Click Synthesis and Biologic Evaluation of (R)- and (S)-2-Amino-3-[1-(2-[¹⁸F]Fluoroethyl)-1H-[1,2,3]Triazol-4-yl]Propanoic Acid for Brain Tumor Imaging with Positron Emission Tomography

Abstract

The (R)- and (S)-enantiomers of 2-amino-3-[1-(2-[18F]fluoroethyl)-1H-[1,2,3]triazol-4-yl]propanoic acid (4) were synthesized and evaluated in the rat 9L gliosarcoma brain tumor model using cell uptake assays, biodistribution studies, and micro-positron emission tomography (microPET). The (R)- and (S)-enantiomers of [18F]4 were radiolabeled separately using the click reaction in 57% and 51% decay-corrected yields, respectively. (S)-[18F]4 was a substrate for cationic amino acid transport and, to a lesser extent, system L transport in vitro. In vivo biodistribution studies demonstrated that (S)-[18F]4 provided higher tumor uptake and higher tumor to brain ratios (15:1 at the 30- and 60-minute time points) compared to the (R)-enantiomer (7:1 at the 30- and 60-minute time points). MicroPET studies with (S)-[18F]4 confirmed that this tracer provides good target to background ratios for both subcutaneous and intracranial 9L gliosarcoma tumors. Based on these results, the 1H-[1,2,3]triazole-substituted amino acid (S)-[18F]4 has promising PET properties for brain tumors and represents a novel class of radiolabeled amino acids for tumor imaging.

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

“…29 Mouse DBT glioma cells were cultured at 1 × 10 5 per 24 wells (Corning, NY, USA) for 48 h in a 5% carbon dioxide atmosphere in 10% fetal bovine serum (FBS) DMEM culture medium. Two buffer conditions with and without sodium were used for the assays.…”

“…26–28 Finally, lead compounds targeting cationic amino acid transporters including ( S )-2-amino-3-[1-(2-[ 18 F]fluoroethyl)-1 H -[1,2,3]triazol-4-yl]-propanoic acid (( S )-[ 18 F]AFETP) and N -2-[ 18 F]fluoroethyl- N -methyl-2-aminoethyltyrosine ([ 18 F]FEMAET) have been recently developed and reported. 2,29,30 …”

Radiolabeled Amino Acids for Oncologic Imaging

“…Recently, AA tracer development has explored several different transport systems for oncologic imaging, including system A (20), system xCT (21,22), glutamine transporters (23,24), and cationic AA transporters (25,26). The availability of these new tracers will provide important tools to probe the roles of these AA transport systems in specific cancers and for particular applications.…”

Facile purification and click labeling with 2-[18F]fluoroethyl azide using solid phase extraction cartridges

“…4 Although one-pot click labeling can be readily adapted to automated production, for some compounds the requirement for larger amounts of alkyne precursors and the alkaline reaction conditions lead to difficulties in purification and promote side reactions. 5,6 A vacuum trap-to-trap method has been used to efficiently isolate [ 18 F] 2 , but the low temperature trap is not compatible with automated modules. 7 The increasing use of and demand for automated production of PET tracers including [ 18 F]ICMT-11, 8 [ 18 F]AFTEP, 9 and [ 18 F]FluorApotrace (WC-4-116), 10 have led us to develop a solid phase method for click labeling which can be readily incorporated in the automated production of these tracers using [ 18 F] 2 .…”

“…Because the reactivity of alkynes varies considerably depending on the electronic and steric environment of the substrate, consideration should be given to those factors during a labeling of new tracers. Using this method, we were able to make [ 18 F] AFTEP ( 7a ) 6 using only 1–1.5 mg substrate and establish the automated production of 8a (FluorApotrace).…”