Synthesis and characterization of fluorescent ligands for the norepinephrine transporter: potential neuroblastoma imaging agents.
Radiolabeled m-iodobenzylguanidine (MIBG) is a tumor-seeking radioactive drug used in the diagnosis and treatment of pheochromocytomas and neuroblastomas. It is transported into the tumor cells by the neuronal norepinephrine (NE) transporter (NET) which is expressed in almost all neuroblastoma cells. Here, we describe the synthesis and some pharmacological properties of a series of fluorescent compounds structurally related to the NET substrate, MIBG, or to the NET inhibitors, (-)-(2R,3S)-cocaine and nisoxetine. Three of 10 synthesized fluorescent compounds, 1-(1-naphthylmethyl)guanidinium sulfate (1), 1-[2-(dibenz[b, f]azepin-5-yl)ethyl]guanidinium sulfate (2), and (2R, 3S)-2beta-ethoxycarbonyl-3beta-tropanyl 5-(dimethylamino)naphthalene-1-sulfonate (6), exhibited high affinity (IC(50) about 50 nM) for the NET. The nisoxetine derivatives 8 (rac-N-[(3-methylamino-1-phenyl)propyl]-5-(dimethylamino)-1-naphthale nesulfonamide) and 9 (rac-4-[(3-methylamino-1-phenyl)propyl]amino-7-nitro-2,1, 3-benzoxadiazole) and especially the guanidine derivative 4 (1-[4-(4-phenyl-1,3-butadienyl)benzyl]guanidinium sulfate) which are characterized by intermediate affinity for the NET (IC(50) 370-850 nM) caused significant and nisoxetine-sensitive cell fluorescence. At least the guanidine derivative 4 might represent a potentially useful agent for imaging of neuroblastoma cells.
Hadrich
D
D
Kekulé-Institut für Organische Chemie und Biochemie, Universität Bonn, Gerhard-Domagk-Strasse 1, D-53121 Bonn, Germany.
Berthold
F
F
Steckhan
E
E
Bönisch
H
H
D002352:Carrier Proteins / Q000378:metabolism*; D003042:Cocaine / Q000737:chemistry; D004095:Dihydropyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D005456:Fluorescent Dyes / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D005473:Fluoxetine / Q000031:analogs & derivatives / Q000737:chemistry; D006146:Guanidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D007555:Isoxazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D008024:Ligands; D009447:Neuroblastoma / Q000378:metabolism; D009638:Norepinephrine / Q000378:metabolism*; D050484:Norepinephrine Plasma Membrane Transport Proteins; D013329:Structure-Activity Relationship; D027981:Symporters; D014407:Tumor Cells, Cultured
D002352:Carrier Proteins; D004095:Dihydropyridines; D005456:Fluorescent Dyes; D006146:Guanidines; D007555:Isoxazoles; D008024:Ligands; D050484:Norepinephrine Plasma Membrane Transport Proteins; C493227:SLC6A2 protein, human; D027981:Symporters; C120835:diethyl 2,6-dimethyl-4-(5-(1-naphthylethyl)-3-methylisoxazol-4-yl)-1,4-dihydropyridine-3,5-dicarboxylate; D005473:Fluoxetine; C011386:nisoxetine; D003042:Cocaine; D009638:Norepinephrine