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Article

Novel Bimodal Bifunctional Ligands for Radioimmunotherapy and Targeted MRI

Supporting Info

Hyun-Soon Chong*^†, Hyun A. Song^†, Xiang Ma^†, Diane E. Milenic^‡, Erik D. Brady^‡, Sooyoun Lim^†, Haisung Lee^†, Kwamena Baidoo^‡, Dengfeng Cheng^† and Martin W. Brechbiel^‡

Chemistry Division, Biological, Chemical, and Physical Sciences Department, Illinois Institute of Technology, Chicago, Illinois, Radioimmune and Inorganic Chemistry Section, Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland

Bioconjugate Chem., 2008, 19 (7), pp 1439–1447

DOI: 10.1021/bc800050x

Publication Date (Web): June 20, 2008

* To whom correspondence should be addressed. E-mail: Chong@iit.edu, Phone: 312-567-3235, Fax: 312-567-3494. Mailing address: 3101 S. Dearborn St, LS 182, Illinois Institute of Technology, Chemistry Division, Biological, Chemical, and Physical Science Department, Chicago, IL, 60616.

†

Illinois Institute of Technology.

‡

National Cancer Institute.

Abstract

The structurally novel bifunctional ligands C-NETA and C-NE3TA, each possessing both acyclic and macrocyclic moieties, were prepared and evaluated as potential chelates for radioimmunotherapy (RIT) and targeted magnetic resonance imaging (MRI). Heptadentate C-NE3TA was fortuitously discovered during the preparation of C-NETA. An optimized synthetic method to C-NETA and C-NE3TA including purification of the polar and tailing reaction intermediates, tert-butyl C-NETA (2) and tert-butyl C-NE3TA (3) using semiprep HPLC was developed. The new Gd(III) complexes of C-NETA and C-NE3TA were prepared as contrast enhancement agents for use in targeted MRI. The T₁ relaxivity data indicate that Gd(C-NETA) and Gd(C-NE3TA) possess higher relaxivity than Gd(C-DOTA), a bifunctional version of a commercially available MRI contrast agent; Gd(DOTA). C-NETA and C-NE3TA were radiolabeled with ¹⁷⁷Lu, ⁹⁰Y, ²⁰³Pb, ^205/6Bi, and ¹⁵³Gd; and in vitro stability of the radiolabeled corresponding complexes was assessed in human serum. The in vitro studies indicate that the evaluated radiolabeled complexes were stable in serum for 11 days with the exception being the ²⁰³Pb complexes of C-NETA and C-NE3TA, which dissociated in serum. C-NETA and C-NE3TA radiolabeled ¹⁷⁷Lu, ⁹⁰Y, or ¹⁵³Gd complexes were further evaluated for in vivo stability in athymic mice and possess excellent or acceptable in vivo biodistribution profile. ^205/6Bi-C-NE3TA exhibited extremely rapid blood clearance and low radioactivity level at the normal organs, while ^205/6Bi-C-NETA displayed low radioactivity level in the blood and all of the organs except for the kidney where relatively high renal uptake of radioactivity is observed. C-NETA and C-NE3TA were further modified for conjugation to the monoclonal antibody Trastuzumab.