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.