title: Synthesis and application of 188Re-MN-16ET/Lipiodol in a hepatocellular carcinoma animal model.
abstract: BACKGROUND
  Hepatocellular carcinoma is the most common form of primary hepatic carcinoma. A new N(2)S(2) tetradentate ligand, N-[2-(triphenylmethyl)thioethyl]-3-aza-19-ethyloxycarbonyl-3-[2-(triphenylmethyl)thioethyl]octadecanoate (H(3)MN-16ET), was introduced and labeled with (188)Re to create (188)Re-MN-16ET in the Lipiodol phase. The potential of (188)Re-MN-16ET/Lipiodol for hepatoma therapy was evaluated in a hepatocellular carcinoma animal model of Sprague-Dawley rats implanted with the N1S1 cell line.
  
  
  METHODS
  Synthesis of H(3)MN-16ET was described, and characterization was identified by infrared, nuclear magnetic resonance and mass spectra. We compared the effects of transchelating agents (glucoheptonate or tartaric acid) and a reducing agent (stannous chloride) on the complexing of (188)Re-perrhenate and H(3)MN-16ET. Twenty-four rats implanted with hepatoma were injected with 3.7 MBq/0.1 ml of (188)Re-MN-16ET/Lipiodol or (188)Re-MN-16ET via transcatheter arterial embolization. Biodistribution experiments and single-photon emission computed tomography imaging were performed to investigate tumor accumulation.
  
  
  RESULTS
  H(3)MN-16ET was proved to easily conjugate with the Re isotope and showed good solubility in Lipiodol. The radiochemical purity of (188)Re-MN-16ET/Lipiodol with 10 mg tartaric acid and stannous chloride was shown to be more than 90%. The major distribution sites of (188)Re-MN-16ET in Sprague-Dawley rats were hepatoma and the liver. However, the radioactivity at the tumor site postadministered with (188)Re-MN-16ET was quickly decreased from 9.15±0.23 (at 1 h) to 2.71%±0.18% of injected dose/g (at 48 h). The biodistribution and micro-single-photon emission computed tomography/computed tomography image data showed that (188)Re-MN-16ET/Lipiodol was selectively retained at the tumor site, with 11.55±1.44, 13.16±1.46 and 10.67%±0.95% of injected dose/g at 1, 24 and 48 h postinjection, respectively. The radioactivity in normal liver tissue was high but significantly lower than that of the tumors.
  
  
  CONCLUSIONS
  H(3)MN-16ET is a suitable tetradentate ligand for (188)Re labeling. From the animal data, we suggest that (188)Re-MN-16ET/Lipiodol has the potential to be a therapeutic radiopharmaceutical for hepatoma treatment.
authors.affiliation: Isotope Application Division, Institute of Nuclear Energy Research, Taoyuan, Taiwan 32546.
authors.forename: I-Chang
authors.initials: IC
authors.lastname: Tang
authors.forename: Tsai-Yueh
authors.initials: TY
authors.lastname: Luo
authors.forename: Show-Wen
authors.initials: SW
authors.lastname: Liu
authors.forename: Sun-Ho
authors.initials: SH
authors.lastname: Chan
authors.forename: Hong-Chang
authors.initials: HC
authors.lastname: Kung
authors.forename: Cheng-Liang
authors.initials: CL
authors.lastname: Peng
authors.forename: Wan-Yu
authors.initials: WY
authors.lastname: Lin
authors.forename: Yu
authors.initials: Y
authors.lastname: Chang
authors.forename: Wuu-Jyh
authors.initials: WJ
authors.lastname: Lin
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000000981:diagnostic imaging / Q000378:metabolism / Q000532:radiotherapy*; D045744:Cell Line, Tumor; D056831:Coordination Complexes / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004998:Ethiodized Oil / Q000737:chemistry*; D005998:Glycine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D008113:Liver Neoplasms / Q000000981:diagnostic imaging / Q000378:metabolism / Q000532:radiotherapy*; D008297:Male; D010169:Palmitic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011854:Radiochemistry; D011868:Radioisotopes / Q000627:therapeutic use*; D051381:Rats; D012211:Rhenium / Q000627:therapeutic use*; D013228:Stearates / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D015899:Tomography, Emission-Computed, Single-Photon
chemical_list: C569624:188Re-MN-16ET; D056831:Coordination Complexes; C569623:N-(2-(triphenylmethyl)thioethyl)-3-aza-19-ethyloxycarbonyl-3-(2-(triphenylmethyl)thioethyl)octadecanoate; D010169:Palmitic Acids; D011868:Radioisotopes; D013228:Stearates; D012211:Rhenium; D004998:Ethiodized Oil; D005998:Glycine