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Preparation of a promising angiogenesis PET imaging agent: 68Ga-labeled c(RGDyK)-isothiocyanatobenzyl-1,4,7-triazacyclononane-1,4,7-triacetic acid and feasibility studies in mice

Cited 167 time in Web of Science Cited 168 time in Scopus
Authors
Jeong, Jae Min; Hong, Mee Kyung; Chang, Young Soo; Lee, Yun-Sang; Kim, Young Joo; Cheon, Gi Jeong; Lee, Dong Soo; Chung, June-Key; Lee, Myung Chul
Issue Date
2008-04-17
Publisher
The Society of Nuclear Medicine Inc
Citation
J Nucl Med. 2008;49(5):830-836
Keywords
AnimalsAnoxia/radionuclide imagingFeasibility StudiesGallium RadioisotopesHeterocyclic Compounds/chemical synthesis/*chemistry/*diagnostic useHindlimb/blood supply/pathologyHumansIschemia/radionuclide imagingIsothiocyanates/chemical synthesis/*chemistry/*diagnostic useMaleMiceNeovascularization, Pathologic/*radionuclide imagingOligopeptides/*chemistryPositron-Emission Tomography/*methodsStaining and LabelingTransplantation, Heterologous
Abstract
Arg-Gly-Asp (RGD) derivatives have been labeled with various radioisotopes for the imaging of angiogenesis in ischemic tissue, in which alpha(v)beta(3) integrin plays an important role. In this study, cyclic Arg-Gly-Asp-D-Tyr-Lys [c(RGDyK)] was conjugated with 2-(p-isothiocyanatobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid (SCN-Bz-NOTA) and then labeled with (68)Ga. The labeled RGD so produced was subjected to an in vitro binding assay and in vivo biodistribution and PET studies. METHODS: A mixture of SCN-Bz-NOTA (660 nmol) and c(RGDyK) (600 nmol) in 0.1 M sodium carbonate buffer (pH 9.5) was allowed to react for 20 h at room temperature in the dark for thiourea bond formation. The conjugate obtained was purified by semipreparative high-performance liquid chromatography (HPLC). The purified c(RGDyK)-SCN-Bz-NOTA (NOTA-RGD) was then labeled with (68)Ga from a (68)Ge/(68)Ga generator and purified by semipreparative HPLC. A competitive binding assay for c(RGDyK) and NOTA-RGD was performed with (125)I-c(RGDyK) as a radioligand and alpha(v)beta(3) integrin-coated plates as a solid phase. (68)Ga-NOTA-RGD (0.222 MBq/100 microL) was injected, through a tail vein, into mice with hind limb ischemia and into mice bearing human colon cancer SNU-C4 xenografts. Biodistribution and imaging studies were performed at 1 and 2 h after injection. RESULTS: The labeling of NOTA-RGD with (68)Ga was straightforward. The K(i) values of c(RGDyK) and NOTA-RGD were 1.3 and 1.9 nM, respectively. In the biodistribution study, the mean +/- SD uptake of (68)Ga-NOTA-RGD by ischemic muscles was 1.6+/-0.2 percentage injected dose per gram (%ID/g); this uptake was significantly blocked by cold c(RGDyK) to 0.6+/-0.3 %ID/g (P<0.01). Tumor uptake was 5.1+/-1.0 %ID/g, and the tumor-to-blood ratio was 10.3+/-4.8. Small-animal PET revealed rapid excretion through the urine and high levels of tumor and kidney uptake. CONCLUSION: Stable (68)Ga-NOTA-RGD was obtained in a straightforward manner at a high yield and showed a high affinity for alpha(v)beta(3) integrin, specific uptake by angiogenic muscles, a high level of uptake by tumors, and rapid renal excretion. (68)Ga-NOTA-RGD was found to be a promising radioligand for the imaging of angiogenesis.
ISSN
0161-5505 (Print)
Language
English
URI
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18413379

http://jnm.snmjournals.org/cgi/reprint/49/5/830.pdf

http://hdl.handle.net/10371/67753
DOI
https://doi.org/10.2967/jnumed.107.047423
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College of Medicine/School of Medicine (의과대학/대학원)Nuclear Medicine (핵의학전공)Journal Papers (저널논문_핵의학전공)
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