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 Nε-maleoyl-l-lysyl-glycine (MAL) linkage demonstrated low renal radioactivity levels in mice, from early postinjection times. This study tested the hypothesis whether a 64Cu-labeled NODAGA-exendin-4 peptide with a MAL linkage ([64Cu]NODAGA-MAL-exendin-4) could decrease kidney radioactivity levels in rats, compared to a [64Cu]NODAGA-exendin-4 reference, without impairing the radioactivity levels in the target tissue.
Methods
NODAGA-MAL-exendin-4 was synthesized in a tw... More
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 Nε-maleoyl-l-lysyl-glycine (MAL) linkage demonstrated low renal radioactivity levels in mice, from early postinjection times. This study tested the hypothesis whether a 64Cu-labeled NODAGA-exendin-4 peptide with a MAL linkage ([64Cu]NODAGA-MAL-exendin-4) could decrease kidney radioactivity levels in rats, compared to a [64Cu]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 [64Cu]CuCl2, which was produced via the 64Ni(p,n)64Cu nuclear reaction. The in vitro and in vivo stability, lipophilicity, and distribution kinetics in major rat organs for [64Cu]NODAGA-MAL-exendin-4 were studied and compared to [64Cu]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 64Cu with high specific radioactivity. Serum incubation studies showed high stability for [64Cu]NODAGA-MAL-exendin-4. Similar tissue distribution kinetics was observed for [64Cu]NODAGA-MAL-exendin-4 and [64Cu]NODAGA-exendin-4, with high kidney radioactivity levels.
Conclusions
The incorporated MAL linkage in [64Cu]NODAGA-MAL-exendin-4 was unable to reduce kidney radioactivity levels, compared to [64Cu]NODAGA-exendin-4. The applicability of metabolizable linkages in the design of kidney-saving exendin-4 analogs requires further investigation.
