Synthesis and Characterization of Radioiodinated N-(3-Iodopropen-1-yl)-2.beta.-carbomethoxy-3.beta.-(4-chlorophenyl)tropanes: Potential Dopamine Reuptake Site Imaging Agents
Autor: | Mei-Ping Kung, George W. Kabalka, Robert Switzer, M. M. Goodman, Hank F. Kung |
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Rok vydání: | 1994 |
Předmět: |
Male
Stereochemistry Dopamine Dopamine Plasma Membrane Transport Proteins Nerve Tissue Proteins In Vitro Techniques Binding Competitive Reuptake Iodine Radioisotopes Rats Sprague-Dawley chemistry.chemical_compound Cocaine Drug Discovery medicine Animals Tissue Distribution Binding site Dopamine transporter Tomography Emission-Computed Single-Photon Membrane Glycoproteins Mazindol biology Membrane Transport Proteins Stereoisomerism Tropane Corpus Striatum Rats chemistry Isotope Labeling biology.protein Molecular Medicine Carrier Proteins Reuptake inhibitor Protein Binding Tropanes medicine.drug |
Zdroj: | Journal of Medicinal Chemistry. 37:1535-1542 |
ISSN: | 1520-4804 0022-2623 |
Popis: | Methods have been developed for the preparation of radioiodinated N-substituted 2 beta-carbomethoxy-3 beta-(4-chlorophenyl)tropanes. The syntheses, physical properties, radiolabeling, and characterization of the pharmacological properties of N-(3(Z)-iodopropen-1-yl)-2 beta-carbomethoxy-3 beta-(4-chlorophenyl)tropane (12) and N-(3(E)-iodopropen-1-yl)-2 beta-carbomethoxy-3 beta-(4-chlorophenyl)tropane (13) are described. 2 beta-Carbomethoxy-3 beta-(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)-2 beta-carbomethoxy-3 beta-(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. |
Databáze: | OpenAIRE |
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