Synthesis and evaluation of macrocyclic amino acid derivatives for tumor imaging by gallium-68 positron emission tomography

• Published in: Bioorganic & medicinal chemistry 2010-11, Vol.18 (21), p.7338-7347
• Main Authors: Shetty, Dinesh, Jeong, Jae Min, Ju, Chang Hwan, Kim, Young Ju, Lee, Ji-Youn, Lee, Yun-Sang, Lee, Dong Soo, Chung, June-Key, Lee, Myung Chul
• Format: Article
• Language: English
• Subjects: 68Ga; Amino acid; Amino acids; Animals; Biological and medical sciences; Blood Proteins - chemistry; Blood Proteins - metabolism; Cell Line, Tumor; Chelating Agents - chemical synthesis; Chelating Agents - chemistry; Contrast media. Radiopharmaceuticals; DOTA; Ga-68; Gallium Radioisotopes - chemistry; Heterocyclic Compounds - chemical synthesis; Heterocyclic Compounds - chemistry; Heterocyclic Compounds, 1-Ring - chemical synthesis; Heterocyclic Compounds, 1-Ring - chemistry; Humans; Medical sciences; Mice; Neoplasms - diagnostic imaging; NOTA; Pharmacology. Drug treatments; Positron-Emission Tomography; Protein Binding; Radiopharmaceuticals - chemical synthesis; Radiopharmaceuticals - chemistry
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2010.09.022

We have developed series of macrocyclic-amino acid derivatives for 68Ga labeling and evaluated for tumor PET imaging. 68Ga PET imaging in clinical oncology represents a notable development because the availability of 68Ga is not dependent on a cyclotron. Furthermore, labeled amino acid derivatives have been proven to be useful for the imaging many tumor types. In the present study, we synthesized β-aminoalanine, γ-aminohomoalanine, and lysine conjugates of macrocyclic bifunctional chelating agents, such as, NOTA ( 1a– c) and DOTA ( 2a– c). The compounds produced were found to be potential useful as 68Ga-PET imaging agents. In particular, they showed high tumor uptakes in vitro and in vivo, and had high labeling yields and excellent stabilities. The co-ordination chemistry of NOTA-monoamide compound 1a was studied by multinuclear NMR. In vitro studies showed that the synthesized compounds were taken up by cancer cells more than controls ( 68Ga-NOTA and 68Ga-DOTA). Furthermore, in vivo studies showed that they have high tumor to muscle and tumor to blood ratios, and small-animal PET imaging revealed high tumor uptakes as compared with other organs, and high bladder activities, indicating rapid renal excretion. These results might motivate the use of 68Ga amino acid PET for tumor diagnosis.