TY - JOUR
T1 - Effect of α-Methyl versus α-Hydrogen Substitution on Brain Availability and Tumor Imaging Properties of Heptanoic [F-18]Fluoroalkyl Amino Acids for Positron Emission Tomography (PET)
AU - Bouhlel, Ahlem
AU - Alyami, Wadha
AU - Li, Aixiao
AU - Yuan, Liya
AU - Rich, Keith
AU - McConathy, Jonathan
N1 - Funding Information:
This research was supported through grants from the National Cancer Institute (K08CA154790) and Department of Energy (SC0004832). We thank also the Siteman Cancer Center Small Animal Imaging Core for the use of the Pre-Clinical PET/CT Imaging Facility, which provided biodistribution and small animal PET/CT services. The Siteman Cancer Center is funded in part through the National Cancer Institute (P30CA091842). The Siemens Inveon scanner was acquired through an NIH High-End Instrumentation grant (S10 RR 025097). We would like to thank the Department of Chemistry staff and the Washington University High Resolution NMR Facility for assistance with NMR spectra; purchase of the 400 MHz NMR instrument was partially supported by S10 RR027207 from the NIH Shared Instrument Grant program. The mass spectral data from Washington University Mass Spectrometry Resource were supported by grants from the National Institute of General Medical Sciences (8 P41 GM103422-35) from the National Institutes of Health.
Publisher Copyright:
© 2016 American Chemical Society.
PY - 2016/4/28
Y1 - 2016/4/28
N2 - Two [18F]fluoroalkyl substituted amino acids differing only by the presence or absence of a methyl group on the α-carbon, (S)-2-amino-7-[18F]fluoro-2-methylheptanoic acid ((S)-[18F]FAMHep, (S)-[18F]14) and (S)-2-amino-7-[18F]fluoroheptanoic acid ((S)-[18F]FAHep, (S)-[18F]15), were developed for brain tumor imaging and compared to the well-established system L amino acid tracer, O-(2-[18F]fluoroethyl)-l-tyrosine ([18F]FET), in the delayed brain tumor (DBT) mouse model of high-grade glioma. Cell uptake, biodistribution, and PET/CT imaging studies showed differences in amino acid transport of these tracer by DBT cells. Recognition of (S)-[18F]15 but not (S)-[18F]14 by system L amino acid transporters led to approximately 8-10-fold higher uptake of the α-hydrogen substituted analogue (S)-[18F]15 in normal brain. (S)-[18F]15 had imaging properties similar to those of (S)-[18F]FET in the DBT tumor model while (S)-[18F]14 afforded higher tumor to brain ratios due to much lower uptake by normal brain. These results have important implications for the future development of α-alkyl and α,α-dialkyl substituted amino acids for brain tumor imaging.
AB - Two [18F]fluoroalkyl substituted amino acids differing only by the presence or absence of a methyl group on the α-carbon, (S)-2-amino-7-[18F]fluoro-2-methylheptanoic acid ((S)-[18F]FAMHep, (S)-[18F]14) and (S)-2-amino-7-[18F]fluoroheptanoic acid ((S)-[18F]FAHep, (S)-[18F]15), were developed for brain tumor imaging and compared to the well-established system L amino acid tracer, O-(2-[18F]fluoroethyl)-l-tyrosine ([18F]FET), in the delayed brain tumor (DBT) mouse model of high-grade glioma. Cell uptake, biodistribution, and PET/CT imaging studies showed differences in amino acid transport of these tracer by DBT cells. Recognition of (S)-[18F]15 but not (S)-[18F]14 by system L amino acid transporters led to approximately 8-10-fold higher uptake of the α-hydrogen substituted analogue (S)-[18F]15 in normal brain. (S)-[18F]15 had imaging properties similar to those of (S)-[18F]FET in the DBT tumor model while (S)-[18F]14 afforded higher tumor to brain ratios due to much lower uptake by normal brain. These results have important implications for the future development of α-alkyl and α,α-dialkyl substituted amino acids for brain tumor imaging.
UR - http://www.scopus.com/inward/record.url?scp=84966359534&partnerID=8YFLogxK
U2 - 10.1021/acs.jmedchem.6b00189
DO - 10.1021/acs.jmedchem.6b00189
M3 - Article
C2 - 26967318
AN - SCOPUS:84966359534
SN - 0022-2623
VL - 59
SP - 3515
EP - 3531
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 7
ER -