title: Synthesis and evaluation of (18)F-labeled choline analogs as oncologic PET tracers.
abstract: Elevated levels of choline (trimethyl-2-hydroxyethylammonium) and choline kinase (CK) activity in neoplasms have motivated the development of positron-labeled choline analogs for noninvasive detection of cancer using PET. The aim of this study was to further evaluate [(18)F]fluorocholine (fluoromethyl-dimethyl-2-hydroxyethylammonium [FCH]) as an oncologic probe in comparison with several other closely related molecules.
  
  
  METHODS
  FCH, [(18)F]fluoromethyl-methylethyl-2-hydroxyethylammonium (FMEC), [(18)F]fluoroethyl-dimethyl-2-hydroxyethylammonium (FEC), and [(18)F]fluoropropyl-dimethyl-2-hydroxyethylammonium (FPC) were synthesized through [(18)F]fluoroalkylation reactions. In vitro phosphorylation rates of the (18)F-labeled choline analogs and [methyl-(14)C]choline (CH) were studied using yeast CK. Several choline radiotracers were also evaluated in cultured PC-3 human prostate cancer cells. Data on chemical stability, radiation dosimetry, and toxicity of FCH were obtained. PET studies with FCH were performed on a patient with prostate cancer and a patient with a brain tumor.
  
  
  RESULTS
  FCH and FMEC revealed in vitro phosphorylation by CK that was similar to that of choline, whereas rates of phosphorylation of FEC and FPC were 30% (P < 0.01) and 60% (P < 0.01) lower, respectively. Accumulations of FCH, CH, and FPC in cultured PC-3 cancer cells were comparable, whereas uptake of FEC was approximately one fifth that of FCH. Dosimetry estimates using FCH biodistribution data in mice indicated that the kidneys are radiation-dose-critical organs for FCH. PET images of a patient with recurrent prostate cancer showed uptake of FCH in the prostatic bed and in metastases to lymph nodes. FCH PET showed uptake in malignancies in a patient with metastatic breast cancer. PET revealed FCH uptake in biopsy-proven recurrent brain tumor with little confounding uptake by normal brain tissues.
  
  
  CONCLUSIONS
  The fluoromethyl choline analog FCH may serve as a probe of choline uptake and phosphorylation in cancer cells, whereas fluoroethyl (FEC) and fluoropropyl (FPC) analogs appear to have relatively poorer biologic compatibility. Preliminary PET studies on patients with prostate cancer and with breast cancer and brain tumor support further studies to evaluate the usefulness of FCH as an oncologic probe.
authors.affiliation: Department of Radiology, Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: T R
authors.initials: TR
authors.lastname: DeGrado
authors.forename: S W
authors.initials: SW
authors.lastname: Baldwin
authors.forename: S
authors.initials: S
authors.lastname: Wang
authors.forename: M D
authors.initials: MD
authors.lastname: Orr
authors.forename: R P
authors.initials: RP
authors.lastname: Liao
authors.forename: H S
authors.initials: HS
authors.lastname: Friedman
authors.forename: R
authors.initials: R
authors.lastname: Reiman
authors.forename: D T
authors.initials: DT
authors.lastname: Price
authors.forename: R E
authors.initials: RE
authors.lastname: Coleman
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D001932:Brain Neoplasms / Q000000981:diagnostic imaging; D001943:Breast Neoplasms / Q000000981:diagnostic imaging; D002794:Choline / Q000031:analogs & derivatives; D005260:Female; D005462:Fluorine Radioisotopes; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008875:Middle Aged; D011471:Prostatic Neoplasms / Q000000981:diagnostic imaging; D000644:Quaternary Ammonium Compounds; D011874:Radiometry; D019275:Radiopharmaceuticals; D014018:Tissue Distribution; D014055:Tomography, Emission-Computed
chemical_list: D005462:Fluorine Radioisotopes; D000644:Quaternary Ammonium Compounds; D019275:Radiopharmaceuticals; C419185:fluoromethyl dimethyl-2-hydroxyethylammonium; D002794:Choline