Radiosynthesis and evaluation of [11C]EMPA as a potential PET tracer for orexin 2 receptors

Changning Wang; Christian K. Moseley; Stephen M. Carlin; Colin M. Wilson; Ramesh Neelamegam; Jacob M. Hooker

doi:10.1016/j.bmcl.2013.03.079

Radiosynthesis and evaluation of [¹¹C]EMPA as a potential PET tracer for orexin 2 receptors

Changning Wang, Christian K. Moseley, Stephen M. Carlin, Colin M. Wilson, Ramesh Neelamegam, Jacob M. Hooker

Research output: Contribution to journal › Article › peer-review

15 Scopus citations

Abstract

EMPA is a selective antagonist of orexin 2 (OX₂) receptors. Previous literature with [³H]-EMPA suggest that it may be used as an imaging agent for OX₂ receptors; however, brain penetration is known to be modest. To evaluate the potential of EMPA as a PET radiotracer in non-human primate (as a step to imaging in man), we radiolabeled EMPA with carbon-11. Radiosynthesis of [¹¹C]N-ethyl-2-(N-(6-methoxypyridin-3- yl)-2-methylphenylsulfonamido)-N-(pyridin-3-ylmethyl)acetamide ([ ¹¹C]EMPA), and evaluation as a potential PET tracer for OX ₂ receptors is described. Synthesis of an appropriate non-radioactive O-desmethyl precursor was achieved from EMPA with sodium iodide and chlorotrimethylsilane. Selective O-methylation using [¹¹C]CH ₃I in the presence of cesium carbonate in DMSO at room temp afforded [¹¹C]EMPA in 1.5-2.5% yield (non-decay corrected relative to trapped [¹¹C]CH₃I at EOS) with ≥95% chemical and radiochemical purities. The total synthesis time was 34-36 min from EOB. Studies in rodent suggested that uptake in tissue was dominated by nonspecific binding. However, [¹¹C]EMPA also showed poor uptake in both rats and baboon as measured with PET imaging.

Original language	English (US)
Pages (from-to)	3389-3392
Number of pages	4
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	23
Issue number	11
DOIs	https://doi.org/10.1016/j.bmcl.2013.03.079
State	Published - Jun 1 2013
Externally published	Yes

Keywords

Brain
Carbon-11
EMPA
Orexin
PET radiotracer

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

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10.1016/j.bmcl.2013.03.079

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@article{6d94ddc9e26a4064a60fd71e6a6a4702,

title = "Radiosynthesis and evaluation of [11C]EMPA as a potential PET tracer for orexin 2 receptors",

abstract = "EMPA is a selective antagonist of orexin 2 (OX2) receptors. Previous literature with [3H]-EMPA suggest that it may be used as an imaging agent for OX2 receptors; however, brain penetration is known to be modest. To evaluate the potential of EMPA as a PET radiotracer in non-human primate (as a step to imaging in man), we radiolabeled EMPA with carbon-11. Radiosynthesis of [11C]N-ethyl-2-(N-(6-methoxypyridin-3- yl)-2-methylphenylsulfonamido)-N-(pyridin-3-ylmethyl)acetamide ([ 11C]EMPA), and evaluation as a potential PET tracer for OX 2 receptors is described. Synthesis of an appropriate non-radioactive O-desmethyl precursor was achieved from EMPA with sodium iodide and chlorotrimethylsilane. Selective O-methylation using [11C]CH 3I in the presence of cesium carbonate in DMSO at room temp afforded [11C]EMPA in 1.5-2.5% yield (non-decay corrected relative to trapped [11C]CH3I at EOS) with ≥95% chemical and radiochemical purities. The total synthesis time was 34-36 min from EOB. Studies in rodent suggested that uptake in tissue was dominated by nonspecific binding. However, [11C]EMPA also showed poor uptake in both rats and baboon as measured with PET imaging.",

keywords = "Brain, Carbon-11, EMPA, Orexin, PET radiotracer",

author = "Changning Wang and Moseley, {Christian K.} and Carlin, {Stephen M.} and Wilson, {Colin M.} and Ramesh Neelamegam and Hooker, {Jacob M.}",

note = "Funding Information: This research was carried out at the Athinoula A. Martinos Center for Biomedical Imaging at the Massachusetts General Hospital, using resources provided by the Center for Functional Neuroimaging Technologies , P41EB015896 , a P41 Regional Resource supported by the National Institute of Biomedical Imaging and Bioengineering (NIBIB) , National Institutes of Health. This work also involved the use of instrumentation supported by the NIH Shared Instrumentation Grant Program and/or High-End Instrumentation Grant Program; specifically, Grant numbers: S10RR017208 , S10RR026666 , S10RR022976 , S10RR019933 , S10RR029495 . We would like to thank members of the Hooker laboratory for helpful discussions. The authors are grateful to Joseph Mandeville, Grae Arabsz, Shirley Hsu, and Helen Deng for assistance during NHP imaging.",

year = "2013",

month = jun,

day = "1",

doi = "10.1016/j.bmcl.2013.03.079",

language = "English (US)",

volume = "23",

pages = "3389--3392",

journal = "Bioorganic and Medicinal Chemistry Letters",

issn = "0960-894X",

publisher = "Elsevier Limited",

number = "11",

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TY - JOUR

T1 - Radiosynthesis and evaluation of [11C]EMPA as a potential PET tracer for orexin 2 receptors

AU - Wang, Changning

AU - Moseley, Christian K.

AU - Carlin, Stephen M.

AU - Wilson, Colin M.

AU - Neelamegam, Ramesh

AU - Hooker, Jacob M.

N1 - Funding Information: This research was carried out at the Athinoula A. Martinos Center for Biomedical Imaging at the Massachusetts General Hospital, using resources provided by the Center for Functional Neuroimaging Technologies , P41EB015896 , a P41 Regional Resource supported by the National Institute of Biomedical Imaging and Bioengineering (NIBIB) , National Institutes of Health. This work also involved the use of instrumentation supported by the NIH Shared Instrumentation Grant Program and/or High-End Instrumentation Grant Program; specifically, Grant numbers: S10RR017208 , S10RR026666 , S10RR022976 , S10RR019933 , S10RR029495 . We would like to thank members of the Hooker laboratory for helpful discussions. The authors are grateful to Joseph Mandeville, Grae Arabsz, Shirley Hsu, and Helen Deng for assistance during NHP imaging.

PY - 2013/6/1

Y1 - 2013/6/1

N2 - EMPA is a selective antagonist of orexin 2 (OX2) receptors. Previous literature with [3H]-EMPA suggest that it may be used as an imaging agent for OX2 receptors; however, brain penetration is known to be modest. To evaluate the potential of EMPA as a PET radiotracer in non-human primate (as a step to imaging in man), we radiolabeled EMPA with carbon-11. Radiosynthesis of [11C]N-ethyl-2-(N-(6-methoxypyridin-3- yl)-2-methylphenylsulfonamido)-N-(pyridin-3-ylmethyl)acetamide ([ 11C]EMPA), and evaluation as a potential PET tracer for OX 2 receptors is described. Synthesis of an appropriate non-radioactive O-desmethyl precursor was achieved from EMPA with sodium iodide and chlorotrimethylsilane. Selective O-methylation using [11C]CH 3I in the presence of cesium carbonate in DMSO at room temp afforded [11C]EMPA in 1.5-2.5% yield (non-decay corrected relative to trapped [11C]CH3I at EOS) with ≥95% chemical and radiochemical purities. The total synthesis time was 34-36 min from EOB. Studies in rodent suggested that uptake in tissue was dominated by nonspecific binding. However, [11C]EMPA also showed poor uptake in both rats and baboon as measured with PET imaging.

AB - EMPA is a selective antagonist of orexin 2 (OX2) receptors. Previous literature with [3H]-EMPA suggest that it may be used as an imaging agent for OX2 receptors; however, brain penetration is known to be modest. To evaluate the potential of EMPA as a PET radiotracer in non-human primate (as a step to imaging in man), we radiolabeled EMPA with carbon-11. Radiosynthesis of [11C]N-ethyl-2-(N-(6-methoxypyridin-3- yl)-2-methylphenylsulfonamido)-N-(pyridin-3-ylmethyl)acetamide ([ 11C]EMPA), and evaluation as a potential PET tracer for OX 2 receptors is described. Synthesis of an appropriate non-radioactive O-desmethyl precursor was achieved from EMPA with sodium iodide and chlorotrimethylsilane. Selective O-methylation using [11C]CH 3I in the presence of cesium carbonate in DMSO at room temp afforded [11C]EMPA in 1.5-2.5% yield (non-decay corrected relative to trapped [11C]CH3I at EOS) with ≥95% chemical and radiochemical purities. The total synthesis time was 34-36 min from EOB. Studies in rodent suggested that uptake in tissue was dominated by nonspecific binding. However, [11C]EMPA also showed poor uptake in both rats and baboon as measured with PET imaging.

KW - Brain

KW - Carbon-11

KW - EMPA

KW - Orexin

KW - PET radiotracer

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