Synthesis and Characterization of Radioiodinated N-(3-Iodopropen-1-yl)-2β-carbomethoxy-3β-(4-chlorophenyl)tropanes

Potential Dopamine Reuptake Site Imaging Agents

Mark M. Goodman, Mei Ping Kung, George Kabalka, Hank F. Kung, Robert Switzer

Research output: Contribution to journalArticle

85 Citations (Scopus)

Abstract

Methods have been developed for the preparation of radioiodinated N-substituted 2β-carbomethoxy-3β-(4-chlorophenyl)tropanes. The syntheses, physical properties, radiolabeling, and characterization of the pharmacological properties of N-(3(Z)-iodopropen-1-yl)-2β-carbomethoxy-3β-(4-chlorophenyl)tropane (12) and N-(3(E)-iodopropen-1-yl)-2β-carbomethoxy-3β-(4-chlorophenyl)tropane (13) are described. 2β-Carbomethoxy-3β-(p-substituted-phenyl)tropanes are potent ligands for the dopamine transporter. The radioiodinated derivatives are of interest because of the high uptake and prolonged striatal retention that may result from specific binding to low-capacity, high-affinity, dopamine reuptake sites. Radioiodine was introduced into the 3Z and 3E-position of N-(3-iodopropen-1-yl)-2β-carbomethoxy-3β-(4-chlorophenyl)tropane by iododemetalation of the corresponding 3-(tri-n-butylstannyl) derivatives. Competition binding data of various dopamine reuptake ligands with rat striatal tissue preparation for either [125I]-12 or [125I]-13 exhibited the following order of potency: E-13 > Z-12 > GBR 12909 ≫ mazindol ⋙ (-)-cocaine. Tissue distribution studies in rats showed that the E-13 was the best analogue. E-13 showed high striatal uptake (60 min, 1.23% dose/g; 120 min, 0.61% dose/g) and high striatal to cerebellum ratios (60 min, 15.9/1; 120 min, 16.5/1). These studies indicate that iodine-123-labeled E-13 is a potentially useful agent for imaging the dopamine reuptake sites by single-photon-emission computerized tomography.

Original languageEnglish (US)
Pages (from-to)1535-1542
Number of pages8
JournalJournal of Medicinal Chemistry
Volume37
Issue number10
DOIs
StatePublished - May 1 1994
Externally publishedYes

Fingerprint

Corpus Striatum
Dopamine
Tropanes
Mazindol
Ligands
Dopamine Agents
Dopamine Plasma Membrane Transport Proteins
Tissue Distribution
Single-Photon Emission-Computed Tomography
Cocaine
Iodine
Cerebellum
Pharmacology
N-(3-iodopropen-1-yl)-2-carbomethoxy-3-(4-chlorophenyl)tropane

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

Cite this

Synthesis and Characterization of Radioiodinated N-(3-Iodopropen-1-yl)-2β-carbomethoxy-3β-(4-chlorophenyl)tropanes : Potential Dopamine Reuptake Site Imaging Agents. / Goodman, Mark M.; Kung, Mei Ping; Kabalka, George; Kung, Hank F.; Switzer, Robert.

In: Journal of Medicinal Chemistry, Vol. 37, No. 10, 01.05.1994, p. 1535-1542.

Research output: Contribution to journalArticle

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abstract = "Methods have been developed for the preparation of radioiodinated N-substituted 2β-carbomethoxy-3β-(4-chlorophenyl)tropanes. The syntheses, physical properties, radiolabeling, and characterization of the pharmacological properties of N-(3(Z)-iodopropen-1-yl)-2β-carbomethoxy-3β-(4-chlorophenyl)tropane (12) and N-(3(E)-iodopropen-1-yl)-2β-carbomethoxy-3β-(4-chlorophenyl)tropane (13) are described. 2β-Carbomethoxy-3β-(p-substituted-phenyl)tropanes are potent ligands for the dopamine transporter. The radioiodinated derivatives are of interest because of the high uptake and prolonged striatal retention that may result from specific binding to low-capacity, high-affinity, dopamine reuptake sites. Radioiodine was introduced into the 3Z and 3E-position of N-(3-iodopropen-1-yl)-2β-carbomethoxy-3β-(4-chlorophenyl)tropane by iododemetalation of the corresponding 3-(tri-n-butylstannyl) derivatives. Competition binding data of various dopamine reuptake ligands with rat striatal tissue preparation for either [125I]-12 or [125I]-13 exhibited the following order of potency: E-13 > Z-12 > GBR 12909 ≫ mazindol ⋙ (-)-cocaine. Tissue distribution studies in rats showed that the E-13 was the best analogue. E-13 showed high striatal uptake (60 min, 1.23{\%} dose/g; 120 min, 0.61{\%} dose/g) and high striatal to cerebellum ratios (60 min, 15.9/1; 120 min, 16.5/1). These studies indicate that iodine-123-labeled E-13 is a potentially useful agent for imaging the dopamine reuptake sites by single-photon-emission computerized tomography.",
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