title: Synthesis, in vitro validation and in vivo pharmacokinetics of [125I]N-[2-(4-iodophenyl)ethyl]-N-methyl-2-(1-piperidinyl) ethylamine: a high-affinity ligand for imaging sigma receptor positive tumors.
abstract: N-[2-(4-iodophenyl)ethyl]-N-methyl-2-(1-piperidinyl)ethylamine, IPEMP, and the corresponding bromo derivative, BrPEMP, have been synthesized and characterized. Both BrPEMP and IPEMP were evaluated for sigma-1 and sigma-2 subtype receptor affinities and found to possess very high affinities for both receptor subtypes. The precursor for radioiodination n-tributylstannylphenylethylpiperidinylethylamine was prepared from its bromo derivative by palladium-catalyzed stannylation reaction. Radioiodinated 4-[125I]PEMP was readily prepared in high yields and high specific activity by oxidative iododestannylation reaction using chloramine-T as oxidizing agent. Sites labeled by 4-[125I]PEMP in guinea pig brain membranes showed high affinity for BD1008, haloperidol, and (+)-pentazocine (Ki = 5.06 +/- 0.40, 32.6 +/- 2.75, and 48.1 +/- 8.60 nM, respectively), which is consistent with sigma receptor pharmacology. Competition binding studies of 4-[125I]PEMP in melanoma (A375) and MCF-7 breast cancer cells showed a high affinity, dose-dependent inhibition of binding with known sigma ligand N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(1-pyrrolidinyl) ethylamine, BD1008 (Ki = 5, 11 nM, respectively), supporting the labeling of sigma sites in these cells. Haloperidol, however showed a weaker (Ki = 100-200 nM) affinity for the sites labeled by 4-[125I]PEMP in these cells. Biodistribution studies of 4-[125I]PEMP in rats showed a fast clearance of this radiopharmaceutical from blood, liver, lung, and other organs. A co-injection of 4-IPEMP with 4-[125I]PEMP resulted in 37%, 69%, and 35% decrease in activity in liver, kidney, and brain (organs possessing sigma receptors), respectively at 1-h postinjection. These results suggest that 4-[125I]PEMP is a promising radiopharmaceutical for pursuing further studies in animal models with tumors.
authors.affiliation: Radiopharmaceutical Chemistry Section, George Washington University Medical Center, Washington, DC 20037, USA. Johncs@gwis2.circ.gwu.edu
authors.forename: C S
authors.initials: CS
authors.lastname: John
authors.forename: M E
authors.initials: ME
authors.lastname: Gulden
authors.forename: B J
authors.initials: BJ
authors.lastname: Vilner
authors.forename: W D
authors.initials: WD
authors.lastname: Bowen
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism / Q000648:ultrastructure; D001943:Breast Neoplasms / Q000000981:diagnostic imaging / Q000378:metabolism / Q000648:ultrastructure*; D006168:Guinea Pigs; D006801:Humans; D007457:Iodine Radioisotopes; D007553:Isotope Labeling; D008024:Ligands; D008545:Melanoma / Q000000981:diagnostic imaging / Q000378:metabolism / Q000648:ultrastructure*; D010880:Piperidines / Q000138:chemical synthesis* / Q000378:metabolism / Q000493:pharmacokinetics*; D011877:Radionuclide Imaging; D051381:Rats; D017207:Rats, Sprague-Dawley; D017480:Receptors, sigma / Q000378:metabolism*; D015203:Reproducibility of Results; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured
chemical_list: D007457:Iodine Radioisotopes; D008024:Ligands; C104324:N-(2-(4-bromophenyl)ethyl)-N-methyl-2-(1-piperidinyl)ethylamine; C104323:N-(2-(4-iodophenyl)ethyl)--N-methyl-2-(1-piperidinyl)ethylamine; D010880:Piperidines; D017480:Receptors, sigma