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Bolin M, Nag S, Arakawa R, Varrone A, Farde L, Martarello L, Kaliszczak MA, Halldin C, Morén AF. In vivo quantification of [ 11C]BIO-1819578 in non-human primates, a novel radioligand for O-GlcNAcase. J Cereb Blood Flow Metab 2025:271678X251332487. [PMID: 40219925 PMCID: PMC11994644 DOI: 10.1177/0271678x251332487] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2024] [Revised: 02/19/2025] [Accepted: 03/17/2025] [Indexed: 04/14/2025]
Abstract
Neurofibrillary tangles (NFTs), composed of aggregated tau protein, in the brain is a neuropathological hallmark and feature of Alzheimer's disease (AD) and other tauopathies. One promising approach to prevent tau aggregates is to inhibit O-GlcNAcase (OGA), an enzyme that regulates tau O-GlcNAcylation. [11C]BIO-1819578 has emerged as a promising candidate to determine target occupancy of such OGA inhibitor drugs. The aim of this study was to further evaluate the pharmacokinetic properties of [11C]BIO-1819578 in non-human primates (NHPs) and to estimate its effective dose. Kinetic compartment analyses of [11C]BIO-1819578 binding to OGA in the brain were performed on positron emission tomography (PET) measurements conducted in three cynomolgus NHPs. Whole-body PET measurements were carried out in two NHPs to estimate the effective radiation dose. Both the 1-tissue-compartment (1TCM) and 2-tissue-compartment model (2TCM) could describe the regional time activity curves of [11C]BIO-1819578. The 2TCM was the statistically preferred model. The effective radiation dose was estimated to be 0.0033 mSv/MBq. The results showed that [11C]BIO-1819578 has suitable characteristics for reliable quantification of OGA using full kinetic modelling. The effective dose was on par with other 11C radioligands and is unlikely to pose an issue for human use.
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Affiliation(s)
- Martin Bolin
- Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, & Stockholm Health Care Services, Region Stockholm, Sweden
| | - Sangram Nag
- Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, & Stockholm Health Care Services, Region Stockholm, Sweden
| | - Ryosuke Arakawa
- Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, & Stockholm Health Care Services, Region Stockholm, Sweden
| | - Andrea Varrone
- Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, & Stockholm Health Care Services, Region Stockholm, Sweden
| | - Lars Farde
- Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, & Stockholm Health Care Services, Region Stockholm, Sweden
| | | | | | - Christer Halldin
- Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, & Stockholm Health Care Services, Region Stockholm, Sweden
- Department of Biophysics and Radiation Biology, and HUN-REN TKI, Semmelweis University, Budapest, Hungary
| | - Anton Forsberg Morén
- Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, & Stockholm Health Care Services, Region Stockholm, Sweden
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Sala A, Gosseries O, Laureys S, Annen J. Advances in neuroimaging in disorders of consciousness. HANDBOOK OF CLINICAL NEUROLOGY 2025; 207:97-127. [PMID: 39986730 DOI: 10.1016/b978-0-443-13408-1.00008-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/24/2025]
Abstract
Disorders of consciousness (DoC) are a heterogeneous spectrum of clinical conditions, including coma, unresponsive wakefulness syndrome, and minimally conscious state. DoC are clinically defined on the basis of behavioral cues expressed by the patients, on the assumption that such behavioral responses of the patient are representative of the patient's degree of consciousness impairment. However, many studies have highlighted the issues arising from formulating a DoC diagnosis merely on behavioral assessment. Overcoming the limitations of behavioral assessment, neuroimaging provides a direct window on the cerebral activity of the patient, bypassing the motor, perceptual, or cognitive deficits that might hamper the patient's ability to produce an appropriate behavioral response. This chapter provides an overview of available molecular, functional, and structural neuroimaging evidence in patients with DoC. This chapter introduces the neuroimaging tools available in the clinical settings of nuclear medicine and neuroradiology and presents the evidence on the role of neuroimaging tools to improve the clinical management of DoC patients, from the standpoint of differential diagnosis and prognosis. Last, we outline the open questions in the field, and point at actions that are urgently needed to fully exploit neuroimaging tools to advance scientific understanding and clinical management of DoC.
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Affiliation(s)
- Arianna Sala
- Coma Science Group, GIGA-Consciousness, University of Liège, Liège, Belgium; Department of Neurology, Centre du Cerveau (2), University Hospital of Liège, Liège, Belgium
| | - Olivia Gosseries
- Coma Science Group, GIGA-Consciousness, University of Liège, Liège, Belgium; Department of Neurology, Centre du Cerveau (2), University Hospital of Liège, Liège, Belgium
| | - Steven Laureys
- Coma Science Group, GIGA-Consciousness, University of Liège, Liège, Belgium; Department of Neurology, Centre du Cerveau (2), University Hospital of Liège, Liège, Belgium
| | - Jitka Annen
- Coma Science Group, GIGA-Consciousness, University of Liège, Liège, Belgium; Department of Neurology, Centre du Cerveau (2), University Hospital of Liège, Liège, Belgium; Department of Data Analysis, University of Ghent, Ghent, Belgium
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3
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Jonker I, Doorduin J, Knegtering H, van't Hag E, Dierckx RA, de Vries EFJ, Schoevers RA, Klein HC. Antiviral treatment in schizophrenia: a randomized pilot PET study on the effects of valaciclovir on neuroinflammation. Psychol Med 2023; 53:7087-7095. [PMID: 37016791 PMCID: PMC10719624 DOI: 10.1017/s0033291723000430] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Revised: 01/22/2023] [Accepted: 02/03/2023] [Indexed: 04/06/2023]
Abstract
BACKGROUND Patients with schizophrenia experience cognitive impairment, which could be related to neuroinflammation in the hippocampus. The cause for such hippocampal inflammation is still unknown, but it has been suggested that herpes virus infection is involved. This study therefore aimed to determine whether add-on treatment of schizophrenic patients with the anti- viral drug valaciclovir would reduce hippocampal neuroinflammation and consequently improve cognitive symptoms. METHODS We performed a double-blind monocenter study in 24 male and female patients with schizophrenia, experiencing active psychotic symptoms. Patients were orally treated with the anti-viral drug valaciclovir for seven consecutive days (8 g/day). Neuroinflammation was measured with Positron Emission Tomography using the translocator protein ligand [11C]-PK11195, pre-treatment and at seven days post-treatment, as were psychotic symptoms and cognition. RESULTS Valaciclovir treatment resulted in reduced TSPO binding (39%) in the hippocampus, as well as in the brainstem, frontal lobe, temporal lobe, parahippocampal gyrus, amygdala, parietal lobe, occipital lobe, insula and cingulate gyri, nucleus accumbens and thalamus (31-40%) when using binding potential (BPND) as an outcome. With total distribution volume (VT) as outcome we found essentially the same results, but associations only approached statistical significance (p = 0.050 for hippocampus). Placebo treatment did not affect neuroinflammation. No effects of valaciclovir on psychotic symptoms or cognitive functioning were found. CONCLUSION We found a decreased TSPO binding following antiviral treatment, which could suggest a viral underpinning of neuroinflammation in psychotic patients. Whether this reduced neuroinflammation by treatment with valaciclovir has clinical implications and is specific for schizophrenia warrants further research.
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Affiliation(s)
- Iris Jonker
- Department of Psychiatry, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Janine Doorduin
- Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Henderikus Knegtering
- Department of Psychiatry, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
- Lentis Mental Health Institution, Groningen, The Netherlands
| | - Erna van't Hag
- Department of Psychiatry, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Rudi A. Dierckx
- Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Erik F. J. de Vries
- Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Robert A. Schoevers
- Department of Psychiatry, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Hans C. Klein
- Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
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4
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Lippi M, Fanelli G, Fabbri C, De Ronchi D, Serretti A. The dilemma of polypharmacy in psychosis: is it worth combining partial and full dopamine modulation? Int Clin Psychopharmacol 2022; 37:263-275. [PMID: 35815937 PMCID: PMC9521590 DOI: 10.1097/yic.0000000000000417] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Accepted: 05/16/2022] [Indexed: 02/04/2023]
Abstract
Antipsychotic polypharmacy in psychotic disorders is widespread despite international guidelines favoring monotherapy. Previous evidence indicates the utility of low-dose partial dopamine agonist (PDAs) add-ons to mitigate antipsychotic-induced metabolic adverse effects or hyperprolactinemia. However, clinicians are often concerned about using PDAs combined with high-potency, full dopaminergic antagonists (FDAs) due to the risk of psychosis relapse. We, therefore, conducted a literature review to find studies investigating the effects of combined treatment with PDAs (i.e. aripiprazole, cariprazine and brexpiprazole) and FDAs having a strong D 2 receptor binding affinity. Twenty studies examining the combination aripiprazole - high-potency FDAs were included, while no study was available on combinations with cariprazine or brexpiprazole. Studies reporting clinical improvement suggested that this may require a relatively long time (~11 weeks), while studies that found symptom worsening observed this happening in a shorter timeframe (~3 weeks). Patients with longer illness duration who received add-on aripiprazole on ongoing FDA monotherapy may be at greater risk for symptomatologic worsening. Especially in these cases, close clinical monitoring is therefore recommended during the first few weeks of combined treatment. These indications may be beneficial to psychiatrists who consider using this treatment strategy. Well-powered randomized clinical trials are needed to derive more solid clinical recommendations.
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Affiliation(s)
- Matteo Lippi
- Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy
| | - Giuseppe Fanelli
- Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy
- Department of Human Genetics, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, The Netherlands
| | - Chiara Fabbri
- Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy
- Social, Genetic & Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, UK
| | - Diana De Ronchi
- Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy
| | - Alessandro Serretti
- Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy
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5
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Varrone A, Bundgaard C, Bang-Andersen B. PET as a Translational Tool in Drug Development for Neuroscience Compounds. Clin Pharmacol Ther 2022; 111:774-785. [PMID: 35201613 PMCID: PMC9305164 DOI: 10.1002/cpt.2548] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Accepted: 01/29/2022] [Indexed: 11/05/2022]
Abstract
In central nervous system drug discovery programs, early development of new chemical entities (NCEs) requires a multidisciplinary strategy and a translational approach to obtain proof of distribution, proof of occupancy, and proof of function in specific brain circuits. Positron emission tomography (PET) provides a way to assess in vivo the brain distribution of NCEs and their binding to the target of interest, provided that radiolabeling of the NCE is possible or that a suitable radioligand is available. PET is therefore a key tool for early phases of drug discovery programs. This review will summarize the main applications of PET in early drug development and discuss the usefulness of PET microdosing studies performed with direct labelling of the NCE and PET occupancy studies. The purpose of this review is also to propose an alignment of the nomenclatures used by drug metabolism and pharmacokinetic scientists and PET imaging scientists to indicate key pharmacokinetic parameters and to provide guidance in the performance and interpretation of PET studies.
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Affiliation(s)
- Andrea Varrone
- Translational Biomarkers and Imaging, H. Lundbeck A/S, Copenhagen, Denmark
| | | | - Benny Bang-Andersen
- Translational Biomarkers and Imaging, H. Lundbeck A/S, Copenhagen, Denmark.,Medicinal Chemistry & Translational DMPK, H. Lundbeck A/S, Copenhagen, Denmark
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6
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Chaudhari AJ, Badawi RD. Application-specific nuclear medical in vivoimaging devices. Phys Med Biol 2021; 66:10TR01. [PMID: 33770765 DOI: 10.1088/1361-6560/abf275] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2019] [Accepted: 03/26/2021] [Indexed: 11/11/2022]
Abstract
Nuclear medical imaging devices, such as those enabling photon emission imaging (gamma camera, single photon emission computed tomography, or positron emission imaging), that are typically used in today's clinics are optimized for assessing large portions of the human body, and are classified as whole-body imaging systems. These systems have known limitations for organ imaging, therefore application-specific devices have been designed, constructed and evaluated. These devices, given their compact nature and superior technical characteristics, such as their higher detection sensitivity and spatial resolution for organ imaging compared to whole-body imaging systems, have shown promise for niche applications. Several of these devices have further been integrated with complementary anatomical imaging devices. The objectives of this review article are to (1) provide an overview of such application-specific nuclear imaging devices that were developed over the past two decades (in the twenty-first century), with emphasis on brain, cardiac, breast, and prostate imaging; and (2) discuss the rationale, advantages and challenges associated with the translation of these devices for routine clinical imaging. Finally, a perspective on the future prospects for application-specific devices is provided, which is that sustained effort is required both to overcome design limitations which impact their utility (where these exist) and to collect the data required to define their clinical value.
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Affiliation(s)
- Abhijit J Chaudhari
- Department of Radiology, University of California Davis, Sacramento, CA 95817, United States of America
- Center for Molecular and Genomic Imaging, University of California Davis, Davis, CA 95616, United States of America
| | - Ramsey D Badawi
- Department of Radiology, University of California Davis, Sacramento, CA 95817, United States of America
- Department of Biomedical Engineering, University of California Davis, Davis, CA 95616, United States of America
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7
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Arakawa R, Takano A, Halldin C. PET technology for drug development in psychiatry. Neuropsychopharmacol Rep 2020; 40:114-121. [PMID: 32463584 PMCID: PMC7722687 DOI: 10.1002/npr2.12084] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2019] [Revised: 10/05/2019] [Accepted: 10/18/2019] [Indexed: 12/14/2022] Open
Abstract
Positron emission tomography (PET) is a non‐invasive imaging method to measure the molecule in vivo. PET imaging can evaluate the central nervous system drugs as target engagement in the human brain. For antipsychotic drugs, adequate dopamine D2 receptor occupancy (“therapeutic window”) is reported to be from 65%‐70% to 80% to achieve the antipsychotic effect without extrapyramidal symptoms. For antidepressants, the clinical threshold of serotonin transporter (5‐HTT) occupancy is reported to be 70%‐80% although the relation between the side effect and 5‐HTT occupancy has not yet been established. Evaluation of norepinephrine transporter (NET) occupancy for antidepressant is ongoing as adequate PET radioligands for NET were developed recently. Measurement of the target occupancy has been a key element to evaluate the in vivo target engagement of the drugs. In order to evaluate new drug targets for disease conditions such as negative symptoms/cognitive impairment of schizophrenia and treatment‐resistant depression, new PET radioligands need to be developed concurrently with the drug development. PET imaging can evaluate the central nervous system drugs as target engagement in the human brain. The uptake of [11C]raclopride for dopamine D2 receptors decreased from (A) baseline to (B) antipsychotic administration conditions.![]()
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Affiliation(s)
- Ryosuke Arakawa
- Center for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet and Stockholm County Council, Stockholm, Sweden
| | - Akihiro Takano
- Center for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet and Stockholm County Council, Stockholm, Sweden.,Takeda Development Center Japan, Takeda Pharmaceutical Company Limited, Osaka, Japan
| | - Christer Halldin
- Center for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet and Stockholm County Council, Stockholm, Sweden
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8
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Varrone A, Varnäs K, Jucaite A, Cselényi Z, Johnström P, Schou M, Vazquez-Romero A, Moein MM, Halldin C, Brown AP, Vishwanathan K, Farde L. A PET study in healthy subjects of brain exposure of 11C-labelled osimertinib - A drug intended for treatment of brain metastases in non-small cell lung cancer. J Cereb Blood Flow Metab 2020; 40:799-807. [PMID: 31006308 PMCID: PMC7168784 DOI: 10.1177/0271678x19843776] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2019] [Revised: 03/05/2019] [Accepted: 03/11/2019] [Indexed: 12/19/2022]
Abstract
Osimertinib is a tyrosine kinase inhibitor (TKI) of the mutated epidermal growth factor receptor (EGFRm) with observed efficacy in patients with brain metastases. Brain exposure and drug distribution in tumor regions are important criteria for evaluation and confirmation of CNS efficacy. The aim of this PET study was therefore to determine brain distribution and exposure of 11C-labelled osimertinib administered intravenously in subjects with an intact blood-brain barrier. Eight male healthy subjects (age 52 ± 8 years) underwent one PET measurement with 11C-osimertinib. The pharmacokinetic parameters Cmax(brain) (standardized uptake value), Tmax(brain) and AUC0-90 minbrain/blood ratio were calculated. The outcome measure for 11C-osimertinib brain exposure was the total distribution volume (VT). 11C-osimertinib distributed rapidly to the brain, with higher uptake in grey than in white matter. Mean Cmax, Tmax and AUC0-90 minbrain/blood ratio were 1.5 (range 1-1.8), 13 min (range 5-30 min), and 3.8 (range 3.3-4.1). Whole brain and white matter VT were 14 mL×cm-3 (range 11-18) and 7 mL×cm-3 (range 5-12). This study in healthy volunteers shows that 11C-osimertinib penetrates the intact blood-brain barrier. The approach used further illustrates the role of molecular imaging in facilitating the development of novel drugs for the treatment of malignancies affecting the brain.
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Affiliation(s)
- Andrea Varrone
- Department of Clinical Neuroscience, Centre for Psychiatry Research, Karolinska Institutet and Stockholm County Council, Stockholm, Sweden
| | - Katarina Varnäs
- Department of Clinical Neuroscience, Centre for Psychiatry Research, Karolinska Institutet and Stockholm County Council, Stockholm, Sweden
| | - Aurelija Jucaite
- Department of Clinical Neuroscience, Centre for Psychiatry Research, Karolinska Institutet and Stockholm County Council, Stockholm, Sweden
- PET Science Centre, Precision Medicine and Genomics, IMED Biotech Unit, AstraZeneca, Karolinska Institutet, Stockholm, Sweden
| | - Zsolt Cselényi
- Department of Clinical Neuroscience, Centre for Psychiatry Research, Karolinska Institutet and Stockholm County Council, Stockholm, Sweden
- PET Science Centre, Precision Medicine and Genomics, IMED Biotech Unit, AstraZeneca, Karolinska Institutet, Stockholm, Sweden
| | - Peter Johnström
- Department of Clinical Neuroscience, Centre for Psychiatry Research, Karolinska Institutet and Stockholm County Council, Stockholm, Sweden
- PET Science Centre, Precision Medicine and Genomics, IMED Biotech Unit, AstraZeneca, Karolinska Institutet, Stockholm, Sweden
| | - Magnus Schou
- Department of Clinical Neuroscience, Centre for Psychiatry Research, Karolinska Institutet and Stockholm County Council, Stockholm, Sweden
- PET Science Centre, Precision Medicine and Genomics, IMED Biotech Unit, AstraZeneca, Karolinska Institutet, Stockholm, Sweden
| | - Ana Vazquez-Romero
- Department of Clinical Neuroscience, Centre for Psychiatry Research, Karolinska Institutet and Stockholm County Council, Stockholm, Sweden
| | - Mohammad M Moein
- Department of Clinical Neuroscience, Centre for Psychiatry Research, Karolinska Institutet and Stockholm County Council, Stockholm, Sweden
| | - Christer Halldin
- Department of Clinical Neuroscience, Centre for Psychiatry Research, Karolinska Institutet and Stockholm County Council, Stockholm, Sweden
| | | | - Karthick Vishwanathan
- Quantitative Clinical Pharmacology, Early Clinical Development, IMED Biotech Unit, AstraZeneca, Waltham, MA, USA
| | - Lars Farde
- Department of Clinical Neuroscience, Centre for Psychiatry Research, Karolinska Institutet and Stockholm County Council, Stockholm, Sweden
- PET Science Centre, Precision Medicine and Genomics, IMED Biotech Unit, AstraZeneca, Karolinska Institutet, Stockholm, Sweden
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9
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Vermeulen K, Vandamme M, Bormans G, Cleeren F. Design and Challenges of Radiopharmaceuticals. Semin Nucl Med 2019; 49:339-356. [PMID: 31470930 DOI: 10.1053/j.semnuclmed.2019.07.001] [Citation(s) in RCA: 75] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
This review describes general concepts with regard to radiopharmaceuticals for diagnostic or therapeutic applications that help to understand the specific challenges encountered during the design, (radio)synthesis, in vitro and in vivo evaluation and clinical translation of novel radiopharmaceuticals. The design of a radiopharmaceutical requires upfront decisions with regard to combining a suitable vector molecule with an appropriate radionuclide, considering the type and location of the molecular target, the desired application, and the time constraints imposed by the relatively short half-life of radionuclides. Well-designed in vitro and in vivo experiments allow nonclinical validation of radiotracers. Ultimately, in combination with a limited toxicology package, the radiotracer becomes a radiopharmaceutical for clinical evaluation, produced in compliance with regulatory requirements for medicines for intravenous (IV) injection.
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Affiliation(s)
- Koen Vermeulen
- Laboratory for Radiopharmaceutical Research, Department of Pharmaceutical and Pharmacological Sciences, University of Leuven, Leuven, Belgium
| | - Mathilde Vandamme
- Laboratory for Radiopharmaceutical Research, Department of Pharmaceutical and Pharmacological Sciences, University of Leuven, Leuven, Belgium
| | - Guy Bormans
- Laboratory for Radiopharmaceutical Research, Department of Pharmaceutical and Pharmacological Sciences, University of Leuven, Leuven, Belgium.
| | - Frederik Cleeren
- Laboratory for Radiopharmaceutical Research, Department of Pharmaceutical and Pharmacological Sciences, University of Leuven, Leuven, Belgium
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10
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Suh M, Lee DS. Brain Theranostics and Radiotheranostics: Exosomes and Graphenes In Vivo as Novel Brain Theranostics. Nucl Med Mol Imaging 2018; 52:407-419. [PMID: 30538772 PMCID: PMC6261865 DOI: 10.1007/s13139-018-0550-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2018] [Revised: 09/10/2018] [Accepted: 10/05/2018] [Indexed: 12/17/2022] Open
Abstract
Brain disease is one of the greatest threats to public health. Brain theranostics is recently taking shape, indicating the treatments of stroke, inflammatory brain disorders, psychiatric diseases, neurodevelopmental disease, and neurodegenerative disease. However, several factors, such as lack of endophenotype classification, blood-brain barrier (BBB), target determination, ignorance of biodistribution after administration, and complex intercellular communication between brain cells, make brain theranostics application difficult, especially when it comes to clinical application. So, a more thorough understanding of each aspect is needed. In this review, we focus on recent studies regarding the role of exosomes in intercellular communication of brain cells, therapeutic effect of graphene quantum dots, transcriptomics/epitranscriptomics approach for target selection, and in vitro/in vivo considerations.
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Affiliation(s)
- Minseok Suh
- Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul, 03080 Republic of Korea
- Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, 03080 Republic of Korea
| | - Dong Soo Lee
- Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul, 03080 Republic of Korea
- Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, 03080 Republic of Korea
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11
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Plavén-Sigray P, Schain M, Zanderigo F, Rabiner EA, Gunn RN, Ogden RT, Cervenka S. Accuracy and reliability of [ 11C]PBR28 specific binding estimated without the use of a reference region. Neuroimage 2018; 188:102-110. [PMID: 30500425 DOI: 10.1016/j.neuroimage.2018.11.020] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2018] [Revised: 11/06/2018] [Accepted: 11/16/2018] [Indexed: 12/22/2022] Open
Abstract
[11C]PBR28 is a positron emission tomography radioligand used to examine the expression of the 18 kDa translocator protein (TSPO). TSPO is located in glial cells and can function as a marker for immune activation. Since TSPO is expressed throughout the brain, no true reference region exists. For this reason, an arterial input function is required for accurate quantification of [11C]PBR28 binding and the most common outcome measure is the total distribution volume (VT). Notably, VT reflects both specific binding and non-displaceable binding. Therefore, estimates of specific binding, such as binding potential (e.g. BPND) and specific distribution volume (VS) should theoretically be more sensitive to underlying differences in TSPO expression. It is unknown, however, if unbiased and accurate estimates of these outcome measures are obtainable for [11C]PBR28. The Simultaneous Estimation (SIME) method uses time-activity-curves from multiple brain regions with the aim to obtain a brain-wide estimate of the non-displaceable distribution volume (VND), which can subsequently be used to improve the estimation of BPND and VS. In this study we evaluated the accuracy of SIME-derived VND, and the reliability of resulting estimates of specific binding for [11C]PBR28, using a combination of simulation experiments and in vivo studies in healthy humans. The simulation experiments, based on data from 54 unique [11C]PBR28 examinations, showed that VND values estimated using SIME were both precise and accurate. Data from a pharmacological competition challenge (n = 5) showed that SIME provided VND values that were on average 19% lower than those obtained using the Lassen plot, but similar to values obtained using the Likelihood-Estimation of Occupancy technique. Test-retest data (n = 11) showed that SIME-derived VS values exhibited good reliability and precision, while larger variability was observed in SIME-derived BPND values. The results support the use of SIME for quantifying specific binding of [11C]PBR28, and suggest that VS can be used in complement to the conventional outcome measure VT. Additional studies in patient cohorts are warranted.
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Affiliation(s)
- Pontus Plavén-Sigray
- Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, & Stockholm Health Care Services, Stockholm County Council, Karolinska University Hospital, SE-171 76 Stockholm, Sweden.
| | - Martin Schain
- Neurobiology Research Unit, Copenhagen University Hospital, Copenhagen, Denmark
| | - Francesca Zanderigo
- Department of Psychiatry, Columbia University, New York, NY, USA; Molecular Imaging and Neuropathology Division, New York State Psychiatric Institute, New York, USA
| | | | | | - Roger N Gunn
- Invicro LLC, London, UK; Division of Brain Sciences, Imperial College London, London, UK
| | - R Todd Ogden
- Department of Psychiatry, Columbia University, New York, NY, USA; Molecular Imaging and Neuropathology Division, New York State Psychiatric Institute, New York, USA; Department of Biostatistics, Mailman School of Public Health, Columbia University, New York, USA
| | - Simon Cervenka
- Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, & Stockholm Health Care Services, Stockholm County Council, Karolinska University Hospital, SE-171 76 Stockholm, Sweden
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12
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Plavén-Sigray P, Matheson GJ, Collste K, Ashok AH, Coughlin JM, Howes OD, Mizrahi R, Pomper MG, Rusjan P, Veronese M, Wang Y, Cervenka S. Positron Emission Tomography Studies of the Glial Cell Marker Translocator Protein in Patients With Psychosis: A Meta-analysis Using Individual Participant Data. Biol Psychiatry 2018; 84:433-442. [PMID: 29653835 PMCID: PMC7893597 DOI: 10.1016/j.biopsych.2018.02.1171] [Citation(s) in RCA: 97] [Impact Index Per Article: 13.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2017] [Revised: 02/13/2018] [Accepted: 02/20/2018] [Indexed: 12/20/2022]
Abstract
BACKGROUND Accumulating evidence suggests that the immune system may be an important target for new treatment approaches in schizophrenia. Positron emission tomography and radioligands binding to the translocator protein (TSPO), which is expressed in glial cells in the brain including immune cells, represents a potential method for patient stratification and treatment monitoring. This study examined whether patients with first-episode psychosis and schizophrenia had altered TSPO levels compared with healthy control subjects. METHODS PubMed was searched for studies comparing patients with psychosis with healthy control subjects using second-generation TSPO radioligands. The outcome measure was total distribution volume (VT), an index of TSPO levels, in frontal cortex, temporal cortex, and hippocampus. Bayes factors (BFs) were applied to examine the relative support for higher, lower, or no difference in patients' TSPO levels compared with healthy control subjects. RESULTS Five studies, with 75 participants with first-episode psychosis or schizophrenia and 77 healthy control subjects, were included. BFs showed strong support for lower VT in patients relative to no difference (all BFs > 32), or relative to higher VT (all BFs > 422), in all brain regions. From the posterior distributions, mean patient-control differences in standardized VT values were -0.48 for frontal cortex (95% credible interval [CredInt] = -0.88 to 0.09), -0.47 for temporal cortex (CredInt = -0.87 to -0.07), and -0.63 for hippocampus (CredInt = -1.00 to -0.25). CONCLUSIONS The lower levels of TSPO observed in patients may correspond to altered function or lower density of brain immune cells. Future studies should focus on investigating the underlying biological mechanisms and their relevance for treatment.
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Affiliation(s)
- Pontus Plavén-Sigray
- Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet and Stockholm Health Care Services, Stockholm County Council, Stockholm, Sweden.
| | - Granville J Matheson
- Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet and Stockholm Health Care Services, Stockholm County Council, Stockholm, Sweden
| | - Karin Collste
- Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet and Stockholm Health Care Services, Stockholm County Council, Stockholm, Sweden
| | - Abhishekh H Ashok
- Institute of Psychiatry, Psychology, & Neuroscience, King's College London, London, United Kingdom; Medical Research Council London Institute of Medical Sciences, Hammersmith Hospital, London, United Kingdom; Institute of Clinical Sciences, Faculty of Medicine, Imperial College London, London, United Kingdom
| | - Jennifer M Coughlin
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins Medical Institutions, Baltimore, Maryland; Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins Medical Institutions, Baltimore, Maryland
| | - Oliver D Howes
- Institute of Psychiatry, Psychology, & Neuroscience, King's College London, London, United Kingdom; Medical Research Council London Institute of Medical Sciences, Hammersmith Hospital, London, United Kingdom; Institute of Clinical Sciences, Faculty of Medicine, Imperial College London, London, United Kingdom
| | - Romina Mizrahi
- Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada
| | - Martin G Pomper
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins Medical Institutions, Baltimore, Maryland; Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins Medical Institutions, Baltimore, Maryland
| | - Pablo Rusjan
- Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada
| | - Mattia Veronese
- Department of Neuroimaging, Institute of Psychiatry, Psychology, & Neuroscience, King's College London, London, United Kingdom
| | - Yuchuan Wang
- Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins Medical Institutions, Baltimore, Maryland
| | - Simon Cervenka
- Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet and Stockholm Health Care Services, Stockholm County Council, Stockholm, Sweden
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13
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Srinivas N, Maffuid K, Kashuba ADM. Clinical Pharmacokinetics and Pharmacodynamics of Drugs in the Central Nervous System. Clin Pharmacokinet 2018; 57:1059-1074. [PMID: 29464550 PMCID: PMC6062484 DOI: 10.1007/s40262-018-0632-y] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Despite contributing significantly to the burden of global disease, the translation of new treatment strategies for diseases of the central nervous system (CNS) from animals to humans remains challenging, with a high attrition rate in the development of CNS drugs. The failure of clinical trials for CNS therapies can be partially explained by factors related to pharmacokinetics/pharmacodynamics (PK/PD), such as lack of efficacy or improper selection of the initial dosage. A focused assessment is needed for CNS-acting drugs in first-in-human studies to identify the differences in PK/PD from animal models, as well as to choose the appropriate dose. In this review, we summarize the available literature from human studies on the PK and PD in brain tissue, cerebrospinal fluid, and interstitial fluid for drugs used in the treatment of psychosis, Alzheimer's disease and neuro-HIV, and address critical questions in the field. We also explore newer methods to characterize PK/PD relationships that may lead to more efficient dose selection in CNS drug development.
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Affiliation(s)
- Nithya Srinivas
- Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina, 1094 Genetic Medicine Building, CB# 7361, 120 Mason Farm Road, Chapel Hill, NC, 27599, USA
| | - Kaitlyn Maffuid
- Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina, 1094 Genetic Medicine Building, CB# 7361, 120 Mason Farm Road, Chapel Hill, NC, 27599, USA
| | - Angela D M Kashuba
- Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina, 1094 Genetic Medicine Building, CB# 7361, 120 Mason Farm Road, Chapel Hill, NC, 27599, USA.
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14
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Stott KE, Hope W. Pharmacokinetics–pharmacodynamics of antifungal agents in the central nervous system. Expert Opin Drug Metab Toxicol 2018; 14:803-815. [DOI: 10.1080/17425255.2018.1492551] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/28/2022]
Affiliation(s)
- Katharine E Stott
- Antimicrobial Pharmacodynamics and Therapeutics Laboratory, Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK
- Malawi-Liverpool-Wellcome Trust Clinical Research Programme, Blantyre, Malawi
| | - William Hope
- Antimicrobial Pharmacodynamics and Therapeutics Laboratory, Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK
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15
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Abstract
The dopamine (DA) system is considered to be centrally involved in the pathophysiology of several major psychiatric disorders. Using positron emission tomography (PET), aberrations in dopamine D2/D3-receptors (D2-R) levels and uptake of the DA precursor FDOPA have been shown for schizophrenia, substance abuse and depression. Radioligands for the dopamine D1-receptor (D1-R) have been available for more than three decades, however this receptor subtype has received much less attention in psychiatry research. Here, studies investigating D1-R in psychiatric patients in comparison to healthy control subjects are summarized. Although small sample sizes, medication effects and heterogeneous methods of quantification limit the conclusions that can be drawn, the data is suggestive of higher levels of cortical D1-R in drug naïve patients with psychosis, and lower D1-R in patients with affective disorders. Data sharing and reanalysis using harmonized methodology are important next steps towards clarifying the role of D1-R in these disorders.
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Affiliation(s)
- Simon Cervenka
- Department of Clinical Neuroscience, Center for Psychiatry Research, Karolinska Institutet and Stockholm County Council, SE-171 76 Stockholm, Sweden.
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16
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Donat CK, Mirzaei N, Tang SP, Edison P, Sastre M. Imaging of Microglial Activation in Alzheimer's Disease by [ 11C]PBR28 PET. Methods Mol Biol 2018; 1750:323-339. [PMID: 29512083 DOI: 10.1007/978-1-4939-7704-8_22] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/08/2023]
Abstract
Deficits in neuronal function and synaptic plasticity in Alzheimer's disease (AD) are believed to be linked to microglial activation. A hallmark of reactive microglia is the upregulation of mitochondrial translocator protein (TSPO) expression. Positron emission tomography (PET) is a nuclear imaging technique that measures the distribution of trace doses of radiolabeled compounds in the body over time. PET imaging using the 2nd generation TSPO tracer [11C]PBR28 provides an opportunity for accurate visualization and quantification of changes in microglial density in transgenic mouse models of Alzheimer's disease (AD). Here, we describe the methodology for the in vivo use of [11C]PBR28 in AD patients and the 5XFAD transgenic mouse model of AD and compare the results against healthy individuals and wild-type controls. To confirm the results, autoradiography with [3H]PBR28 and immunochemistry was carried out in the same mouse brains. Our data shows that [11C]PBR28 is suitable as a tool for in vivo monitoring of microglial activation and may be useful to assess treatment response in future studies.
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Affiliation(s)
- Cornelius K Donat
- Division of Brain Sciences, Imperial College London, Hammersmith Hospital, London, UK
| | - Nazanin Mirzaei
- Division of Brain Sciences, Imperial College London, Hammersmith Hospital, London, UK
| | | | - Paul Edison
- Division of Brain Sciences, Imperial College London, Hammersmith Hospital, London, UK
| | - Magdalena Sastre
- Division of Brain Sciences, Imperial College London, Hammersmith Hospital, London, UK.
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17
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Lower levels of the glial cell marker TSPO in drug-naive first-episode psychosis patients as measured using PET and [ 11C]PBR28. Mol Psychiatry 2017; 22:850-856. [PMID: 28194003 DOI: 10.1038/mp.2016.247] [Citation(s) in RCA: 74] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2016] [Revised: 09/30/2016] [Accepted: 11/22/2016] [Indexed: 11/08/2022]
Abstract
Several lines of evidence are indicative of a role for immune activation in the pathophysiology of schizophrenia. Nevertheless, studies using positron emission tomography (PET) and radioligands for the translocator protein (TSPO), a marker for glial activation, have yielded inconsistent results. Whereas early studies using a radioligand with low signal-to-noise in small samples showed increases in patients, more recent studies with improved methodology have shown no differences or trend-level decreases. Importantly, all patients investigated thus far have been on antipsychotic medication, and as these compounds may dampen immune cell activity, this factor limits the conclusions that can be drawn. Here, we examined 16 drug-naive, first-episode psychosis patients and 16 healthy controls using PET and the TSPO radioligand [11C]PBR28. Gray matter (GM) volume of distribution (VT) derived from a two-tissue compartmental analysis with arterial input function was the main outcome measure. Statistical analyses were performed controlling for both TSPO genotype, which is known to affect [11C]PBR28 binding, and gender. There was a significant reduction of [11C]PBR28 VT in patients compared with healthy controls in GM as well as in secondary regions of interest. No correlation was observed between GM VT and clinical or cognitive measures after correction for multiple comparisons. The observed decrease in TSPO binding suggests reduced numbers or altered function of immune cells in brain in early-stage schizophrenia.
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18
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PET microdosing of CNS drugs. Clin Transl Imaging 2017. [DOI: 10.1007/s40336-017-0226-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
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19
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Schain M, Kreisl WC. Neuroinflammation in Neurodegenerative Disorders—a Review. Curr Neurol Neurosci Rep 2017; 17:25. [DOI: 10.1007/s11910-017-0733-2] [Citation(s) in RCA: 187] [Impact Index Per Article: 23.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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20
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Khalil MM. Basics and Advances of Quantitative PET Imaging. BASIC SCIENCE OF PET IMAGING 2017:303-322. [DOI: 10.1007/978-3-319-40070-9_13] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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21
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Personalizing NSCLC therapy by characterizing tumors using TKI-PET and immuno-PET. Lung Cancer 2016; 107:1-13. [PMID: 27319335 DOI: 10.1016/j.lungcan.2016.05.025] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2016] [Revised: 05/20/2016] [Accepted: 05/29/2016] [Indexed: 12/24/2022]
Abstract
Non-small cell lung cancer (NSCLC) therapy has entered a rapidly advancing era of precision medicine with an ever increasing number of drugs directed against a variety of specific tumor targets. Amongst these new agents, tyrosine kinase inhibitors (TKIs) and monoclonal antibodies (mAbs) are most frequently used. However, as only a sensitive subgroup of patients benefits from targeting drugs, predictive biomarkers are needed. Positron emission tomography (PET) may offer such a biomarker for predicting therapy efficacy. Some of the TKIs and mAbs that are in clinical use can be radioactively labeled and used as tracers. PET can visualize and quantify tumor specific uptake of radiolabeled targeting drugs, allowing for characterization of their pharmacokinetic behavior. In this review, the clinical potential of PET using radiolabeled TKIs (TKI-PET) and mAbs (immuno-PET) in NSCLC is discussed, and an overview is provided of the most relevant preclinical and clinical studies.
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22
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Pike VW. Considerations in the Development of Reversibly Binding PET Radioligands for Brain Imaging. Curr Med Chem 2016; 23:1818-69. [PMID: 27087244 PMCID: PMC5579844 DOI: 10.2174/0929867323666160418114826] [Citation(s) in RCA: 143] [Impact Index Per Article: 15.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2016] [Revised: 04/04/2016] [Accepted: 04/15/2016] [Indexed: 12/17/2022]
Abstract
The development of reversibly binding radioligands for imaging brain proteins in vivo, such as enzymes, neurotransmitter transporters, receptors and ion channels, with positron emission tomography (PET) is keenly sought for biomedical studies of neuropsychiatric disorders and for drug discovery and development, but is recognized as being highly challenging at the medicinal chemistry level. This article aims to compile and discuss the main considerations to be taken into account by chemists embarking on programs of radioligand development for PET imaging of brain protein targets.
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Affiliation(s)
- Victor W Pike
- Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Rm. B3C346A, 10 Center Drive, Bethesda, MD 20892, USA.
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23
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Zeng Q, Wang J, Cheng Z, Chen K, Johnström P, Varnäs K, Li DY, Yang ZF, Zhang X. Discovery and Evaluation of Clinical Candidate AZD3759, a Potent, Oral Active, Central Nervous System-Penetrant, Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor. J Med Chem 2015; 58:8200-15. [DOI: 10.1021/acs.jmedchem.5b01073] [Citation(s) in RCA: 90] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Affiliation(s)
- Qingbei Zeng
- Innovation Center China, Asia & Emerging Markets iMed, AstraZeneca Innovative Medicines and Early Development, 199 Liangjing Road, Zhangjiang Hi-Tech Park, Shanghai 201203, China
| | - Jiabing Wang
- Innovation Center China, Asia & Emerging Markets iMed, AstraZeneca Innovative Medicines and Early Development, 199 Liangjing Road, Zhangjiang Hi-Tech Park, Shanghai 201203, China
| | - Ziqiang Cheng
- Innovation Center China, Asia & Emerging Markets iMed, AstraZeneca Innovative Medicines and Early Development, 199 Liangjing Road, Zhangjiang Hi-Tech Park, Shanghai 201203, China
| | - Kan Chen
- Innovation Center China, Asia & Emerging Markets iMed, AstraZeneca Innovative Medicines and Early Development, 199 Liangjing Road, Zhangjiang Hi-Tech Park, Shanghai 201203, China
| | - Peter Johnström
- AstraZeneca Translational Centre, Personal Healthcare and Biomarkers iMed, AstraZeneca R&D, Karolinska Institutet, Department of Clinical Neuroscience, R5:U1 Karolinska University Hospital, SE-171 76 Stockholm, Sweden
- Karolinska Institutet, Department of Clinical Neuroscience,
Centre for Psychiatry Research, R5:02 Karolinska University Hospital, SE-171 76 Stockholm, Sweden
| | - Katarina Varnäs
- Karolinska Institutet, Department of Clinical Neuroscience,
Centre for Psychiatry Research, R5:02 Karolinska University Hospital, SE-171 76 Stockholm, Sweden
| | - David Yunzhi Li
- Innovation Center China, Asia & Emerging Markets iMed, AstraZeneca Innovative Medicines and Early Development, 199 Liangjing Road, Zhangjiang Hi-Tech Park, Shanghai 201203, China
| | - Zhen Fan Yang
- Innovation Center China, Asia & Emerging Markets iMed, AstraZeneca Innovative Medicines and Early Development, 199 Liangjing Road, Zhangjiang Hi-Tech Park, Shanghai 201203, China
| | - Xiaolin Zhang
- Innovation Center China, Asia & Emerging Markets iMed, AstraZeneca Innovative Medicines and Early Development, 199 Liangjing Road, Zhangjiang Hi-Tech Park, Shanghai 201203, China
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24
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Improved simultaneous estimation of tracer kinetic models with artificial immune network based optimization method. Appl Radiat Isot 2015; 107:71-76. [PMID: 26433131 DOI: 10.1016/j.apradiso.2015.09.012] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2015] [Accepted: 09/21/2015] [Indexed: 11/20/2022]
Abstract
Tracer kinetic modeling (TKM) is a promising quantitative method for physiological and biochemical processes in vivo. In this paper, we investigated the applications of an immune-inspired method to better address the issues of Simultaneous Estimation (SIME) of TKM with multimodal optimization. Experiments of dynamic FDG PET imaging experiments and simulation studies were carried out. The proposed artificial immune network (TKM_AIN) shows more scalable and effective when compared with the gradient-based Marquardt-Levenberg algorithm and the scholastic-based simulated annealing method.
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25
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Abstract
![]()
Decades after its discovery, positron emission tomography (PET)
remains the premier tool for imaging neurochemistry in living humans.
Technological improvements in radiolabeling methods, camera design,
and image analysis have kept PET in the forefront. In addition, the
use of PET imaging has expanded because researchers have developed
new radiotracers that visualize receptors, transporters, enzymes,
and other molecular targets within the human brain. However,
of the thousands of proteins in the central nervous system
(CNS), researchers have successfully imaged fewer than 40 human proteins.
To address the critical need for new radiotracers, this Account expounds
on the decisions, strategies, and pitfalls of CNS radiotracer development
based on our current experience in this area. We discuss the
five key components of radiotracer development for
human imaging: choosing a biomedical question, selection of a biological
target, design of the radiotracer chemical structure, evaluation of
candidate radiotracers, and analysis of preclinical imaging. It is
particularly important to analyze the market of scientists or companies
who might use a new radiotracer and carefully select a relevant biomedical
question(s) for that audience. In the selection of a specific biological
target, we emphasize how target localization and identity can constrain
this process and discuss the optimal target density and affinity ratios
needed for binding-based radiotracers. In addition, we discuss various
PET test–retest variability requirements for monitoring changes
in density, occupancy, or functionality for new radiotracers. In the synthesis of new radiotracer structures, high-throughput,
modular syntheses have proved valuable, and these processes provide
compounds with sites for late-stage radioisotope installation. As
a result, researchers can manage the time constraints associated with
the limited half-lives of isotopes. In order to evaluate brain uptake,
a number of methods are available to predict bioavailability, blood–brain
barrier (BBB) permeability, and the associated issues of nonspecific
binding and metabolic stability. To evaluate the synthesized chemical
library, researchers need to consider high-throughput affinity assays,
the analysis of specific binding, and the importance of fast binding
kinetics. Finally, we describe how we initially assess preclinical
radiotracer imaging, using brain uptake, specific binding, and preliminary
kinetic analysis to identify promising radiotracers that may be useful
for human brain imaging. Although we discuss these five design components
separately and linearly in this Account, in practice we develop new
PET-based radiotracers using these design components nonlinearly and
iteratively to develop new compounds in the most efficient way possible.
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Affiliation(s)
- Genevieve C. Van de Bittner
- Athinoula
A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, United States
| | - Emily L. Ricq
- Athinoula
A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, United States
- Department
of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, United States
| | - Jacob M. Hooker
- Athinoula
A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, United States
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26
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Sai KKS, Fan J, Tu Z, Zerkel P, Mach RH, Kharasch ED. Automated radiochemical synthesis and biodistribution of [¹¹C]l-α-acetylmethadol ([¹¹C]LAAM). Appl Radiat Isot 2014; 91:135-40. [PMID: 24935116 DOI: 10.1016/j.apradiso.2014.05.019] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2013] [Revised: 03/18/2014] [Accepted: 05/20/2014] [Indexed: 12/25/2022]
Abstract
Long-acting opioid agonists methadone and l-α-acetylmethadol (LAAM) prevent withdrawal in opioid-dependent persons. Attempts to synthesize [(11)C]-methadone for PET evaluation of brain disposition were unsuccessful. Owing, however, to structural and pharmacologic similarities, we aimed to develop [(11)C]LAAM as a PET ligand to probe the brain exposure of long-lasting opioids in humans. This manuscript describes [(11)C]LAAM synthesis and its biodistribution in mice. The radiochemical synthetic strategy afforded high radiochemical yield, purity and specific activity, thereby making the synthesis adaptable to automated modules.
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Affiliation(s)
- Kiran Kumar Solingapuram Sai
- Department of Radiology, Washington University in St. Louis, St. Louis, MO 63110, USA; Department of Radiology, Wake Forest School of Medicine, 1 Medical Center Blvd, Winston Salem, NC 27157, USA
| | - Jinda Fan
- Department of Radiology, Washington University in St. Louis, St. Louis, MO 63110, USA; Department of Radiology, University of Alabama School of Medicine, 720 2nd Ave S, Birmingham, AL 35294, USA
| | - Zhude Tu
- Department of Radiology, Washington University in St. Louis, St. Louis, MO 63110, USA
| | - Patrick Zerkel
- Department of Radiology, Washington University in St. Louis, St. Louis, MO 63110, USA
| | - Robert H Mach
- Department of Radiology, Washington University in St. Louis, St. Louis, MO 63110, USA; Department of Radiology, Perelman School of Medicine, University of Pennsylvania, 231 S. 34th Street, Philadelphia, PA 19104, USA
| | - Evan D Kharasch
- Department of Anesthesiology, and Department of Biochemistry and Molecular Biophysics, Washington University in St. Louis, 660 S. Euclid Ave., Campus Box 8054, St. Louis, MO 63110, USA.
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27
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Fehler SK, Maschauer S, Höfling SB, Bartuschat AL, Tschammer N, Hübner H, Gmeiner P, Prante O, Heinrich MR. Fast and efficient (18) F-labeling by [(18) f]fluorophenylazocarboxylic esters. Chemistry 2013; 20:370-5. [PMID: 24339325 DOI: 10.1002/chem.201303409] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2013] [Indexed: 01/19/2023]
Abstract
Introduction of [(18) F]fluoride ion into the aromatic core of phenylazocarboxylic esters was achieved in only 30 seconds, with radiochemical yields of up to 95 % (85(±10) %). For labeling purposes, the resulting (18) F-substituted azoester can be further converted in radical-arylation reactions to give biaryls, or in substitutions at its carbonyl unit to produce azocarboxamides.
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Affiliation(s)
- Stefanie K Fehler
- Abteilung für Chemie und Pharmazie, Pharmazeutische Chemie, Friedrich-Alexander-Universität Erlangen-Nürnberg, Schuhstrasse 19, 91052 Erlangen (Germany)
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