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Shegani A, Kealey S, Luzi F, Basagni F, Machado JDM, Ekici SD, Ferocino A, Gee AD, Bongarzone S. Radiosynthesis, Preclinical, and Clinical Positron Emission Tomography Studies of Carbon-11 Labeled Endogenous and Natural Exogenous Compounds. Chem Rev 2023; 123:105-229. [PMID: 36399832 PMCID: PMC9837829 DOI: 10.1021/acs.chemrev.2c00398] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Indexed: 11/19/2022]
Abstract
The presence of positron emission tomography (PET) centers at most major hospitals worldwide, along with the improvement of PET scanner sensitivity and the introduction of total body PET systems, has increased the interest in the PET tracer development using the short-lived radionuclides carbon-11. In the last few decades, methodological improvements and fully automated modules have allowed the development of carbon-11 tracers for clinical use. Radiolabeling natural compounds with carbon-11 by substituting one of the backbone carbons with the radionuclide has provided important information on the biochemistry of the authentic compounds and increased the understanding of their in vivo behavior in healthy and diseased states. The number of endogenous and natural compounds essential for human life is staggering, ranging from simple alcohols to vitamins and peptides. This review collates all the carbon-11 radiolabeled endogenous and natural exogenous compounds synthesised to date, including essential information on their radiochemistry methodologies and preclinical and clinical studies in healthy subjects.
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Affiliation(s)
- Antonio Shegani
- School
of Biomedical Engineering & Imaging Sciences, King’s College London, King’s Health Partners, St Thomas’ Hospital, London SE1 7EH, United Kingdom
| | - Steven Kealey
- School
of Biomedical Engineering & Imaging Sciences, King’s College London, King’s Health Partners, St Thomas’ Hospital, London SE1 7EH, United Kingdom
| | - Federico Luzi
- School
of Biomedical Engineering & Imaging Sciences, King’s College London, King’s Health Partners, St Thomas’ Hospital, London SE1 7EH, United Kingdom
| | - Filippo Basagni
- Department
of Pharmacy and Biotechnology, Alma Mater
Studiorum−University of Bologna, via Belmeloro 6, 40126 Bologna, Italy
| | - Joana do Mar Machado
- School
of Biomedical Engineering & Imaging Sciences, King’s College London, King’s Health Partners, St Thomas’ Hospital, London SE1 7EH, United Kingdom
| | - Sevban Doğan Ekici
- School
of Biomedical Engineering & Imaging Sciences, King’s College London, King’s Health Partners, St Thomas’ Hospital, London SE1 7EH, United Kingdom
| | - Alessandra Ferocino
- Institute
of Organic Synthesis and Photoreactivity, Italian National Research Council, via Piero Gobetti 101, 40129 Bologna, Italy
| | - Antony D. Gee
- School
of Biomedical Engineering & Imaging Sciences, King’s College London, King’s Health Partners, St Thomas’ Hospital, London SE1 7EH, United Kingdom
| | - Salvatore Bongarzone
- School
of Biomedical Engineering & Imaging Sciences, King’s College London, King’s Health Partners, St Thomas’ Hospital, London SE1 7EH, United Kingdom
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Yang KC, Takano A, Halldin C, Farde L, Finnema SJ. Serotonin concentration enhancers at clinically relevant doses reduce [ 11C]AZ10419369 binding to the 5-HT 1B receptors in the nonhuman primate brain. Transl Psychiatry 2018; 8:132. [PMID: 30013068 PMCID: PMC6048172 DOI: 10.1038/s41398-018-0178-7] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2017] [Revised: 02/14/2018] [Accepted: 04/03/2018] [Indexed: 12/25/2022] Open
Abstract
The serotonin (5-HT) system plays an important role in the pathophysiology and treatment of several major psychiatric disorders. Currently, no suitable positron emission tomography (PET) imaging paradigm is available to assess 5-HT release in the living human brain. [11C]AZ10419369 binds to 5-HT1B receptors and is one of the most 5-HT-sensitive radioligands available. This study applied 5-HT concentration enhancers which can be safely studied in humans, and examined their effect on [11C]AZ10419369 binding at clinically relevant doses, including amphetamine (1 mg/kg), 3,4-methylenedioxymethamphetamine (MDMA; 1 mg/kg) or 5-hydroxy-L-tryptophan (5-HTP; 5 mg/kg). Twenty-six PET measurements (14 for amphetamine, 6 for MDMA and 6 for 5-HTP) using a bolus and constant infusion protocol were performed in four cynomolgus monkeys before or after drug administration. Binding potential (BPND) values were determined with the equilibrium method (integral interval: 63-123 min) using cerebellum as the reference region. BPND values were significantly decreased in several examined brain regions after administration of amphetamine (range: 19-31%), MDMA (16-25%) or 5-HTP (13-31%). Reductions in [11C]AZ10419369 binding were greater in striatum than cortical regions after administration of 5-HTP, while no prominent regional differences were found for amphetamine and MDMA. In conclusion, [11C]AZ10419369 binding is sensitive to changes in 5-HT concentration induced by amphetamine, MDMA or 5-HTP. The robust changes in BPND, following pretreatment drugs administered at clinically relevant doses, indicate that the applied PET imaging paradigms hold promise to be successfully used in future human studies.
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Affiliation(s)
- Kai-Chun Yang
- Department of Clinical Neuroscience, Center for Psychiatric Research, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
| | - Akihiro Takano
- Department of Clinical Neuroscience, Center for Psychiatric Research, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Christer Halldin
- Department of Clinical Neuroscience, Center for Psychiatric Research, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Lars Farde
- Department of Clinical Neuroscience, Center for Psychiatric Research, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
- Personalized Health Care and Biomarkers, AstraZeneca PET Science Center at Karolinska Institutet, Stockholm, Sweden
| | - Sjoerd J Finnema
- Department of Clinical Neuroscience, Center for Psychiatric Research, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
- Department of Radiology and Biomedical Imaging, Yale University, New Haven, CT, USA
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Furmark T, Marteinsdottir I, Frick A, Heurling K, Tillfors M, Appel L, Antoni G, Hartvig P, Fischer H, Långström B, Eriksson E, Fredrikson M. Serotonin synthesis rate and the tryptophan hydroxylase-2: G-703T polymorphism in social anxiety disorder. J Psychopharmacol 2016; 30:1028-35. [PMID: 27189957 DOI: 10.1177/0269881116648317] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
It is disputed whether anxiety disorders, like social anxiety disorder, are characterized by serotonin over- or underactivity. Here, we evaluated whether our recent finding of elevated neural serotonin synthesis rate in patients with social anxiety disorder could be reproduced in a separate cohort, and whether allelic variation in the tryptophan hydroxylase-2 (TPH2) G-703T polymorphism relates to differences in serotonin synthesis assessed with positron emission tomography. Eighteen social anxiety disorder patients and six healthy controls were scanned during 60 minutes in a resting state using positron emission tomography and 5-hydroxy-L-[β -(11)C]tryptophan, [(11)C]5-HTP, a substrate of the second enzymatic step in serotonin synthesis. Parametric images were generated, using the reference Patlak method, and analysed using Statistical Parametric Mapping (SPM8). Blood samples for genotyping of the TPH2 G-703T polymorphism were obtained from 16 social anxiety disorder patients (T carriers: n=5, GG carriers: n=11). A significantly elevated [(11)C]5-HTP accumulation rate, indicative of enhanced decarboxylase activity and thereby serotonin synthesis capacity, was detected in social anxiety disorder patients compared with controls in the hippocampus and basal ganglia nuclei and, at a more lenient (uncorrected) statistical threshold, in the amygdala and anterior cingulate cortex. In patients, the serotonin synthesis rate in the amygdala and anterior cingulate cortex was significantly elevated in TPH2 T carriers in comparison with GG homozygotes. Our results support that social anxiety disorder entails an overactive presynaptic serotonergic system that, in turn, seems functionally influenced by the TPH2 G-703T polymorphism in emotionally relevant brain regions.
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Affiliation(s)
- Tomas Furmark
- Department of Psychology, Uppsala University, Uppsala, Sweden
| | - Ina Marteinsdottir
- Centre for Social and Affective Neuroscience, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden
| | - Andreas Frick
- Department of Psychology, Uppsala University, Uppsala, Sweden
| | - Kerstin Heurling
- Section of Nuclear Medicine and PET, Department of Surgical Sciences, Uppsala University, Uppsala, Sweden
| | - Maria Tillfors
- Centre for Health and Medical Psychology, Örebro University, Örebro, Sweden
| | - Lieuwe Appel
- Section of Nuclear Medicine and PET, Department of Surgical Sciences, Uppsala University, Uppsala, Sweden
| | - Gunnar Antoni
- Department of Medicinal Chemistry, Uppsala University, Uppsala, Sweden
| | - Per Hartvig
- Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark
| | - Håkan Fischer
- Department of Psychology, Stockholm University, Stockholm, Sweden
| | - Bengt Långström
- Department of Chemistry, Uppsala University, Uppsala, Sweden Odense University Hospital, Southern Denmark University, Odense, Denmark
| | - Elias Eriksson
- Department of Pharmacology, Göteborg University, Göteborg, Sweden
| | - Mats Fredrikson
- Department of Psychology, Uppsala University, Uppsala, Sweden Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden
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Li J, Karunananthan J, Pelham B, Kandeel F. Imaging pancreatic islet cells by positron emission tomography. World J Radiol 2016; 8:764-774. [PMID: 27721939 PMCID: PMC5039672 DOI: 10.4329/wjr.v8.i9.764] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2015] [Revised: 04/15/2016] [Accepted: 08/08/2016] [Indexed: 02/06/2023] Open
Abstract
It was estimated that every year more than 30000 persons in the United States - approximately 80 people per day - are diagnosed with type 1 diabetes (T1D). T1D is caused by autoimmune destruction of the pancreatic islet (β cells) cells. Islet transplantation has become a promising therapy option for T1D patients, while the lack of suitable tools is difficult to directly evaluate of the viability of the grafted islet over time. Positron emission tomography (PET) as an important non-invasive methodology providing high sensitivity and good resolution, is able to accurate detection of the disturbed biochemical processes and physiological abnormality in living organism. The successful PET imaging of islets would be able to localize the specific site where transplanted islets engraft in the liver, and to quantify the level of islets remain alive and functional over time. This information would be vital to establishing and evaluating the efficiency of pancreatic islet transplantation. Many novel imaging agents have been developed to improve the sensitivity and specificity of PET islet imaging. In this article, we summarize the latest developments in carbon-11, fluorine-18, copper-64, and gallium-68 labeled radioligands for the PET imaging of pancreatic islet cells.
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Eriksson O, Espes D, Selvaraju RK, Jansson E, Antoni G, Sörensen J, Lubberink M, Biglarnia AR, Eriksson JW, Sundin A, Ahlström H, Eriksson B, Johansson L, Carlsson PO, Korsgren O. Positron emission tomography ligand [11C]5-hydroxy-tryptophan can be used as a surrogate marker for the human endocrine pancreas. Diabetes 2014; 63:3428-37. [PMID: 24848067 DOI: 10.2337/db13-1877] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
In humans, a well-developed serotonin system is localized to the pancreatic islets while being absent in exocrine pancreas. Assessment of pancreatic serotonin biosynthesis could therefore be used to estimate the human endocrine pancreas. Proof of concept was tested in a prospective clinical trial by comparisons of type 1 diabetic (T1D) patients, with extensive reduction of β-cells, with healthy volunteers (HVs). C-peptide-negative (i.e., insulin-deficient) T1D subjects (n = 10) and HVs (n = 9) underwent dynamic positron emission tomography with the radiolabeled serotonin precursor [(11)C]5-hydroxy-tryptophan ([(11)C]5-HTP). A significant accumulation of [(11)C]5-HTP was obtained in the pancreas of the HVs, with large interindividual variation. A substantial and highly significant reduction (66%) in the pancreatic uptake of [(11)C]5-HTP in T1D subjects was observed, and this was most evident in the corpus and caudal regions of the pancreas where β-cells normally are the major constituent of the islets. [(11)C]5-HTP retention in the pancreas was reduced in T1D compared with nondiabetic subjects. Accumulation of [(11)C]5-HTP in the pancreas of both HVs and subjects with T1D was in agreement with previously reported morphological observations on the β-cell volume, implying that [(11)C]5-HTP retention is a useful noninvasive surrogate marker for the human endocrine pancreas.
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Affiliation(s)
- Olof Eriksson
- Department of Medicinal Chemistry, Preclinical PET Platform, Uppsala University, Uppsala, Sweden
| | - Daniel Espes
- Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden
| | - Ram K Selvaraju
- Department of Medicinal Chemistry, Preclinical PET Platform, Uppsala University, Uppsala, Sweden
| | - Emma Jansson
- Department of Radiology, Oncology, and Radiation Sciences, Uppsala University, Uppsala, Sweden
| | - Gunnar Antoni
- Department of Radiology, Oncology, and Radiation Sciences, Uppsala University, Uppsala, Sweden
| | - Jens Sörensen
- Department of Radiology, Oncology, and Radiation Sciences, Uppsala University, Uppsala, Sweden
| | - Mark Lubberink
- Department of Radiology, Oncology, and Radiation Sciences, Uppsala University, Uppsala, Sweden
| | | | - Jan W Eriksson
- AstraZeneca R&D, Mölndal, Sweden Department of Medical Sciences, Uppsala University, Uppsala, Sweden
| | - Anders Sundin
- Department of Radiology, Oncology, and Radiation Sciences, Uppsala University, Uppsala, Sweden
| | - Håkan Ahlström
- Department of Radiology, Oncology, and Radiation Sciences, Uppsala University, Uppsala, Sweden
| | - Barbro Eriksson
- Department of Medical Sciences, Uppsala University, Uppsala, Sweden
| | - Lars Johansson
- Department of Radiology, Oncology, and Radiation Sciences, Uppsala University, Uppsala, Sweden AstraZeneca R&D, Mölndal, Sweden
| | - Per-Ola Carlsson
- Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden Department of Medical Sciences, Uppsala University, Uppsala, Sweden
| | - Olle Korsgren
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
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Eriksson O, Selvaraju RK, Johansson L, Eriksson JW, Sundin A, Antoni G, Sörensen J, Eriksson B, Korsgren O. Quantitative imaging of serotonergic biosynthesis and degradation in the endocrine pancreas. J Nucl Med 2014; 55:460-5. [PMID: 24525204 DOI: 10.2967/jnumed.113.125187] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
UNLABELLED Serotonergic biosynthesis in the endocrine pancreas, of which the islets of Langerhans is the major constituent, has been implicated in insulin release and β cell proliferation. In this study, we investigated the feasibility of quantitative noninvasive imaging of the serotonergic metabolism in the pancreas using the PET tracer (11)C-5-hydroxy-l-tryptophan ((11)C-5-HTP). METHODS Uptake of (11)C-5-HTP, and its specificity for key enzymes in the serotonergic metabolic pathway, was assessed in vitro (INS-1 and PANC1 cells and human islet and exocrine preparations) and in vivo (nonhuman primates and healthy and diabetic rats). RESULTS In vitro tracer uptake in endocrine cells (INS-1 and human islets), but not PANC1 and exocrine cells, was mediated specifically by intracellular conversion into serotonin. Pancreatic uptake of (11)C-5-HTP in nonhuman primates was markedly decreased by inhibition of the enzyme dopa decarboxylase, which converts (11)C-5-HTP to (11)C-serotonin and increased after inhibition of monoamine oxidase-A, the main enzyme responsible for serotonin degradation. Uptake in the rat pancreas was similarly modulated by inhibition of monoamine oxidase-A and was reduced in animals with induced diabetes. CONCLUSION The PET tracer (11)C-5-HTP can be used for quantitative imaging of the serotonergic system in the endocrine pancreas.
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Affiliation(s)
- Olof Eriksson
- Department of Medicinal Chemistry, Preclinical PET Platform, Uppsala University, Uppsala, Sweden
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Visser AKD, Ramakrishnan NK, Willemsen ATM, Di Gialleonardo V, de Vries EFJ, Kema IP, Dierckx RAJO, van Waarde A. [(11)C]5-HTP and microPET are not suitable for pharmacodynamic studies in the rodent brain. J Cereb Blood Flow Metab 2014; 34:118-25. [PMID: 24084697 PMCID: PMC3887351 DOI: 10.1038/jcbfm.2013.171] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2013] [Revised: 08/08/2013] [Accepted: 09/02/2013] [Indexed: 11/09/2022]
Abstract
The PET tracer [(11)C]5-hydroxytryptophan ([(11)C]5-HTP), which is converted to [(11)C]5-hydroxytryptamine ([(11)C]5-HT) by aromatic amino acid decarboxylase (AADC), is thought to measure 5-HT synthesis rates. But can we measure these synthesis rates by kinetic modeling of [(11)C]5-HTP in rat? Male rats were scanned with [(11)C]5-HTP (60 minutes) after different treatments. Scans included arterial blood sampling and metabolite analysis. 5-HT synthesis rates were calculated by a two-tissue compartment model (2TCM) with irreversible tracer trapping or Patlak analysis. Carbidopa (inhibitor peripheral AADC) dose-dependently increased [(11)C]5-HTP brain uptake, but did not influence 2TCM parameters. Therefore, 10 mg/kg carbidopa was applied in all subsequent study groups. These groups included treatment with NSD 1015 (general AADC inhibitor) or p-chlorophenylalanine (PCPA, inhibitor of tryptophan hydroxylase, TPH). In addition, the effect of a low-tryptophan (Trp) diet was investigated. NSD 1015 or Trp depletion did not affect any model parameters, but PCPA reduced [(11)C]5-HTP uptake, and the k3. This was unexpected as NSD 1015 directly inhibits the enzyme converting [(11)C]5-HTP to [(11)C]5-HT, suggesting that trapping of radioactivity does not distinguish between parent tracer and its metabolites. As different results have been acquired in monkeys and humans, [(11)C]5-HTP-PET may be suitable for measuring 5-HT synthesis in primates, but not in rodents.
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Affiliation(s)
- Anniek K D Visser
- Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Nisha K Ramakrishnan
- Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Antoon T M Willemsen
- Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Valentina Di Gialleonardo
- 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
| | - Ido P Kema
- Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Rudi A J O Dierckx
- Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Aren van Waarde
- Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
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Eriksson O, Selvaraju R, Borg B, Asplund V, Estrada S, Antoni G. 5-Fluoro-[β-11C]-L-tryptophan is a functional analogue of 5-hydroxy-[β-11C]-L-tryptophan in vitro but not in vivo. Nucl Med Biol 2013; 40:567-75. [DOI: 10.1016/j.nucmedbio.2013.02.005] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2012] [Revised: 01/21/2013] [Accepted: 02/04/2013] [Indexed: 11/29/2022]
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Takano H, Ito H, Takahashi H, Arakawa R, Okumura M, Kodaka F, Otsuka T, Kato M, Suhara T. Serotonergic neurotransmission in the living human brain: A positron emission tomography study using [11C]dasb and [11C]WAY100635 in young healthy men. Synapse 2011; 65:624-33. [DOI: 10.1002/syn.20883] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2010] [Accepted: 11/10/2010] [Indexed: 12/21/2022]
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Measuring serotonin synthesis: from conventional methods to PET tracers and their (pre)clinical implications. Eur J Nucl Med Mol Imaging 2010; 38:576-91. [PMID: 21113591 PMCID: PMC3034914 DOI: 10.1007/s00259-010-1663-2] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2010] [Accepted: 11/01/2010] [Indexed: 12/20/2022]
Abstract
The serotonergic system of the brain is complex, with an extensive innervation pattern covering all brain regions and endowed with at least 15 different receptors (each with their particular distribution patterns), specific reuptake mechanisms and synthetic processes. Many aspects of the functioning of the serotonergic system are still unclear, partially because of the difficulty of measuring physiological processes in the living brain. In this review we give an overview of the conventional methods of measuring serotonin synthesis and methods using positron emission tomography (PET) tracers, more specifically with respect to serotonergic function in affective disorders. Conventional methods are invasive and do not directly measure synthesis rates. Although they may give insight into turnover rates, a more direct measurement may be preferred. PET is a noninvasive technique which can trace metabolic processes, like serotonin synthesis. Tracers developed for this purpose are α-[11C]methyltryptophan ([11C]AMT) and 5-hydroxy-L-[β-11C]tryptophan ([11C]5-HTP). Both tracers have advantages and disadvantages. [11C]AMT can enter the kynurenine pathway under inflammatory conditions (and thus provide a false signal), but this tracer has been used in many studies leading to novel insights regarding antidepressant action. [11C]5-HTP is difficult to produce, but trapping of this compound may better represent serotonin synthesis. AMT and 5-HTP kinetics are differently affected by tryptophan depletion and changes of mood. This may indicate that both tracers are associated with different enzymatic processes. In conclusion, PET with radiolabelled substrates for the serotonergic pathway is the only direct way to detect changes of serotonin synthesis in the living brain.
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Yamamoto S, Onoe H, Tsukada H, Watanabe Y. Effects of increased endogenous serotonin on the in vivo binding of [11C]DASB to serotonin transporters in conscious monkey brain. Synapse 2007; 61:724-31. [PMID: 17559093 DOI: 10.1002/syn.20422] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
Using a combination of positron emission tomography (PET) and the microdialysis technique, the effects of increased endogenous serotonin (5-hydroxytryptamine; 5-HT) on the binding of [(11)C]DASB to 5-HT transporters (5-HTT) were investigated in the conscious monkey brain. Five rhesus monkeys (Macaca mulatta) were scanned with [(11)C]DASB under the control condition and the increased endogenous 5-HT condition, in which 5-hydroxy-L-tryptophan (5-HTP) was administered (20 mg/kg, i.v.) before the PET scan. Compared with the control scan, the 5-HTP administration significantly decreased the binding potential (BP) (BP = B(max)/K(d)) of [(11)C]DASB in several brain regions. The mean % decrease of BP was biggest in the caudate and putamen. Two monkeys were scanned with [(11)C]5-HTP to assess the amino acid decarboxylase (AADC) activity in the brain, resulting in the high activity in the caudate and putamen. Microdialysis measurements showed that although 5-HTP administration (20 mg/kg, i.v.) increased the extracellular 5-HT levels in both the prefrontal cortex and caudate, the increase of the 5-HT level in the caudate was 27 times higher than that in the prefrontal cortex. These results suggest that the caudate and putamen, both of which show high AADC activity, convert 5-HTP to 5-HT at a high rate, and the increased 5-HT competes with [(11)C]DASB for the 5-HTT.
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Affiliation(s)
- Shigeyuki Yamamoto
- Department of Physiology, Osaka City University Graduate School of Medicine, Abeno-ku, Osaka, Japan.
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Lundquist P, Hartvig P, Blomquist G, Hammarlund-Udenaes M, Långström B. 5-Hydroxy-L-[beta-11C]tryptophan versus alpha-[11C]methyl-L-tryptophan for positron emission tomography imaging of serotonin synthesis capacity in the rhesus monkey brain. J Cereb Blood Flow Metab 2007; 27:821-30. [PMID: 16896348 DOI: 10.1038/sj.jcbfm.9600381] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
The purpose of this study was to compare two positron emission tomography (PET) tracers that were developed to follow serotonin (5HT) synthesis by performing sequential PET scanning of the same rhesus monkey (n=4) on the same day. alpha-[11C]Methyl-L-tryptophan ([11C]AMT) and 5-Hydroxy-L-[beta-11C]tryptophan ([11C]HTP) are substrates in the first and second enzymatic steps, respectively, in the biosynthesis of 5HT. Regional net accumulation rate constants were derived from kinetic (two-tissue compartment model with irreversible tracer trapping) and graphic (Patlak) analyses, using the arterial plasma concentrations as input. The kinetic data analysis showed that the rate constant for the transfer of [11C]HTP into the brain (K1) was higher than that for [11C]AMT in the striatum and thalamus but was similar in other brain regions. The rate constant for tracer trapping (k3) was also higher for [11C]HTP than for [11C]AMT in the striatum (0.046+/-0.024 versus 0.019+/-0.006 min(-1)) and thalamus (0.039+/-0.013 versus 0.016+/-0.007 min(-1)). In agreement with previously reported regional HTP accumulation rates, the net accumulation rate constant (K(acc)) for [11C]HTP was also higher in these regions than in other brain regions; this is in contrast to the uniform distribution of [11C]AMT K(acc) values. This suggests that the regional net accumulation rates obtained with these two PET tracers will be of different magnitude, which might be related to the activity of each targeted enzyme.
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Affiliation(s)
- Pinelopi Lundquist
- Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy, Uppsala University, Uppsala, Sweden.
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13
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Johansson A, Engler H, Blomquist G, Scott B, Wall A, Aquilonius SM, Långström B, Askmark H. Evidence for astrocytosis in ALS demonstrated by [11C](L)-deprenyl-D2 PET. J Neurol Sci 2007; 255:17-22. [PMID: 17346749 DOI: 10.1016/j.jns.2007.01.057] [Citation(s) in RCA: 104] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2006] [Revised: 01/19/2007] [Accepted: 01/23/2007] [Indexed: 12/11/2022]
Abstract
OBJECTIVE To use deuterium-substituted [11C](L)-deprenyl PET to depict astrocytosis in vivo in patients with amyotrophic lateral sclerosis (ALS). BACKGROUND In human brain, the enzyme MAO-B is primarily located in astrocytes. L-deprenyl binds to MAO-B and autoradiography with 3H-L-deprenyl has been used to map astrocytosis in vitro. Motor neuron loss in ALS is accompanied by astrocytosis and astrocytes may play an active role in the neurodegenerative process. Deuterium-substituted [11C](L)-deprenyl PET provides an opportunity to localize astrocytosis in vivo in the brain of patients with ALS. METHODS Deuterium-substituted [11C](L)-deprenyl PET was performed in seven patients with ALS and seven healthy control subjects. RESULTS Increased uptake rate of [11C](L)-deprenyl was demonstrated in ALS in pons and white matter. CONCLUSION This study provides evidence that astrocytosis may be detected in vivo in ALS by the use of deuterium-substituted [11C](L)-deprenyl PET though further studies are needed to determine whether deuterium-substituted [11C](L)-deprenyl binding tracks disease progression and reflects astrocytosis.
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Affiliation(s)
- Anders Johansson
- Department of Neurology, University Hospital, S-751 85 Uppsala, Sweden.
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