68Ga-labeled alanine derivatives as a novel PET agent for cancer imaging

Objectives Various amino acids labeled with ¹⁸F and ¹¹C for PET are used. However, they require expensive cyclotron and complicate synthesis procedure. We developed alanine derivatives, NOTA-ala and DOTA-ala, for labeling with ⁶⁸Ga, a generator nuclide.

Methods Protected β-amino-L-alanine was synthesizedstarting from tBoc-L-serine methyl ester by mesyl protection, azide formation and catalytic reduction. And then it was conjugated to NOTA and DOTA in aqueous solution using EDC as a coupling agent. Protecting groups were removed by lithium hydroxide (4 eq) and hydrochloric acid (30%), successively. The final products were obtained as HCl salts by HPLC purification. DOTA-ala (26.3 µg) and NOTA-ala (21.3 µg) were labeled with ⁶⁸Ga in pH 3.7~5.2. Labeling efficiencies were checked by ITLC. Biodistribution and PET imaging studies were performed using balb/c mice xenografted with CT-26.

Results Both DOTA-ala and NOTA-ala were labeled with ⁶⁸Ga in high yields (>98%). In biodistribution study, tumor uptakes were 3.3 and 2.9% ID/g at 10 min and 2.8 and 2.5% ID/g at 60 min for ⁶⁸Ga-DOTA-ala and ⁶⁸Ga-NOTA-ala, respectively. The tumor to muscle and tumor to blood uptake ratio showed significantly higher value for ⁶⁸Ga-NOTA-ala than ⁶⁸Ga-DOTA-ala. Micro PET images for both labeled compounds showed a high bladder activity at 1 h. High uptakes were found in tumors along with kidney on 2 h images comparing to other organs.

Conclusions We synthesized ⁶⁸Ga labeled amino acid derivatives for tumor PET which can be labeled by one step reaction within 10 min. The NOTA-ala derivatives showed high tumor uptakes in biodistribution and animal PET studies.