title: A new norepinephrine transporter imaging agent for cardiac sympathetic nervous function imaging: radioiodinated (R)-N-methyl-3-(2-iodophenoxy)-3-phenylpropanamine.
abstract: Changes of the cardiac norepinephrine transporter (NET) have been reported in several cardiac failures. (R)-N-methyl-3-(2-iodophenoxy)-3-phenylpropanamine (MIPP), the 3-phenoxy-3-phenylpropylamine analogue iodinated at the 2-position of the phenoxy ring, was synthesized and evaluated as a potential radiopharmaceutical for investigating the cardiac norepinephrine transporter by single photon emission computed tomography (SPECT). (R)-[(125)I]MIPP was synthesized via a halogen exchange reaction under no-carrier-added conditions and purified by high-performance liquid chromatography (HPLC) with high radiochemical yield (60%) and high radiochemical purity (> 98%). The binding affinity of (R)-MIPP for cardiac NET was measured in terms of the displacement of [(3)H]desipramine and (R)-[(125)I]MIPP from binding sites in rat heart membranes. The binding data revealed that the affinity of (R)-MIPP was 5 times that of nisoxetine which is a selective NET inhibitor. In biodistribution studies, (R)-[(125)I]MIPP showed a high uptake followed by rapid clearance in the heart. (R)-[(125)I]MIPP binding sites were saturable and the administration of nisoxetine and desipramine, selective NET inhibitors, decreased the cardiac accumulation of (R)-[(125)I]MIPP. These results suggested that (R)-[(123)I]MIPP may be an useful radiopharmaceutical for imaging cardiac sympathetic nervous functions.
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003891:Desipramine / Q000494:pharmacology; D005473:Fluoxetine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics* / Q000494:pharmacology; D006321:Heart / Q000000981:diagnostic imaging* / Q000187:drug effects / Q000294:innervation*; D006352:Heart Ventricles / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007457:Iodine Radioisotopes / Q000493:pharmacokinetics; D007553:Isotope Labeling / Q000379:methods; D008297:Male; D008657:Metabolic Clearance Rate; D009206:Myocardium / Q000378:metabolism*; D050484:Norepinephrine Plasma Membrane Transport Proteins; D009928:Organ Specificity; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D013564:Sympathetic Nervous System / Q000000981:diagnostic imaging* / Q000187:drug effects / Q000378:metabolism*; D027981:Symporters / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014018:Tissue Distribution
chemical_list: D007457:Iodine Radioisotopes; C483738:N-methyl-3-(2-iodophenoxy)-3-phenylpropanamine; D050484:Norepinephrine Plasma Membrane Transport Proteins; D019275:Radiopharmaceuticals; C493227:SLC6A2 protein, human; C493226:Slc6a2 protein, rat; D027981:Symporters; D005473:Fluoxetine; C011386:nisoxetine; D003891:Desipramine