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

Keywords

  • A-85380
  • Bifunctional radiopharmaceutical
  • Cyclopentadienyltricarbonyl technetium
  • Nicotinic acetylcholine receptors
  • Single-photon emission computed tomography

ASJC Scopus subject areas

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

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