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. 2008 Jan 10;51(1):118-25.
doi: 10.1021/jm070401q. Epub 2007 Dec 7.

Rational design and generation of a bimodal bifunctional ligand for antibody-targeted radiation cancer therapy

Hyun-Soon Chong  1 , Xiang Ma, Thien Le, Baidoo Kwamena, Diane E Milenic, Erik D Brady, Hyun A Song, Martin W Brechbiel
Affiliations

Rational design and generation of a bimodal bifunctional ligand for antibody-targeted radiation cancer therapy

Hyun-Soon Chong et al. J Med Chem. .

Abstract

An antibody-targeted radiation therapy (radioimmunotherapy, RIT) employs a bifunctional ligand that can effectively hold a cytotoxic metal with clinically acceptable complexation kinetics and stability while being attached to a tumor-specific antibody. Clinical exploration of the therapeutic potential of RIT has been challenged by the absence of adequate ligand, a critical component for enhancing the efficacy of the cancer therapy. To address this deficiency, the bifunctional ligand C-NETA in a unique structural class possessing both a macrocyclic cavity and a flexible acyclic moiety was designed. The practical, reproducible, and readily scalable synthetic route to C-NETA was developed, and its potential as the chelator of (212)Bi, (213)Bi, and (177)Lu for RIT was evaluated in vitro and in vivo. C-NETA rapidly binds both Lu(III) and Bi(III), and the respective metal complexes remain extremely stable in serum for 14 days. (177)Lu -C-NETA and (205/6)Bi -C-NETA possess an excellent or acceptable in vivo biodistribution profile.

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Figures

Figure 1
Figure 1
Synthetic ligands currently in preclinical and clinical use.
Figure 2
Figure 2
Plot of absorbance at 652 nm versus time of Bi(III)–AAIII (○), Bi(III)–C-DOTA (△), and Bi(III)–C-NETA (♦) at pH 2.0 (0.15 M NH4OAc) and 25 °C.
Figure 3
Figure 3
Plot of absorbance at 652 nm versus time of Bi(III)–AAIII (○), Bi(III)–C-DOTA (△), Bi(III)–C-NETA (♦) at pH 4.0 (0.15 M NH4OAc) and 25 °C.
Figure 4
Figure 4
Plot of absorbance at 652 nm versus time of Lu(III)–AAIII (○), Lu(III)–C-DOTA (△), Lu(III)–C-NETA (♦) at pH 4.5 (0.15 M NH4OAc) and 25 °C.
Figure 5
Figure 5
Biodistribution of 205/6Bi–C-NETA in non-tumor-bearing athymic mice.
Figure 6
Figure 6
Biodistribution of 177Lu–C-NETA in non-tumor-bearing athymic mice.
Scheme 1
Scheme 1
Retrosynthetic Route to C-NETA
Scheme 2
Scheme 2
Synthesis of Precursor Molecule 12 for C-NETA
Scheme 3
Scheme 3
Synthesis of C-NETA
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