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Synthesis and evaluation of [¹¹C]Cimbi-806 as a potential PET ligand for 5-HT₇ receptor imaging

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@article{265196273a544e6093ca46ef38bc7936,
title = "Synthesis and evaluation of [¹¹C]Cimbi-806 as a potential PET ligand for 5-HT₇ receptor imaging",
abstract = "2-(2',6'-Dimethoxy-[1,1'-biphenyl]-3-yl)-N,N-dimethylethanamine has been identified as a potent ligand for the serotonin 7 (5-HT(7)) receptor. In this study, we describe the synthesis, radiolabeling and in vivo evaluation of [(11)C]2-(2',6'-dimethoxy-[1,1'-biphenyl]-3-yl)-N,N-dimethylethanamine ([(11)C]Cimbi-806) as a radioligand for imaging brain 5-HT(7) receptors with positron emission tomography (PET). Precursor and reference compound was synthesized and subsequent (11)C-labelling with [(11)C]methyltriflate produced [(11)C]Cimbi-806 in specific activities ranging from 50 to 300 GBq/μmol. Following intravenous injection, brain uptake and distribution of [(11)C]Cimbi-806 was assessed with PET in Danish Landrace pigs. The time-activity curves revealed high brain uptake in thalamic and striatal regions (SUV ∼2.5) and kinetic modeling resulted in distribution volumes (V(T)) ranging from 6 mL/cm(3) in the cerebellum to 12 mL/cm(3) in the thalamus. Pretreatment with the 5-HT(7) receptor antagonist SB-269970 did not result in any significant changes in [(11)C]Cimbi-806 binding in any of the analyzed regions. Despite the high brain uptake and relevant distribution pattern, the absence of appropriate in vivo blocking with a 5-HT(7) receptor selective compounds renders the conclusion that [(11)C]Cimbi-806 is not an appropriate PET radioligand for imaging the 5-HT(7) receptor in vivo.",
keywords = "Animals, Biphenyl Compounds, Brain, Carbon Radioisotopes, Ethylamines, Isotope Labeling, Ligands, Positron-Emission Tomography, Radiopharmaceuticals, Receptors, Serotonin, Swine, Tissue Distribution",
author = "Herth, {Matthias M} and Hansen, {Hanne D} and Anders Ettrup and Agnete Dyssegaard and S Lehel and Kristensen, {Jesper Langgaard} and Knudsen, {Gitte M}",
note = "Copyright {\textcopyright} 2012 Elsevier Ltd. All rights reserved.",
year = "2012",
doi = "10.1016/j.bmc.2012.05.005",
language = "English",
volume = "20",
pages = "4574--81",
journal = "Bioorganic and Medicinal Chemistry",
issn = "0968-0896",
publisher = "Pergamon",
number = "14",

}

RIS

TY - JOUR

T1 - Synthesis and evaluation of [¹¹C]Cimbi-806 as a potential PET ligand for 5-HT₇ receptor imaging

AU - Herth, Matthias M

AU - Hansen, Hanne D

AU - Ettrup, Anders

AU - Dyssegaard, Agnete

AU - Lehel, S

AU - Kristensen, Jesper Langgaard

AU - Knudsen, Gitte M

N1 - Copyright © 2012 Elsevier Ltd. All rights reserved.

PY - 2012

Y1 - 2012

N2 - 2-(2',6'-Dimethoxy-[1,1'-biphenyl]-3-yl)-N,N-dimethylethanamine has been identified as a potent ligand for the serotonin 7 (5-HT(7)) receptor. In this study, we describe the synthesis, radiolabeling and in vivo evaluation of [(11)C]2-(2',6'-dimethoxy-[1,1'-biphenyl]-3-yl)-N,N-dimethylethanamine ([(11)C]Cimbi-806) as a radioligand for imaging brain 5-HT(7) receptors with positron emission tomography (PET). Precursor and reference compound was synthesized and subsequent (11)C-labelling with [(11)C]methyltriflate produced [(11)C]Cimbi-806 in specific activities ranging from 50 to 300 GBq/μmol. Following intravenous injection, brain uptake and distribution of [(11)C]Cimbi-806 was assessed with PET in Danish Landrace pigs. The time-activity curves revealed high brain uptake in thalamic and striatal regions (SUV ∼2.5) and kinetic modeling resulted in distribution volumes (V(T)) ranging from 6 mL/cm(3) in the cerebellum to 12 mL/cm(3) in the thalamus. Pretreatment with the 5-HT(7) receptor antagonist SB-269970 did not result in any significant changes in [(11)C]Cimbi-806 binding in any of the analyzed regions. Despite the high brain uptake and relevant distribution pattern, the absence of appropriate in vivo blocking with a 5-HT(7) receptor selective compounds renders the conclusion that [(11)C]Cimbi-806 is not an appropriate PET radioligand for imaging the 5-HT(7) receptor in vivo.

AB - 2-(2',6'-Dimethoxy-[1,1'-biphenyl]-3-yl)-N,N-dimethylethanamine has been identified as a potent ligand for the serotonin 7 (5-HT(7)) receptor. In this study, we describe the synthesis, radiolabeling and in vivo evaluation of [(11)C]2-(2',6'-dimethoxy-[1,1'-biphenyl]-3-yl)-N,N-dimethylethanamine ([(11)C]Cimbi-806) as a radioligand for imaging brain 5-HT(7) receptors with positron emission tomography (PET). Precursor and reference compound was synthesized and subsequent (11)C-labelling with [(11)C]methyltriflate produced [(11)C]Cimbi-806 in specific activities ranging from 50 to 300 GBq/μmol. Following intravenous injection, brain uptake and distribution of [(11)C]Cimbi-806 was assessed with PET in Danish Landrace pigs. The time-activity curves revealed high brain uptake in thalamic and striatal regions (SUV ∼2.5) and kinetic modeling resulted in distribution volumes (V(T)) ranging from 6 mL/cm(3) in the cerebellum to 12 mL/cm(3) in the thalamus. Pretreatment with the 5-HT(7) receptor antagonist SB-269970 did not result in any significant changes in [(11)C]Cimbi-806 binding in any of the analyzed regions. Despite the high brain uptake and relevant distribution pattern, the absence of appropriate in vivo blocking with a 5-HT(7) receptor selective compounds renders the conclusion that [(11)C]Cimbi-806 is not an appropriate PET radioligand for imaging the 5-HT(7) receptor in vivo.

KW - Animals

KW - Biphenyl Compounds

KW - Brain

KW - Carbon Radioisotopes

KW - Ethylamines

KW - Isotope Labeling

KW - Ligands

KW - Positron-Emission Tomography

KW - Radiopharmaceuticals

KW - Receptors, Serotonin

KW - Swine

KW - Tissue Distribution

U2 - 10.1016/j.bmc.2012.05.005

DO - 10.1016/j.bmc.2012.05.005

M3 - Journal article

C2 - 22682922

VL - 20

SP - 4574

EP - 4581

JO - Bioorganic and Medicinal Chemistry

JF - Bioorganic and Medicinal Chemistry

SN - 0968-0896

IS - 14

ER -

ID: 36809224