Synthesis, Radiolabeling, and Biological Evaluation of (R)- and (S)-2-Amino-5-[¹⁸F]fluoro-2-methylpentanoic Acid ((R)-, (S)-[¹⁸F]FAMPe) as Potential Positron Emission Tomography Tracers for Brain Tumors

Abstract

A novel 18F-labeled α,α-disubstituted amino acid-based tracer, 2-amino-5-[18F]fluoro-2-methylpentanoic acid ([18F]FAMPe), has been developed for brain tumor imaging with a longer alkyl side chain than previously reported compounds to increase brain availability via system L amino acid transport. Both enantiomers of [18F]FAMPe were obtained in good radiochemical yield (24–52% n = 8) and high radiochemical purity (>99%). In vitro uptake assays in mouse DBT gliomas cells revealed that (S)-[18F]FAMPe enters cells partly via sodium-independent system L transporters and also via other nonsystem A transport systems including transporters that recognize glutamine. Biodistribution and small animal PET/CT studies in the mouse DBT model of glioblastoma showed that both (R)- and (S)-[18F]FAMPe have good tumor imaging properties with the (S)-enantiomer providing higher tumor uptake and tumor to brain ratios. Comparison of the SUVs showed that (S)- [18F]FAMPe had higher tumor to brain ratios compared to (S)-[18F]FET, a well-established system L substrate.

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)

“…The subsequent steps were based on the previously reported synthesis of ( S )-[ 18 F]FAMPe. 24 Thus, the alkene on the alkyl side chain of the amino acid was converted into a terminal alcohol to obtain compound ( S )- 3 (54%). The alcohol group of ( S )- 3 was in turn converted into a good leaving group to provide the tosylate labeling precursor ( S )- 4 in moderate yield (36%) with some unreacted starting material remaining (32%).…”

“…The use of the C18 cartridge before the HPLC as described previously for FAMPe was eliminated. 24 Omitting that step reduced the loss of the intermediate, ( S )-[ 18 F] 16 or ( S )-[ 18 F] 17 , in the reaction vessel and increased the overall yield of final radiolabeled product. The collected fractions containing the desired 18 F-labeled product eluted from the HPLC were then combined and passed through a light hydrophilic–lipophilic-balanced (HLB) cartridge that retained the intermediate ( S )-[ 18 F] 16 or ( S )-[ 18 F] 17 and allowed removal of the acetonitrile from the mobile phase.…”

“…The α -hydrogen substituted amino acid, ( S )-[ 18 F] 15 , was a very good substrate for system L, with an in vitro transport profile very similar to that of [ 18 F]FET as previously reported using the same assay conditions and cell line. 24 ( S )-[ 18 F] 14 is not a good substrate for system L, which is somewhat surprising given that aromatic substituted amino acids such as [ 18 F]FAMT and [ 123 I]IMT have been reported by other groups to be effective system L substrates. 20,34,35 In contrast, our in vitro cell uptake studies demonstrate that the presence or absence of an α -methyl group on the amino acid can dramatically change the mechanism of transport of this class of α -alkyl amino acids.…”

“…24,43 Mouse DBT glioma cells were used in these assays. Two buffer conditions (one with and one without sodium) were used for the assays.…”

A silicon‐labelled amino acid suitable for late‐stage fluorination and unexpected oxidative cleavage reactions in the preparation of a key intermediate in the Strecker synthesis

“…Amino acids that can be labelled with [ [18] F]-fluoride are important for accessing peptides and proteins used in positron emission tomography (PET). [1][2][3][4][5][6][7][8][9] Silicon-containing amino acids have emerged as useful residues in this context. [10] Among the more common strategies for [18] F labelling at silicon is the isotopic exchange of Si- [19] F for Si- [18] F (Scheme 1A).…”