title: Evaluation of phenylpiperazines as targeting agents for neuroblastoma.
abstract: The potential of radiolabelled phenylpiperazines as agents for the detection and therapy of tumours of neural crest origin was evaluated by in vitro pharmacological studies with human neuroblastoma cell lines [SK-N-SH and SK-N-BE(2C)], and in vivo by biodistribution measurements. The ability of phenylpiperazines: 4-phenyl-piperazine (PP), 1-carboxamidino-4-phenyl-piperazine (CAPP), [4-(3-chlorophenyl)-piperazine (mCPP), 4-(3-trifluoro methyl phenyl)-piperazine (TFMPP), and (1,1-dimethyl-4-phenyl)-piperazinium hydrochloride (DMPP) and chlorophenyl hydroxypiperidine [CP(OH)P], to inhibit MIBG uptake by neuroblastoma cells was determined by incubation with [125I]MIBG (0.1 microM) for 2 h in the presence of varying concentrations (10(-8)-10(-3) M) of ligand. For measuring uptake, cells were incubated with [125I]IPP (0.1 microM) and cell-associated radioactivity was measured at various times. Retention was studied by incubating cells in the presence of [125I]IPP (0.1 microM) for 2 h, followed by replacement with drug-free medium and determination of cell-bound radioactivity. Selectivity of [125I]IPP uptake was studied by inhibition studies with MIBG, DMI, 5HT and phenylpiperazines. The biodistribution of [125I]IPP was measured in normal rats at 0.083, 0.5, 1, 2 and 24 h (six animals per group). The IC50S (microM) for inhibition of [125I]MIBG uptake were: PP, 1.5; CPP, 2.5; CAPP, 2.5; DMPP, 5; CP(OH)P, 30 and TFMPP, 65. The rate of cellular uptake of [125I]IPP was greatest between 0 and 60 min and decreased after 60 min, similar to MIBG. After an initial rapid washout of approximately 50% of the radioactivity, retention remained constant for 3 h. The IC50S (microM) for inhibition of [125I]IPP uptake were: MIBG, 18-25; DMI, 0.6-1.5; 5HT, > 100; IPP, 1.8-2.5; CPP, 7.0-9.0 and TFMPP, > or = 20. The in vivo studies demonstrated a pattern of distribution similar to MIBG. The results demonstrate that phenylpiperazines display significant affinity for neuroblastoma with uptake and retention characteristics similar to MIBG.
authors.affiliation: Department of Radiology, Massachusetts General Hospital, Boston, USA.
authors.forename: J W
authors.initials: JW
authors.lastname: Babich
authors.forename: W A
authors.initials: WA
authors.lastname: Graham
authors.forename: A J
authors.initials: AJ
authors.lastname: Fischman
mesh_terms: D019797:3-Iodobenzylguanidine; D000818:Animals; D001667:Binding, Competitive; D006801:Humans; D007457:Iodine Radioisotopes; D007462:Iodobenzenes / Q000493:pharmacokinetics; D007553:Isotope Labeling; D008297:Male; D009447:Neuroblastoma / Q000175:diagnosis*; D010879:Piperazines / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured
chemical_list: D007457:Iodine Radioisotopes; D007462:Iodobenzenes; D010879:Piperazines; D019797:3-Iodobenzylguanidine