A1 Refereed original research article in a scientific journal

Synthesis and preclinical characterization of [Cu-64]NODAGA-MAL-exendin-4 with a N-epsilon-maleoyl-l-lysyl-glycine linkage




AuthorsYim CB, Mikkola K, Fagerholm V, Elomaa VV, Ishizu T, Rajander J, Schlesinger J, Roivainen A, Nuutila P, Solin O

PublisherELSEVIER SCIENCE INC

Publication year2013

JournalNuclear Medicine and Biology

Journal name in sourceNUCLEAR MEDICINE AND BIOLOGY

Journal acronymNUCL MED BIOL

Number in series8

Volume40

Issue8

First page 1006

Last page1012

Number of pages7

ISSN0969-8051

DOIhttps://doi.org/10.1016/j.nucmedbio.2013.06.012(external)


Abstract
INTRODUCTION:

Renal localization of high radioactivity levels during targeted imaging compromises tissue visualization in the kidney region and limits diagnostic accuracy. Radioiodinated antibody fragments with a renal enzyme-cleavable N(ε)-maleoyl-L-lysyl-glycine (MAL) linkage demonstrated low renal radioactivity levels in mice, from early postinjection times. This study tested the hypothesis whether a (64)Cu-labeled NODAGA-exendin-4 peptide with a MAL linkage ([(64)Cu]NODAGA-MAL-exendin-4) could decrease kidney radioactivity levels in rats, compared to a [(64)Cu]NODAGA-exendin-4 reference, without impairing the radioactivity levels in the target tissue.


METHODS:

NODAGA-MAL-exendin-4 was synthesized in a two-phase approach using solid support to prepare maleoyl-derivatized NODAGA followed by Michael addition to cysteine-derivatized exendin-4 in solution. Radiolabeling was performed in buffered aqua with [(64)Cu]CuCl2, which was produced via the (64)Ni(p,n)(64)Cu nuclear reaction. The in vitro and in vivo stability, lipophilicity, and distribution kinetics in major rat organs for [(64)Cu]NODAGA-MAL-exendin-4 were studied and compared to [(64)Cu]NODAGA-exendin-4. Labeling of pancreatic islets was assessed using autoradiography.


RESULTS:

NODAGA-MAL-exendin-4 was synthesized, with an overall yield of 9%, and radiolabeled with (64)Cu with high specific radioactivity. Serum incubation studies showed high stability for [(64)Cu]NODAGA-MAL-exendin-4. Similar tissue distribution kinetics was observed for [(64)Cu]NODAGA-MAL-exendin-4 and [(64)Cu]NODAGA-exendin-4, with high kidney radioactivity levels.


CONCLUSIONS:

The incorporated MAL linkage in [(64)Cu]NODAGA-MAL-exendin-4 was unable to reduce kidney radioactivity levels, compared to [(64)Cu]NODAGA-exendin-4. The applicability of metabolizable linkages in the design of kidney-saving exendin-4 analogs requires further investigation.



Last updated on 2024-26-11 at 23:52