title: Improved PET imaging of tumors in mice using a novel (18) F-folate conjugate with an albumin-binding entity.
abstract: OBJECTIVE
  The folate receptor (FR) is a promising target for nuclear imaging due to its overexpression in many different cancer types. A drawback of using folate radioconjugates is the high accumulation of radioactivity in the kidneys. Therefore, the aim of this study was to develop a (18) F-labeled folate conjugate with an albumin-binding entity to enhance the blood circulation time and hence improve the tumor-to-kidney ratio.
  
  
  METHODS
  The novel (18) F-folate was prepared by conjugation of a (18) F-labeled glucose azide to an alkyne-functionalized folate precursor containing an albumin-binding entity via Cu(I)-catalyzed 1,3-dipolar cycloaddition. The radioconjugate was tested in vitro on FR-positive KB tumor cells and by biodistribution and positron emission tomography (PET) imaging studies using KB tumor-bearing mice.
  
  
  RESULTS
  The radiosynthesis of the albumin-binding [(18) F]fluorodeoxyglucose-folate ([(18) F]3) resulted in a radiochemical yield of 1-2 % decay corrected (d.c.) and a radiochemical purity of ≥95 %. The specific activity of [(18) F]3 ranged from 20 to 50 GBq/μmol. In vitro experiments revealed FR-specific binding of [(18) F]3 to KB tumor cells. In vivo we found an increasing uptake of [(18) F]3 into tumor xenografts over time reaching a value of ∼ 15 % injected dose (ID)/g at 4 h post-injection (p.i.). Uptake in the kidneys (∼ 13 % ID/g; 1 h p.i.) was approximately fourfold reduced compared to previously published (18) F-labeled folic acid derivatives. An excellent visualization of tumor xenografts with an unprecedentedly high tumor-to-kidney ratio (∼ 1) was obtained by PET imaging.
  
  
  CONCLUSIONS
  [(18) F]3 showed a favorable accumulation in tumor xenografts compared to the same folate conjugate without albumin-binding properties. Moreover, the increased tumor-to-kidney ratios improved the PET imaging quality significantly, in spite of a somewhat higher background radioactivity which was a consequence of the slower blood clearance of [(18) F]3.
authors.affiliation: Center for Radiopharmaceutical Sciences of ETH, PSI and USZ, Institute of Pharmaceutical Sciences, ETH Zurich, 8093, Zurich, Switzerland.
authors.forename: Cindy R
authors.initials: CR
authors.lastname: Fischer
authors.forename: Viola
authors.initials: V
authors.lastname: Groehn
authors.forename: Josefine
authors.initials: J
authors.lastname: Reber
authors.forename: Roger
authors.initials: R
authors.lastname: Schibli
authors.forename: Simon M
authors.initials: SM
authors.lastname: Ametamey
authors.forename: Cristina
authors.initials: C
authors.lastname: Müller
mesh_terms: D000418:Albumins / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D005260:Female; D019788:Fluorodeoxyglucose F18 / Q000737:chemistry / Q000493:pharmacokinetics*; D005492:Folic Acid / Q000737:chemistry / Q000493:pharmacokinetics*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000000981:diagnostic imaging*; D049268:Positron-Emission Tomography / Q000379:methods*; D019275:Radiopharmaceuticals / Q000737:chemistry / Q000493:pharmacokinetics*; D014018:Tissue Distribution
chemical_list: D000418:Albumins; D019275:Radiopharmaceuticals; D019788:Fluorodeoxyglucose F18; D005492:Folic Acid