The long and short of it: the influence of N-carboxyethyl versusN-carboxymethyl pendant arms on in vitro and in vivo behavior of copper complexes of cross-bridged tetraamine macrocycles

Katie J. Heroux; Katrina S. Woodin; David J. Tranchemontagne; Peter C. B. Widger; Evan Southwick; Edward H. Wong; Gary R. Weisman; Sterling A. Tomellini; Thaddeus J. Wadas; Carolyn J. Anderson; Scott Kassel; James A. Golen; Arnold L. Rheingold

doi:10.1039/B702938A

The long and short of it: the influence of N-carboxyethyl versusN-carboxymethyl pendant arms on in vitro and in vivo behavior of copper complexes of cross-bridged tetraaminemacrocycles

Katie J. Heroux,^a Katrina S. Woodin,^a David J. Tranchemontagne,^a Peter C. B. Widger,^a Evan Southwick,^a Edward H. Wong,*^a Gary R. Weisman,*^a Sterling A. Tomellini,^a Thaddeus J. Wadas,^b Carolyn J. Anderson,*^b Scott Kassel,^c James A. Golen^d and Arnold L. Rheingold^c

Author affiliations

* Corresponding authors

^a Department of Chemistry, University of New Hampshire, Durham, New Hampshire, USA
E-mail: ehw@cisunix.unh.edu, gary.weisman@unh.edu

^b Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Missouri, USA
E-mail: andersoncj@wustl.edu

^c Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California, USA

^d Department of Chemistry and Biochemistry, University of Massachusetts, Dartmouth, North Dartmouth, Massachusetts, USA

Abstract

A cross-bridged cyclam ligand bearing two N-carboxymethyl pendant arms (1) has been found to form a copper(II) complex that exhibits significantly improved biological behavior in recent research towards ⁶⁴Cu-based radiopharmaceuticals. Both the kinetic inertness and resistance to reduction of Cu–1 are believed to be relevant to its enhanced performance. To explore the influence of pendant arm length on these properties, new cross-bridged cyclam and cyclen ligands with longer N-carboxyethyl pendant arms, 2 and 4, and their respective copper(II) complexes have been synthesized. Both mono- as well as di-O-protonated forms of Cu–2 have also been isolated and structurally characterized. The spectral and structural properties of Cu–2 and Cu–4, their kinetic inertness in 5 M HCl, and electrochemical behavior have been obtained and compared to those of their N-carboxymethyl-armed homologs, Cu–1 and Cu–3. Only the cyclam-based Cu–1 and Cu–2 showed unusually high kinetic inertness towards acid decomplexation. While both of these complexes also exhibited quasi-reversible Cu(II)/Cu(I) reductions, Cu–2 is easier to reduce by a substantial margin of +400 mV, bringing it within the realm of physiological reductants. Similarly, of the cyclen-based complexes, Cu–4 is also easier to reduce than Cu–3 though both reductions are irreversible. Biodistribution studies of ⁶⁴Cu-labeled 2 and 4 were performed in Sprague Dawley rats. Despite comparable acid inertness to their shorter-armed congeners, both longer-armed ligand complexes have poorer bio-clearance properties. This inferior in vivo behavior may be a consequence of their higher reduction potentials.

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The long and short of it: the influence of N-carboxyethyl versusN-carboxymethyl pendant arms on in vitro and in vivo behavior of copper complexes of cross-bridged tetraaminemacrocycles

Abstract

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The long and short of it: the influence of N-carboxyethyl versusN-carboxymethyl pendant arms on in vitro and in vivo behavior of copper complexes of cross-bridged tetraamine macrocycles

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