetry derived from rodent estimates, thereby defining safe imaging conditions for further validations in human subjects. Additionally, the tracer penetrated the non-human primate brain and excreted to background levels at later-time points thus pointing to the potential for high signal/noise ratios during noninvasive imaging. Tissue time activity curves (TACs) also show fast initial uptake with maximum projection of activity at 2–6 min post administration followed by clearance of activity at later time-points from cortex, cerebellum, and white matter of nonhuman primate brain. Parametric images confirmed that the 18F-Fluselenamyl has relative high transport rate constant at striatum, thalamus, and cortex.ConclusionsThe data obtained from radiation dosimetry studies in mice indicate that 18F-Fluselenamyl can be safely used for further evaluation in humans. Additionally, 18F-Fluselenamyl demonstrated ability to traverse the blood brain barrier (BBB) and indicated high initial influx, followed by clearance to background levels in non-human primate brains. Combined information indicates that 18F-Fluselenamyl would be a potential candidate for detecting amyloid plaques in the living human brain.
       
  • Improved production of 76Br, 77Br and 80mBr via CoSe cyclotron targets and
           vertical dry distillation
    • Abstract: Publication date: Available online 5 September 2019Source: Nuclear Medicine and BiologyAuthor(s): Paul A. Ellison, Aeli P. Olson, Todd E. Barnhart, Sabrina L.V. Hoffman, Sean W. Reilly, Mehran Makvandi, Jennifer L. Bartels, Dhanabalan Murali, Onofre T. DeJesus, Suzanne E. Lapi, Bryan Bednarz, Robert J. Nickles, Robert H. Mach, Jonathan W. EngleAbstractIntroductionThe radioisotopes of bromine are uniquely suitable radiolabels for small molecule theranostic radiopharmaceuticals but are of limited availability due to production challenges. Significantly improved methods were developed for the production and radiochemical isolation of clinical quality 76Br, 77Br, and 80mBr. The radiochemical quality of the radiobromine produced using these methods was tested through the synthesis of a novel 77Br-labeled inhibitor of poly (ADP-ribose) polymerase-1 (PARP-1), a DNA damage response protein.Methods76Br, 77Br, and 80mBr were produced in high radionuclidic purity via the proton irradiation of novel isotopically-enriched Co76Se, Co77Se, and Co80Se intermetallic targets, respectively. Radiobromine was isolated through thermal chromatographic distillation in a vertical furnace assembly. The 77Br-labeled PARP inhibitor was synthesized via copper-mediated aryl boronic ester radiobromination.ResultsCyclotron production yields were 103 ± 10 MBq∙μA−1∙h−1 for 76Br, 88 ± 10 MBq∙μA−1∙h−1 for 80mBr at 16 MeV and 17 ± 1 MBq∙μA−1∙h−1 for 77Br at 13 MeV. Radiobromide isolation yields were 76 ± 11% in a small volume of aqueous solution. The synthesized 77Br-labeled PARP-1 inhibitor had a measured apparent molar activity up to 700 GBq/μmol at end of synthesis.ConclusionsA novel selenium alloy target enabled clinical-scale production of 76Br, 77Br, and 80mBr with high apparent molar activities, which was used to for the production of a new 77Br-labeled inhibitor of PARP-1.Advances in knowledgeNew methods for the cyclotron production and isolation of radiobromine improved the production capacity of 77Br by a factor of three and 76Br by a factor of six compared with previous methods.Implications for patient carePreclinical translational research of 77Br-based Auger electron radiotherapeutics, such as those targeting PARP-1, will require the production of GBq-scale 77Br, which necessitates next-generation, high-yielding, isotopically-enriched cyclotron targets, such as the novel intermetallic Co77Se.
       
 
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