Synthesis of novel 68Ga-labeled amino acid derivatives for positron emission tomography of cancer cells.
OBJECTIVE
We developed amino acid derivatives of 1,4,7,10-tetraazacyclododecane-1,7-diacetic acid (DO2A) and 1,4,7,10-tetraazacyclododecane-1,4,7,-triacetic acid (DO3A) that can be labeled with (68)Ga, and we investigated their basic biological properties.


METHODS
Alanine derivatives of DO2A and DO3A were synthesized by regiospecific nucleophilic attack of DO2tBu and DO3tBu on the β-position of Boc-l-serine-β-lactone, followed by acid hydrolysis. Also, homoalanine derivatives were synthesized by reacting with the protected bromo derivative of homoalanine, which was synthesized from N-Cbz-l-homoserine lactone. Further catalytic reduction and acid cleavage of protected groups resulted in the required products. All derivatives were labeled with (68)Ga. Cell uptake assays were carried out in Hep3B (human hepatoma) and U87MG (human glioma) cell lines at 37°C. Positron emission tomography (PET) imaging studies were performed using balb/c mice xenografted with CT-26 (mouse colon cancer).


RESULTS
All compounds were labeled with >97% efficiency. According to in vitro studies, the labeled amino acid derivatives showed significantly greater uptakes than the control ((68)Ga 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) in cancer cells. Small animal PET images for labeled compounds showed high tumor uptake, as well as kidney and bladder uptakes, at 30 min postinjection. (68)Ga-DO3A-homoalanine showed the highest standardized uptake value ratio (3.9 ± 0.3), followed by (68)Ga-DO2A-alanine (3.1 ± 0.2), (68)Ga-DO3A-alanine (2.8 ± 0.2) and (68)Ga-DO2A-homoalanine (2.3 ± 0.2).


CONCLUSIONS
These derivatives were found to have high labeling efficiencies, high stabilities, high tumor cell uptakes, high tumor/nontumor xenograft uptakes and low nonspecific uptake in normal organs, except for the kidneys. However, the uptake mechanism of these derivatives remains unclear, and uptake via specific amino acid transporters needs to be demonstrated.
Department of Nuclear Medicine, Institute of Radiation Medicine, Seoul National University College of Medicine, Seoul 110-744, South Korea.
Dinesh
D
Shetty
Jae Min
JM
Jeong
Chang Hwan
CH
Ju
Yun-Sang
YS
Lee
Seo Young
SY
Jeong
Jae Yeon
JY
Choi
Bo Yeun
BY
Yang
Dong Soo
DS
Lee
June-Key
JK
Chung
Myung Chul
MC
Lee
D000596:Amino Acids / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D000818:Animals; D001692:Biological Transport; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D005710:Gallium Radioisotopes; D006801:Humans; D008297:Male; D051379:Mice; D009369:Neoplasms / Q000000981:diagnostic imaging / Q000473:pathology*; D049268:Positron-Emission Tomography / Q000379:methods*; D011854:Radiochemistry
D000596:Amino Acids; D005710:Gallium Radioisotopes