Synthesis, Cu(II) complexation, 64Cu-labeling and biological evaluation of cross-bridged cyclam chelators with phosphonate pendant arms

Riccardo Ferdani; Dannon J. Stigers; Ashley L. Fiamengo; Lihui Wei; Barbara T. Y. Li; James A. Golen; Arnold L. Rheingold; Gary R. Weisman; Edward H. Wong; Carolyn J. Anderson

doi:10.1039/C1DT11743B

Synthesis, Cu(ii) complexation, ⁶⁴Cu-labeling and biological evaluation of cross-bridged cyclam chelators with phosphonate pendant arms†

Riccardo Ferdani,^a Dannon J. Stigers,^b Ashley L. Fiamengo,^a Lihui Wei,^a Barbara T. Y. Li,^b James A. Golen,^c Arnold L. Rheingold,^d Gary R. Weisman,*^be Edward H. Wong*^bf and Carolyn J. Anderson*^agh

Author affiliations

* Corresponding authors

^a Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Missouri, USA

^b Department of Chemistry, University of New Hampshire, Durham, New Hampshire, USA

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

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

^e
E-mail: gary.weisman@unh.edu

^f
E-mail: ehw@unh.edu

^g Department of Biochemistry and Molecular Biophysics; Department of Chemistry, Washington University, St. Louis, Missouri, USA

^h Current address: Department of Radiology, University of Pittsburgh, Pittsburgh, USA
E-mail: andersoncj@upmc.edu

Abstract

A new class of cross-bridged cyclam-based macrocycles featuring phosphonate pendant groups has been developed. 1,4,8,11-tetraazacyclotetradecane-1,8-di(methanephosphonic acid) (CB-TE2P, 1) and 1,4,8,11-tetraazacyclotetradecane-1-(methanephosphonic acid)-8-(methanecarboxylic acid) (CB-TE1A1P, 2) have been synthesized and have been shown to readily form neutral copper(II) complexes at room temperature as the corresponding dianions. Both complexes showed high kinetic inertness to demetallation and crystal structures confirmed complete encapsulation of copper(II) ion within each macrocycle's cleft-like structure. Unprecedented for cross-bridged cyclam derivatives, both CB-TE2P (1) and CB-TE1A1P (2) can be radiolabeled with ⁶⁴Cu at room temperature in less than 1 h with specific activities >1 mCi μg⁻¹. The in vivo behavior of both ⁶⁴Cu-CB-TE2P and ⁶⁴Cu-CB-TE1A1P were investigated through biodistribution studies using healthy male Lewis rats. Both new compounds showed rapid clearance with similar or lower accumulation in non-target organs/tissues when compared to other copperchelators including CB-TE2A, NOTA and Diamsar.

Dalton Transactions

Synthesis, Cu(ii) complexation, ⁶⁴Cu-labeling and biological evaluation of cross-bridged cyclam chelators with phosphonate pendant arms†

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Synthesis, Cu(II) complexation, ⁶⁴Cu-labeling and biological evaluation of cross-bridged cyclam chelators with phosphonate pendant arms

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