[125/123I]IPH: A radioiodinated analog of epibatidine for in vivo studies of nicotinic acetylcholine receptors

John L. Musachio, Victor L. Villemagne, Ursula Scheffel, Marigo Stathis, Paige Finley, Andrew Horti, Edythe D. London, Robert F Dannals

Research output: Contribution to journalArticle

Abstract

Tomographic imaging of central nicotinic acetylcholine receptors (nAChRs) via single photon emission computed tomography (SPECT) has been hampered by the lack of a radioligand with suitable in vivo binding characteristics. Therefore, a novel analog of epibatidine, (±)-exo-2-(2- iodo-5-pyridyl)-7-azabicyclo[2.2.1]heptane (IPH), labeled with [125I] or [123I] was evaluated as an in vivo marker of central nicotinic acetylcholine receptors (nAChRs). [125I]IPH showed substantial brain penetration (4.2% of the injected dose at 30 min) and a cerebral biodistribution in mice consistent with the in vivo labeling of nAChRs (% injected dose/gram of thalamus, superior colliculi >> cerebellum). [125I]IPH binding sites were shown to be saturable with unlabeled IPH (ED50 approximately 1 μg/kg). The uptake of [125I]IPH was blocked significantly by the nicotinic agonists, cytisine, lobeline, and (-)- nicotine, but not by the noncompetitive nAChR antagonist, mecamylamine. Antagonists of muscarinic (scopolamine), serotonin (ketanserin), and opioid (naloxone) receptors had no significant effect on[125I]IPH binding, A preliminary SPECT imaging study with [125I]IPH in a baboon showed [123I]IPH to localize in nAChR-rich areas of brain (thalamus > frontal cortex > cerebellum). [123I]IPH binding in baboon brain was also displaced (35-45% displacement) by a challenge dose of cytisine showing that a well- characterized nicotinic agonist effectively competes for [123I]IPH binding sites. [123I]IPH seems well suited for imaging studies of nAChRs and, to our knowledge, is the first SPECT agent that has allowed for the visualization of nAChRs in primate brain.

Original languageEnglish (US)
Pages (from-to)392-399
Number of pages8
JournalSynapse
Volume26
Issue number4
DOIs
StatePublished - Aug 1997

Fingerprint

epibatidine
Nicotinic Receptors
Single-Photon Emission-Computed Tomography
Nicotinic Agonists
Papio
Brain
Thalamus
Cerebellum
Lobeline
Binding Sites
2-(2-iodo-5-pyridyl)-7-azabicyclo(2.2.1)heptane
Mecamylamine
Ketanserin

Keywords

  • Epibatidine
  • Iodine-123
  • Iodine-125
  • Nicotinic acetylcholine receptor
  • SPECT

ASJC Scopus subject areas

  • Physiology
  • Neuroscience(all)
  • Pharmacology
  • Advanced and Specialized Nursing

Cite this

[125/123I]IPH : A radioiodinated analog of epibatidine for in vivo studies of nicotinic acetylcholine receptors. / Musachio, John L.; Villemagne, Victor L.; Scheffel, Ursula; Stathis, Marigo; Finley, Paige; Horti, Andrew; London, Edythe D.; Dannals, Robert F.

In: Synapse, Vol. 26, No. 4, 08.1997, p. 392-399.

Research output: Contribution to journalArticle

Musachio, John L. ; Villemagne, Victor L. ; Scheffel, Ursula ; Stathis, Marigo ; Finley, Paige ; Horti, Andrew ; London, Edythe D. ; Dannals, Robert F. / [125/123I]IPH : A radioiodinated analog of epibatidine for in vivo studies of nicotinic acetylcholine receptors. In: Synapse. 1997 ; Vol. 26, No. 4. pp. 392-399.
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abstract = "Tomographic imaging of central nicotinic acetylcholine receptors (nAChRs) via single photon emission computed tomography (SPECT) has been hampered by the lack of a radioligand with suitable in vivo binding characteristics. Therefore, a novel analog of epibatidine, (±)-exo-2-(2- iodo-5-pyridyl)-7-azabicyclo[2.2.1]heptane (IPH), labeled with [125I] or [123I] was evaluated as an in vivo marker of central nicotinic acetylcholine receptors (nAChRs). [125I]IPH showed substantial brain penetration (4.2{\%} of the injected dose at 30 min) and a cerebral biodistribution in mice consistent with the in vivo labeling of nAChRs ({\%} injected dose/gram of thalamus, superior colliculi >> cerebellum). [125I]IPH binding sites were shown to be saturable with unlabeled IPH (ED50 approximately 1 μg/kg). The uptake of [125I]IPH was blocked significantly by the nicotinic agonists, cytisine, lobeline, and (-)- nicotine, but not by the noncompetitive nAChR antagonist, mecamylamine. Antagonists of muscarinic (scopolamine), serotonin (ketanserin), and opioid (naloxone) receptors had no significant effect on[125I]IPH binding, A preliminary SPECT imaging study with [125I]IPH in a baboon showed [123I]IPH to localize in nAChR-rich areas of brain (thalamus > frontal cortex > cerebellum). [123I]IPH binding in baboon brain was also displaced (35-45{\%} displacement) by a challenge dose of cytisine showing that a well- characterized nicotinic agonist effectively competes for [123I]IPH binding sites. [123I]IPH seems well suited for imaging studies of nAChRs and, to our knowledge, is the first SPECT agent that has allowed for the visualization of nAChRs in primate brain.",
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