(S)-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-[ 125I]iodo-2-methoxybenzamide hydrochloride, a new selective radioligand for dopamine D-2 receptors

Tomas De Paulis, Aaron Janowsky, Robert M. Kessler, Jeffrey A. Clanton, Howard E. Smith

Research output: Research - peer-reviewArticle

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Abstract

From salicyclic acid, the two enantiomers of N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-iodo-2-methoxybenzamide (6b) were prepared in a five-step synthesis. With use of Heindel's triazene method for introduction of the radionuclide, the iodine-125-labeled substituted benzamide was obtained with a calculated specific activity of 136 Ci/mmol and 14% radiochemical yield. For the preparation of the iodine-125-labeled benzamide with higher specific activity, this method was unsuccessful and utilization of the corresponding tri-n-butyltin derivative was required. Treatment of the latter in dilute hydrochloric acid with sodium iodide-125 and chloramine-T gave [125I](S)-6b in 56% radiochemical yield and at least 97% radiochemical purity. The displacement of [125I](S)-6b and [3H](S)-sulpiride from their respective binding sites in striatal rat brain homogenates using various neuroleptic agents showed that (S)-6b has the same binding profile but more potent binding for dopamine D-2 receptors than has sulpiride. These experiments also indicate that the S enantiomer of 6b is a specific ligand (KD =1.2 nM) for the D-2 receptor. Further, the octanol-water partition coefficient of (S)-6b as determined by reverse-phase high-performance liquid chromatography was found to be 40 times greater than that for sulpiride. Thus (S)-6b has a lipophilicity that will allow a relatively higher uptake into the brain compared to sulpiride. In vivo experiments with rats show that [125I](S)-6b penetrates readily into the brain and is preferentially localized in the striatum as compared to the cerebellum, the ratio of uptake being 7.2 to 1, 60 min after injection. These observations of good brain penetration and high affinity and selectivity for D-2 receptors indicate that the corresponding iodine-123-labeled benzamide may be a useful ligand for the noninvasive visualization study of dopamine D-2 receptor sites in vivo by single photon emission computed tomography.

LanguageEnglish (US)
Pages2027-2033
Number of pages7
JournalJournal of Medicinal Chemistry
Volume31
Issue number10
StatePublished - 1988
Externally publishedYes

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Sulpiride
Dopamine
Brain
iodopride
Iodine
benzamide
Enantiomers
Rats
Ligands
Experiments
Triazenes
Sodium Iodide
Single photon emission computed tomography
Octanols
Hydrochloric Acid
High performance liquid chromatography
Radioisotopes
Antipsychotic Agents
Visualization
Binding Sites

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

(S)-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-[ 125I]iodo-2-methoxybenzamide hydrochloride, a new selective radioligand for dopamine D-2 receptors. / De Paulis, Tomas; Janowsky, Aaron; Kessler, Robert M.; Clanton, Jeffrey A.; Smith, Howard E.

In: Journal of Medicinal Chemistry, Vol. 31, No. 10, 1988, p. 2027-2033.

Research output: Research - peer-reviewArticle

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abstract = "From salicyclic acid, the two enantiomers of N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-iodo-2-methoxybenzamide (6b) were prepared in a five-step synthesis. With use of Heindel's triazene method for introduction of the radionuclide, the iodine-125-labeled substituted benzamide was obtained with a calculated specific activity of 136 Ci/mmol and 14% radiochemical yield. For the preparation of the iodine-125-labeled benzamide with higher specific activity, this method was unsuccessful and utilization of the corresponding tri-n-butyltin derivative was required. Treatment of the latter in dilute hydrochloric acid with sodium iodide-125 and chloramine-T gave [125I](S)-6b in 56% radiochemical yield and at least 97% radiochemical purity. The displacement of [125I](S)-6b and [3H](S)-sulpiride from their respective binding sites in striatal rat brain homogenates using various neuroleptic agents showed that (S)-6b has the same binding profile but more potent binding for dopamine D-2 receptors than has sulpiride. These experiments also indicate that the S enantiomer of 6b is a specific ligand (KD =1.2 nM) for the D-2 receptor. Further, the octanol-water partition coefficient of (S)-6b as determined by reverse-phase high-performance liquid chromatography was found to be 40 times greater than that for sulpiride. Thus (S)-6b has a lipophilicity that will allow a relatively higher uptake into the brain compared to sulpiride. In vivo experiments with rats show that [125I](S)-6b penetrates readily into the brain and is preferentially localized in the striatum as compared to the cerebellum, the ratio of uptake being 7.2 to 1, 60 min after injection. These observations of good brain penetration and high affinity and selectivity for D-2 receptors indicate that the corresponding iodine-123-labeled benzamide may be a useful ligand for the noninvasive visualization study of dopamine D-2 receptor sites in vivo by single photon emission computed tomography.",
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T1 - (S)-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-[ 125I]iodo-2-methoxybenzamide hydrochloride, a new selective radioligand for dopamine D-2 receptors

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AU - Smith,Howard E.

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