⁷⁶Br and ¹²³I radiolabeled amino acids for tumor imaging using PET and SPECT

Objectives Amino acid transport is upregulated in many tumors cells due to increased demand for nutrients, making radiolabeled amino acids useful for tumor imaging and potentially for therapeutic applications. While there are many types of amino acid transporters relevant to tumor imaging, system A is of particular interest due to its unidirectional influx of amino acids into the cell under physiological conditions. The purpose of this work was to exploit this transport by synthesizing the novel ⁷⁶Br-labeled (BrVAIB) and N-methylated/¹²³I-labeled MeIVAIB) analogues of the previously reported (S)-2-amino-2-methyl-4-[¹²³I]-iodo-3-(E)-butenoic acid (IVAIB-Yu,J. Med. Chem., 2007) and compare the properties of these compounds in the mouse DBT glioma model.

Methods The desired vinyl-trimethyl tin precursor was synthesized in four steps from enantiopure N-boc-α-methyl-L-serine. N-methylation required extra steps due to protecting group manipulation. Radioiodination reactions were carried out with [¹²³I]NaI, H₂O₂ and HCl. Bromine labeling was executed using peracetic acid and [⁷⁶Br] NH₄Br in water. Compounds were deprotected, isolated using ion-retardation resin in series with C-18 cartridges and analyzed using chiral high performance liquid chromatography (HPLC).

Results Both (S)-[⁷⁶Br]BrVAIB and (S)-[¹²³I]IVAIB were synthesized in good yields (50-60 % isolated) and purities > 99%. Biodistribution studies demonstrated maximal tumor uptake of [¹²³I]IVAIB at 2.7 + 0.6 %ID/gram 30 min post injection comparative to [⁷⁶Br]BrVAIB with 2.8 + 0.65 %ID/gram at 2 hr. However, IVAIB revealed higher tumor to normal tissues ratios than BrVAIB. Thyroid uptake was lower than tumor and most tissues, indicating that the compound did not undergo significant de-iodination in vivo. Biological and imaging studies with [¹²³I]IMeVAIB are ongoing.

Conclusions (S)-[⁷⁶Br]BrVAIB can be prepared in high radiochemical yield and demonstrates good uptake in DBT tumors.