Synthesis and biological evaluation of Tc-99m-cyclopentadienyltricarbonyl-technetium-labeled A-85380

An imaging probe for single-photon emission computed tomography investigation of nicotinic acetylcholine receptors in the brain

Hiroyuki Kimura, Masashi Ueda, Hidekazu Kawashima, Kenji Arimitsu, Yusuke Yagi, Hideo Saji

Research output: Contribution to journalArticle

Abstract

We have designed (S)-(5-(azetidin-2-ylmethoxy)pyridine-3-yl)methyl cyclopentadienyltricarbonyl technetium carboxylate ([99mTc]CPTT-A-E) with high affinity for nicotinic acetylcholine receptors (nAChRs) using (2(S)-azetidinylmethoxy)-pyridine (A-85380) as the lead compound to develop a Tc-99m-cyclopentadienyltricarbonyl-technetium (99mTc)-labeled nAChR imaging probe. Because technetium does not contain a stable isotope, cyclopentadienyltricarbonyl rhenium (CPTR) was synthesized by coordinating rhenium, which is a homologous element having the same coordination structure as technetium. Further, the binding affinity to nAChR was evaluated. CPTR-A-E exhibited a high binding affinity to nAChR (Ki = 0.55 nM). Through the radiosynthesis of [99mTc]CPTT-A-E, an objective compound could be obtained with a radiochemical yield of 33% and a radiochemical purity of greater than 97%. In vitro autoradiographic study of the brain exhibited that the local nAChR density strongly correlated with the amount of [99mTc]CPTT-A-E that was accumulated in each region of interest. Further, the in vivo evaluation of biodistribution revealed a higher accumulation of [99mTc]CPTT-A-E in the thalamus (characterized by the high nAChR density) when compared with that in the cerebellum (characterized by the low nAChR density). Although additional studies will be necessary to improve the uptake of [99mTc]CPTT-A-E to the brain, [99mTc]CPTT-A-E met the basic requirements for nAChR imaging.

Original languageEnglish
Pages (from-to)2245-2252
Number of pages8
JournalBioorganic and Medicinal Chemistry
Volume27
Issue number11
DOIs
Publication statusPublished - Jun 1 2019
Externally publishedYes

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A 85380
Single photon emission computed tomography
Technetium
Nicotinic Receptors
Single-Photon Emission-Computed Tomography
Brain
Imaging techniques
Rhenium
Lead compounds
Thalamus
Isotopes
Cerebellum

Cite this

@article{1177d621285a4401a2a255ec96c2127f,
title = "Synthesis and biological evaluation of Tc-99m-cyclopentadienyltricarbonyl-technetium-labeled A-85380: An imaging probe for single-photon emission computed tomography investigation of nicotinic acetylcholine receptors in the brain",
abstract = "We have designed (S)-(5-(azetidin-2-ylmethoxy)pyridine-3-yl)methyl cyclopentadienyltricarbonyl technetium carboxylate ([99mTc]CPTT-A-E) with high affinity for nicotinic acetylcholine receptors (nAChRs) using (2(S)-azetidinylmethoxy)-pyridine (A-85380) as the lead compound to develop a Tc-99m-cyclopentadienyltricarbonyl-technetium (99mTc)-labeled nAChR imaging probe. Because technetium does not contain a stable isotope, cyclopentadienyltricarbonyl rhenium (CPTR) was synthesized by coordinating rhenium, which is a homologous element having the same coordination structure as technetium. Further, the binding affinity to nAChR was evaluated. CPTR-A-E exhibited a high binding affinity to nAChR (Ki = 0.55 nM). Through the radiosynthesis of [99mTc]CPTT-A-E, an objective compound could be obtained with a radiochemical yield of 33{\%} and a radiochemical purity of greater than 97{\%}. In vitro autoradiographic study of the brain exhibited that the local nAChR density strongly correlated with the amount of [99mTc]CPTT-A-E that was accumulated in each region of interest. Further, the in vivo evaluation of biodistribution revealed a higher accumulation of [99mTc]CPTT-A-E in the thalamus (characterized by the high nAChR density) when compared with that in the cerebellum (characterized by the low nAChR density). Although additional studies will be necessary to improve the uptake of [99mTc]CPTT-A-E to the brain, [99mTc]CPTT-A-E met the basic requirements for nAChR imaging.",
author = "Hiroyuki Kimura and Masashi Ueda and Hidekazu Kawashima and Kenji Arimitsu and Yusuke Yagi and Hideo Saji",
note = "Copyright {\circledC} 2019. Published by Elsevier Ltd.",
year = "2019",
month = "6",
day = "1",
doi = "10.1016/j.bmc.2019.04.030",
language = "English",
volume = "27",
pages = "2245--2252",
journal = "Bioorganic and Medicinal Chemistry",
issn = "0968-0896",
publisher = "Elsevier Limited",
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TY - JOUR

T1 - Synthesis and biological evaluation of Tc-99m-cyclopentadienyltricarbonyl-technetium-labeled A-85380

T2 - An imaging probe for single-photon emission computed tomography investigation of nicotinic acetylcholine receptors in the brain

AU - Kimura, Hiroyuki

AU - Ueda, Masashi

AU - Kawashima, Hidekazu

AU - Arimitsu, Kenji

AU - Yagi, Yusuke

AU - Saji, Hideo

N1 - Copyright © 2019. Published by Elsevier Ltd.

PY - 2019/6/1

Y1 - 2019/6/1

N2 - We have designed (S)-(5-(azetidin-2-ylmethoxy)pyridine-3-yl)methyl cyclopentadienyltricarbonyl technetium carboxylate ([99mTc]CPTT-A-E) with high affinity for nicotinic acetylcholine receptors (nAChRs) using (2(S)-azetidinylmethoxy)-pyridine (A-85380) as the lead compound to develop a Tc-99m-cyclopentadienyltricarbonyl-technetium (99mTc)-labeled nAChR imaging probe. Because technetium does not contain a stable isotope, cyclopentadienyltricarbonyl rhenium (CPTR) was synthesized by coordinating rhenium, which is a homologous element having the same coordination structure as technetium. Further, the binding affinity to nAChR was evaluated. CPTR-A-E exhibited a high binding affinity to nAChR (Ki = 0.55 nM). Through the radiosynthesis of [99mTc]CPTT-A-E, an objective compound could be obtained with a radiochemical yield of 33% and a radiochemical purity of greater than 97%. In vitro autoradiographic study of the brain exhibited that the local nAChR density strongly correlated with the amount of [99mTc]CPTT-A-E that was accumulated in each region of interest. Further, the in vivo evaluation of biodistribution revealed a higher accumulation of [99mTc]CPTT-A-E in the thalamus (characterized by the high nAChR density) when compared with that in the cerebellum (characterized by the low nAChR density). Although additional studies will be necessary to improve the uptake of [99mTc]CPTT-A-E to the brain, [99mTc]CPTT-A-E met the basic requirements for nAChR imaging.

AB - We have designed (S)-(5-(azetidin-2-ylmethoxy)pyridine-3-yl)methyl cyclopentadienyltricarbonyl technetium carboxylate ([99mTc]CPTT-A-E) with high affinity for nicotinic acetylcholine receptors (nAChRs) using (2(S)-azetidinylmethoxy)-pyridine (A-85380) as the lead compound to develop a Tc-99m-cyclopentadienyltricarbonyl-technetium (99mTc)-labeled nAChR imaging probe. Because technetium does not contain a stable isotope, cyclopentadienyltricarbonyl rhenium (CPTR) was synthesized by coordinating rhenium, which is a homologous element having the same coordination structure as technetium. Further, the binding affinity to nAChR was evaluated. CPTR-A-E exhibited a high binding affinity to nAChR (Ki = 0.55 nM). Through the radiosynthesis of [99mTc]CPTT-A-E, an objective compound could be obtained with a radiochemical yield of 33% and a radiochemical purity of greater than 97%. In vitro autoradiographic study of the brain exhibited that the local nAChR density strongly correlated with the amount of [99mTc]CPTT-A-E that was accumulated in each region of interest. Further, the in vivo evaluation of biodistribution revealed a higher accumulation of [99mTc]CPTT-A-E in the thalamus (characterized by the high nAChR density) when compared with that in the cerebellum (characterized by the low nAChR density). Although additional studies will be necessary to improve the uptake of [99mTc]CPTT-A-E to the brain, [99mTc]CPTT-A-E met the basic requirements for nAChR imaging.

U2 - 10.1016/j.bmc.2019.04.030

DO - 10.1016/j.bmc.2019.04.030

M3 - Article

VL - 27

SP - 2245

EP - 2252

JO - Bioorganic and Medicinal Chemistry

JF - Bioorganic and Medicinal Chemistry

SN - 0968-0896

IS - 11

ER -