RADIOLABELLING AND PET IMAGING OF COPPER-64 LABELED ISODGR DERIVATIVE

Integrins play a pivotal role in many physiological processes such as neo-angiogenesis, cell adhesion and proliferation, and thus are key proteins in pathological disorders such as cancer metastasis, thrombosis, osteoporosis, and autoimmune diseases. For molecular imaging agents based on small peptidic integrin ligands, such as the αvβ3-integrin ligand c(RGDfK), has been found to greatly improve target affinities and in vivo performance. Kessler et al. described the systematic screening of c(-phg-isoDGR-X-) lead motif aiming to confer to the small lead pentapeptide selectivity toward the Fn-binding integrins α5β1 and αvβ6 (1). The cyclic peptide c(-phg-isoDGR-k-) and c(-phg-isoDGR-K-) displayed an antagonistic activity for α5β1, thus representing the first report of a small-sized, highly active, cyclic peptide targeting α5β1 integrins (2). Copper-64 labeled ligands are useful in PET studies because of the clinically suitable nuclear properties of copper-64 and its availability at high molar activity. This property allows sufficient time for clearance of non-specific radioactivity from background tissues to increase image contrast, which requires long times to circulate throughout the whole body. Moreover, copper-64 labeled ligands are demonstrably effective for radioimmunotherapy. Here, we report radiolabeling and evaluation of copper-64 labeled c(-phg-isoDGR-X(DOTA)-) (X:k or K). Copper-64 for radiolabeling were produced at the National Institute of Radiological Science (3). [64Cu]-c(-phg-isoDGR-k(DOTA)-) (1a) and [64Cu]-c(-phg-isoDGR-K(DOTA)-) (1b) was synthesized by DOTA-containing cyclic peptides with [64Cu]CuCl2 in citric buffer solution (pH 5.5) at r.t. for 30 min. High radiolabeling efficiency of copper-64 for DOTA-containing cyclic peptide yielded 1a and 1b with >99% radiochemical purity. In vivo regional distributions were determined in B16B10-bearing mice. PET sacns for 1a and 1b enabled visualization of α5β1 integlins on B16B10 cells in the mice. (1) Frank, A. O. et al. Angew. Chem., Int. Ed. 2010, 49, 9278−9281. (2) Bochen, A. et al. J. Med. Chem. 2013, 56, 1509−1519. (3) Ohya, T. et al. Nucl. Med. Biol. 2016, 43(11), 685-691.
第57回ペプチド討論会