title: Synthesis and in vitro/in vivo evaluation of 99mTc-labeled folate conjugates for folate receptor imaging.
abstract: BACKGROUND
  Folate receptor (FR) is a potential molecular target for radionuclide imaging since it is overexpressed in many human epithelial tumor cells. In this study, a novel folate conjugate was synthesized and labeled with (99m)Tc using different coligands. In vitro and in vivo evaluations of these complexes have been done to explore the effect of coligands on the stable, affinity and pharmacokinetic properties.
  
  
  METHODS
  A novel folate conjugate, HYNIC-NHHN-FA, was synthesized and characterized. This conjugate was radiolabeled with (99m)Tc using tricine, tricine/diphenylphosphinobenzene-3-sulfonic acid sodium (TPPMS) and tricine/trisodium triphenylphosphine-3,3',3''-trisulfonate (TPPTS) as coligands, respectively. The complexes were purified by high-pressure liquid chromatography (HPLC). In vitro and in vivo evaluations were performed with FR-positive KB cells, normal Kunming mice and athymic nude mice bearing KB tumors.
  
  
  RESULTS
  Labeling with (99m)Tc using different coligands resulted in three complexes, (99m)Tc (HYNIC-NHHN-FA)(tricine), 5, (99m)Tc (HYNIC-NHHN-FA)(tricine/TPPMS), 6 and (99m)Tc (HYNIC-NHHN-FA)(tricine/TPPTS), 7. Complex 5 showed at least two isomers and was unstable after being purified by HPLC. Complexes 6 and 7 displayed high stability and similar affinity to FR in vitro. Biodistribution results in athymic nude mice bearing KB tumor showed that complex 7 had a high uptake in FR-positive tumor (9.79±1.66%ID/g at 4 h postinjection), and the results of blockade studies confirmed the specific accumulation of the radiotracer in vivo. However, complex 6 showed a low tumor uptake due to its fast excretion via the gastrointestinal tract.
  
  
  CONCLUSIONS
  The modification of the coligands can significantly alter the pharmacokinetic properties of the corresponding (99m)Tc-HYNIC complexes. (99m)Tc (HYNIC-NHHN-FA)(tricine/TPPTS), 7 could be a promising radiotracer for FR imaging.
authors.affiliation: Key Laboratory of Radiopharmaceuticals, Ministry of Education, College of Chemistry, Beijing Normal University, Beijing 100875, P. R. China. ljie74@bnu.edu.cn
authors.forename: Jie
authors.initials: J
authors.lastname: Lu
authors.forename: Yan
authors.initials: Y
authors.lastname: Pang
authors.forename: Fang
authors.initials: F
authors.lastname: Xie
authors.forename: Hongjuan
authors.initials: H
authors.lastname: Guo
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.forename: Zhi
authors.initials: Z
authors.lastname: Yang
authors.forename: Xuebin
authors.initials: X
authors.lastname: Wang
mesh_terms: D000818:Animals; D058973:Folate Receptors, GPI-Anchored / Q000378:metabolism*; D005492:Folic Acid / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics; D006801:Humans; D007624:KB Cells; D008024:Ligands; D051379:Mice; D057054:Molecular Imaging / Q000379:methods*; D015609:Organotechnetium Compounds / Q000737:chemistry*; D011854:Radiochemistry
chemical_list: D058973:Folate Receptors, GPI-Anchored; D008024:Ligands; D015609:Organotechnetium Compounds; D005492:Folic Acid