(S)- and (R)-[18F]NMeFAMP: PET brain tumor imaging agents

Objectives (S)- and (R)-3-[¹⁸F]fluoro-2-methyl-2-N-(methylamino)propanoic acid (NMeFAMP) were synthesized and evaluated as PET brain tumor imaging agents in a 9L rat gliosarcoma model.

Methods The cyclic sulfamidate labeling precursors were prepared from (R)-and (S)-α-methyl-serine. Treatment with di-t-butyl dicarbonate followed by N,N-dimethylformamide di-t-butyl acetal gave (R)- and (S)-N-Boc α-methyl-serine t-butyl ester. Treatment with SOCl₂, NaIO₄, removal of the N-Boc and N-methylation gave the labeling precursors. (S)-and (R)-[¹⁸F]NMeFAMP were obtained by treatment with K[¹⁸F]F/K₂₂₂, 4N HCl and chromatographic purification. Amino acid transport inhibition studies were performed with 9L rat gliosarcoma cells with 30 min incubations at 37 ^oC under control conditions, with 10 mM of BCH, system L inhibitor, or with 10 mM NMeAIB, system A inhibitor. Biodistribution studies were carried out in 9L tumor-bearing Fisher rats. The uptake (%ID/g) in tumor and normal tissue was measured at 15, 30, 60, 120 min post injection.

Results (S)- and (R)-[¹⁸F]NMeFAMP were obtained in 68% and 64% DCY (n=7), respectively, with radiochemical purity over 99%. The uptake of (S)- and (R)-[¹⁸F]NMeFAMP was inhibited 29-54% by BCH and 79-92% by MeAIB. The tumor to brain uptake ratios of (S)- and (R)-[¹⁸F]NMeFMAP were 18-138:1 with relatively low uptake in bone.

Conclusions (S)-and (R)-[¹⁸F]NMeFAMP were prepared in high DCY. Cell assay results suggested that (S)-and (R)-NMeFAMP entered tumor cells primarily via system A transport. Biodistribution studies with both enantiomers showed a high and prolonged accumulation of radioactivity in tumors with excellent tumor to brain ratios. These results support the candidacy of (S)-and (R)-[¹⁸F]NMeFAMP as PET brain tumor imaging agents.

Research Support Research supported by NIH R21 CA098891, and Nihon Medi-Physics Co., Ltd.