title: Synthesis, in vitro pharmacologic characterization, and preclinical evaluation of N-[2-(1'-piperidinyl)ethyl]-3-[125I]iodo-4-methoxybenzamide (P[125I]MBA) for imaging breast cancer.
abstract: The goal of this study was to investigate the potential use of a radioiodinated benzamide, N-[2-(1'-piperidinyl)ethyl]-3-iodo[125I]-4-methoxybenzamide (P[125I]MBA), a sigma receptor binding radioligand for imaging breast cancer. The chemical and radiochemical syntheses of PIMBA are described. The pharmacological evaluation of PIMBA was carried out for sigma-1 and sigma-2 receptor sites. The in vivo pharmacokinetics of the radioiodinated benzamide were determined in rats and comparison of P[125I]MBA with Tc-99m sestamibi were made in a rat mammary tumor model. Sigma-1 affinity (Ki) for PIMBA in guinea pig brain membranes using [3H](+)pentazocine was found to be 11.82 +/- 0.68 nM, whereas sigma-2 affinity in rat liver using [3H]DTG (1,3-o-di-tolylguanidine) was 206 +/- 11 nM. Sites in guinea pig brain membranes labeled by P[125I]MBA showed high affinity for haloperidol, (+)-pentazocine, BD1008, and PIMBA (Ki = 4.87 +/- 1.49, 8.81 +/- 1.97, 0.057 +/- 0.005, 46.9 +/- 1.8 nM, respectively). Competition binding studies were carried out in human ductal breast carcinoma cells (T47D). A dose-dependent inhibition of specific binding was observed with several sigma ligands. Ki values for the inhibition of P[125I]MBA binding in T47D cells for haloperidol, N-[2-(1'-piperidinyl)]ethyl]4-iodobenzamide (IPAB), N-(N-benzylpiperidin-4-yl)-4-iodobenzamide (4-IBP), and PIMBA were found to be 1.30 +/- 0.07, 13 +/- 1.5, 5.19 +/- 2.3, 1.06 +/- 0.5 nM, respectively. The in vitro binding data in guinea pig brain membranes and breast cancer cells confirmed binding to sigma sites. The saturation binding of P[125I]MBA in T47D cells as studied by Scatchard analysis showed saturable binding, with a Kd = 94 +/- 7 nM and a Bmax = 2035 +/- 305 fmol/mg of proteins. Biodistribution studies in Sprague-Dawley rats showed a rapid clearance of P[125I]MBA from the normal organs. The potential of PIMBA in imaging breast cancer was evaluated in Lewis rats bearing syngeneic RMT breast cancers, a cancer that closely mimics human breast cancer histology. At 1 h postinjection, tumor uptake for P[125I]MBA and Tc-99m sestamibi were found to be 0.35 +/- 0.01 and 0.32 +/- 0.01% injected dose/organ (%ID/g), respectively. The %ID/g for liver, kidneys, and heart were 2, 11, and 20 times lower, respectively, for P[125I]MBA as compared with Tc-sestamibi. Slightly higher uptake of P[125I]MBA in tumors (than Tc-sestamibi) and a low nontarget organ uptake warrants further studies of this and other sigma receptor ligands for their use as breast cancer imaging agents.
authors.affiliation: Department of Biochemistry and Molecular Biology, George Washington University Medical Center, Washington, DC 20037, USA. radcsj@gwumc.edu
authors.forename: C S
authors.initials: CS
authors.lastname: John
authors.forename: W D
authors.initials: WD
authors.lastname: Bowen
authors.forename: S J
authors.initials: SJ
authors.lastname: Fisher
authors.forename: B B
authors.initials: BB
authors.lastname: Lim
authors.forename: B C
authors.initials: BC
authors.lastname: Geyer
authors.forename: B J
authors.initials: BJ
authors.lastname: Vilner
authors.forename: R L
authors.initials: RL
authors.lastname: Wahl
mesh_terms: D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis / Q000493:pharmacokinetics; D001665:Binding Sites; D001943:Breast Neoplasms / Q000000981:diagnostic imaging*; D005260:Female; D006168:Guinea Pigs; D006801:Humans; D007457:Iodine Radioisotopes; D010880:Piperidines / Q000138:chemical synthesis / Q000493:pharmacokinetics; D011877:Radionuclide Imaging; D051381:Rats; D011917:Rats, Inbred Lew; D017207:Rats, Sprague-Dawley; D017480:Receptors, sigma / Q000378:metabolism*; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured
chemical_list: D001549:Benzamides; D007457:Iodine Radioisotopes; C120391:N-(2-(1'-piperidinyl)ethyl)-3-iodo-4-methoxybenzamide; D010880:Piperidines; D017480:Receptors, sigma