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)

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.