TY - JOUR
T1 - Radiosynthesis and biological evaluation of alpha-[F-18]fluoromethyl phenylalanine for brain tumor imaging
AU - Huang, Chaofeng
AU - Yuan, Liya
AU - Rich, Keith M.
AU - McConathy, Jonathan
N1 - Funding Information:
The authors thank the personnel of the Washington University Cyclotron Facility for [ 18 F]fluoride production. We thank the Alvin J. Siteman Cancer Center at Washington University School of Medicine and Barnes-Jewish Hospital in St. Louis, Mo., for the use of the Small Animal Cancer Imaging Core, which provided biodistribution and microPET services. The Siteman Cancer Center is supported in part by an NCI Cancer Center Support Grant #P30 CA91842 . This research was funded by the National Cancer Institute ( K08CA154790 ) and the Mallinckrodt Institute of Radiology .
PY - 2013/5
Y1 - 2013/5
N2 - Objectives: Radiolabeled amino acids have proven utility for imaging brain tumors in humans, particularly those that target system L amino acid transport. We have prepared the novel phenylalanine analogue, α-[18F]fluoromethyl phenylalanine (FMePhe, 9), as part of an effort to develop new system L tracers that can be prepared in high radiochemical yield through nucleophilic [18F]fluorination. The tumor imaging properties of both enantiomers of this new tracer were evaluated through cell uptake, biodistribution and microPET studies in the mouse DBT model of high grade glioma. Methods: The non-radioactive form of 9 and the cyclic sulfamidate labeling precursor were prepared from commercially available racemic α-benzylserine. Racemic [18F]9 was prepared from the labeling precursor in two steps using standard[18F]fluoride nucleophilic reaction conditions followed by acidic deprotection. The individual enantiomers [18F]9a and [18F]9b were isolated using preparative chiral HPLC. In vitro uptake inhibition assays were performed with each enantiomer using DBT cells. Biodistribution and microPET/CT studies were performed with each enantiomer in male BALB/c mice at approximately 2weeks after implantation of DBT tumor cells. Results: Radiolabeling of the cyclic sulfamidate precursor 5 provides racemic [18F]9 in high radiochemical yield (60%-70%, n=4) and high radiochemical purity (>96%, n=4). In vitro uptake assays demonstrate that both [18F]9a and [18F]9b undergo tumor cell uptake through system L transport. The biodistribution studies using the single enantiomers [18F]9a and [18F]9b demonstrated good tumor uptake with lower uptake in most normal tissues, and [18F]9a had higher tumor uptake than [18F]9b. MicroPET imaging demonstrated good tumor visualization within 10min of injection, rapid uptake of radioactivity, and tumor to brain ratios of approximately 6:1 at 60min postinjection. Conclusions: The novel PET tracer, [18F]FMePhe, is readily synthesized in good yield from a cyclic sulfamidate precursor. Biodistribution and microPET studies in the DBT model demonstrate good tumor to tissue ratios and tumor visualization, with enantiomer [18F]9a having higher tumor uptake. However, the brain availability of both enantiomers was lower than expected for system L substrates, suggesting the [18F]fluorine group in the β-position affects uptake of these compounds by system L transporters.
AB - Objectives: Radiolabeled amino acids have proven utility for imaging brain tumors in humans, particularly those that target system L amino acid transport. We have prepared the novel phenylalanine analogue, α-[18F]fluoromethyl phenylalanine (FMePhe, 9), as part of an effort to develop new system L tracers that can be prepared in high radiochemical yield through nucleophilic [18F]fluorination. The tumor imaging properties of both enantiomers of this new tracer were evaluated through cell uptake, biodistribution and microPET studies in the mouse DBT model of high grade glioma. Methods: The non-radioactive form of 9 and the cyclic sulfamidate labeling precursor were prepared from commercially available racemic α-benzylserine. Racemic [18F]9 was prepared from the labeling precursor in two steps using standard[18F]fluoride nucleophilic reaction conditions followed by acidic deprotection. The individual enantiomers [18F]9a and [18F]9b were isolated using preparative chiral HPLC. In vitro uptake inhibition assays were performed with each enantiomer using DBT cells. Biodistribution and microPET/CT studies were performed with each enantiomer in male BALB/c mice at approximately 2weeks after implantation of DBT tumor cells. Results: Radiolabeling of the cyclic sulfamidate precursor 5 provides racemic [18F]9 in high radiochemical yield (60%-70%, n=4) and high radiochemical purity (>96%, n=4). In vitro uptake assays demonstrate that both [18F]9a and [18F]9b undergo tumor cell uptake through system L transport. The biodistribution studies using the single enantiomers [18F]9a and [18F]9b demonstrated good tumor uptake with lower uptake in most normal tissues, and [18F]9a had higher tumor uptake than [18F]9b. MicroPET imaging demonstrated good tumor visualization within 10min of injection, rapid uptake of radioactivity, and tumor to brain ratios of approximately 6:1 at 60min postinjection. Conclusions: The novel PET tracer, [18F]FMePhe, is readily synthesized in good yield from a cyclic sulfamidate precursor. Biodistribution and microPET studies in the DBT model demonstrate good tumor to tissue ratios and tumor visualization, with enantiomer [18F]9a having higher tumor uptake. However, the brain availability of both enantiomers was lower than expected for system L substrates, suggesting the [18F]fluorine group in the β-position affects uptake of these compounds by system L transporters.
KW - Amino acid
KW - Fluorine-18
KW - Glioma
KW - Positron emission tomography
KW - System L
UR - http://www.scopus.com/inward/record.url?scp=84876712066&partnerID=8YFLogxK
U2 - 10.1016/j.nucmedbio.2012.12.013
DO - 10.1016/j.nucmedbio.2012.12.013
M3 - Article
C2 - 23528560
AN - SCOPUS:84876712066
SN - 0969-8051
VL - 40
SP - 498
EP - 506
JO - Nuclear Medicine and Biology
JF - Nuclear Medicine and Biology
IS - 4
ER -