1-(3-4-dimethoxyphenethyl)-4-(3-phenylpropyl)piperazine-dihydrochloride and Glioma

We report the design, synthesis, and evaluation of a series of novel cyclopentadienyl tricarbonyl (99m)Tc complexes as potent σ1 receptor radioligands. Rhenium compounds 3-(4-(1,3-benzodioxol-5-ylmethyl)piperazin-1-yl)propylcarbonylcyclopentadienyl tricarbonyl rhenium (10a) and 4-(4-(1,3-benzodioxol-5-ylmethyl)piperazin-1-yl)butylcarbonylcyclopentadienyl tricarbonyl rhenium (10b) possessed high in vitro affinity for σ1 receptors and moderate to high selectivity for σ2 receptors and the vesicular acetylcholine transporter. Biodistribution studies in mice demonstrated high initial brain uptake for corresponding (99m)Tc derivatives [(99m)Tc]23 and [(99m)Tc]24 of 2.94 and 2.13% injected dose (ID)/g, respectively, at 2 min postinjection. Pretreatment of haloperidol significantly reduced the radiotracer accumulation of [(99m)Tc]23 or [(99m)Tc]24 in the brain. Studies of the cellular uptake of [(99m)Tc]23 in C6 and DU145 tumor cells demonstrated a reduction of accumulation by incubation with haloperidol, 1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl)piperazine (SA4503), or 1,3-di-o-tolyl-guanidine (DTG). Furthermore, blocking studies in C6 glioma-bearing mice confirmed the specific binding of [(99m)Tc]23 to σ1 receptors in the tumor.

Topics: Animals; Brain; Brain Neoplasms; Cell Line, Tumor; Glioma; Haloperidol; Ligands; Male; Mice, Inbred ICR; Molecular Imaging; Molecular Probes; Organotechnetium Compounds; Piperazines; Prostatic Neoplasms; Receptors, sigma; Sigma-1 Receptor; Structure-Activity Relationship; Technetium; Tissue Distribution

Sigma-receptors are strongly overexpressed in most rodent and human tumors and are proliferation markers. To evaluate the potential of a radiolabeled sigma1-ligand for therapy monitoring, we compared early changes of 11C-1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl)piperazine (11C-SA4503) binding and 18F-FDG uptake in gliomas after in vivo chemotherapy.. C6 cells (2.5 x 10(6)) were subcutaneously injected into the right shoulder of male Wistar rats. After 7 d, the tumor volume was 0.60 +/- 0.08 cm3. Animals then received either saline or doxorubicin (8 mg/kg, intraperitoneally). One control and 1 treated rat were imaged simultaneously, 24 or 48 h after treatment, under pentobarbital anesthesia. Rodents (n = 20) were scanned first with 11C-SA4503 (25 MBq, intravenously) followed more than 100 min afterward by 18F-FDG (20 MBq, intravenously), using a dedicated small-animal PET camera (60-min protocol, tumors in the field of view). Tumor homogenates were prepared and subjected to sigma-receptor assays. The biodistribution of 18F-FDG was assessed.. Tumors appeared 4-5 d after inoculation and grew exponentially. No significant reduction of tumor growth was visible within 48 h after doxorubicin treatment. Both PET tracers visualized the tumors and showed reduced uptake after chemotherapy (11C-SA4503: 26.5% +/- 6.5% at 24 h, 26.5% +/- 7.5% at 48 h; 18F-FDG: 22.6% +/- 3.2% at 24 h, 27.4% +/- 3.2% at 48 h; ex vivo 18F-FDG: 22.4% +/- 5.4% at 24 h, 31.7% +/- 12.7% at 48 h). Sigma1-receptor density in treated tumors was also reduced (from 172 +/- 35 to 125 +/- 28 fmol/mg of protein).. Both 11C-SA4503 binding and 18F-FDG uptake declined in gliomas after chemotherapy. Decreased binding of 11C-SA4503 corresponded to a loss of sigma1-receptors from the tumors. Changes in tracer uptake preceded the morphologic changes by at least 48 h.

Topics: Animals; Antibiotics, Antineoplastic; Carbon Radioisotopes; Doxorubicin; Fluorodeoxyglucose F18; Glioma; Male; Piperazines; Positron-Emission Tomography; Rats; Rats, Wistar; Receptors, sigma; Tissue Distribution

Our objective was to study 2 radioligands for visualization of sigma-receptors with PET.. Two radioligands-sigma(1)-selective (11)C-1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl)piperazine ((11)C-SA4503) and nonsubtype-selective 1-(4-2'-(18)F-fluoroethoxy-3-methoxyphenethyl)-4-(3-(4-fluorophenyl)propyl)piperazine ((18)F-FE-SA5845)-were evaluated for tumor imaging.. Binding studies to rat glioma cells (C6) and human nonsmall cell lung cancer cells (N417) indicated interaction of (18)F-FE-SA5845 with 2 sites and interaction of (11)C-SA4503 with a single site. Specific binding of (18)F-FE-SA5845 was 93% +/- 2% and that of (11)C-SA4503 was 78% +/- 6% of the total cellular uptake of radioactivity. Uptake of the (18)F-labeled ligand, but not that of the (11)C-labeled ligand, appeared to be related to the growth phase of the cells. Biodistribution experiments in C6 tumor-bearing nude rats (Ham HSD RNU rnu) indicated tumor-to-plasma ratios of 13.3 for (11)C-SA4503 and 8.0 for (18)F-FE-SA5845 and tumor-to-muscle ratios of 5.0 for (11)C-SA4503 and 4.9 for (18)F-FE-SA5845, 60 min after injection, which were reduced to values ranging from 1.4 to 2.0 after pretreatment of animals with haloperidol (2 micromol/kg). Tumor uptake of (18)F-FE-SA5845 showed a negative correlation with tumor size (P < 0.0001), in contrast to that of (11)C-SA4503, suggesting that tissue binding of the former ligand is related to cellular proliferation. A study with (11)C-SA4503 in a human volunteer indicated high uptake in liver, kidney, and heart but relatively low background in thorax and lower abdomen.. Both (18)F-FE-SA5845 and (11)C-SA4503 demonstrate specific binding to sigma-receptors in vivo and may be useful for the detection of pulmonary and abdominal tumors. However, the (18)F-labeled compound may be better for tumor staging than the (11)C-labeled drug.

Topics: Aged; Animals; Carbon Radioisotopes; Cell Line, Tumor; Feasibility Studies; Female; Glioma; Humans; Metabolic Clearance Rate; Organ Specificity; Piperazines; Radionuclide Imaging; Radiopharmaceuticals; Rats; Rats, Nude; Receptors, sigma; Tissue Distribution