Found: [M + H]+m/z540

Found: [M + H]+m/z540.2311. without compromising its biological activity is a critical step for successful antibody-targeted cancer therapy and imaging. Radioimmunotherapy (RIT) has been recognized as a new promising therapeutic modality for treating numerous cancers by employing a tumor-targeting mAb for selective delivery of a cytotoxic radioactive metal while minimizing exposure of healthy cells.13The proven efficacy4of the first FDA-approved RIT drug, Ibritumomab, for treatment of B-cell non-Hodgkins lymphoma (NHL), has spurred numerous investigations of RIT modality on other cancer types including leukemia and cancers of the breast, colorectum, ovaries, and prostate.5The RIT system generally Mollugin consists of three components: a radionuclide, a mAb, Mouse monoclonal to ZBTB7B and a bifunctional ligand.6The modality requires the use of radioactive metals, which can be very toxic when deposited in vivo in normal tissue. Therefore, the success of clinical applications of RIT heavily depends on the performance of the bifunctional ligand that can rapidly form a stable complex, particularly with a relatively short-lived radioactive metal. Although RIT holds great promise for the treatment of many cancers, as evidenced by Ibritumomab therapy (overall response rate of ~80%),7active clinical exploration of RIT using a variety of antibodies and cytotoxic radionuclides has been challenged by the absence of adequate bifunctional ligands that can bind the radionuclides with clinically acceptable kinetics and in vivo stability and thereby allow for practical and large-scale production of Mollugin stable radioimmunoconjugates. Bone-marrow toxicity is reported to be a major side effect of Ibritumomab therapy, which has been proposed to be related to deposition of90Y (t1/2= 64.1 h,Emax= 2.3 MeV), the bone-seeking radionuclide prematurely leaking from the radiolabeled antibody conjugate.5,8 Research efforts have been directed toward the development of adequate bifunctional ligands for sequestering metallic radionuclides for RIT applications. The most frequently explored macrocyclic ligand for RIT,C-DOTA [2-(p-NO2-Bn)-1,4,7,10-tetraazacyclododecane-N,N,N,N-tetraacetic acid,Figure 1] forms Mollugin a very stable complex with Mollugin radionuclides.9,10However, the extremely slow complex formation rate under mild conditions1113was found to be problematic in many RIT applications, particularly for short half-lived -emitters such as213Bi (t1/2= 47 min).10AcyclicC-DTPA [2-(p-NO2-Bn)-diethylenetriaminepentaacetic acid,Figure 1] rapidly forms a complex with Mollugin radionuclides but is unstable, both in vitro and in vivo, resulting in toxic side effects.14The acyclic ligand 1B4M-DTPA [2-(p-NO2-Bn)-6-methyl-DTPA,Figure 1]15displays significantly improved complexation kinetics with several radionuclides as compared toC-DOTA. However, the corresponding complexes are still less stable both in vitro and in vivo compared to metal-DOTA complexes.16Despite this shortcoming, 1B4M-DTPA is a component of the clinically approved Ibritumomab primarily due to practical and reproducible radiolabeling chemistry.17. == Figure 1. == Synthetic ligands currently in preclinical and clinical use. In an effort to develop an improved bifunctional ligand for RIT, we have designedC-NETA (4-[2-(bis(carboxymethyl)-amino)-3-(4-nitrophenyl)propyl]-7-carboxymethyl[1,4,7]triazonan-1-ylacetic acid) in a unique structural class integrating both a macrocyclic and an acyclic moiety for metal binding. In this new bifunctional ligand, the macrocyclic component chosen is based upon 1,4,7-triazacyclononane-N,N,N-triacetic acid (NOTA,Figure 1), and the acyclic component is a pendant bis(carboxymethyl) amino donor group appended by an ethylene bridge to the macrocyclic ring. The cooperative and bimodal binding of the acyclic pendant donor groups coupled with the macrocyclic effect of the NOTA substructure is hypothesized to accelerate complexation with the metals while maintaining a high level of complex stability. The strategy is to use acyclic pendant donor groups to rapidly capture and initiate coordination to the metal, as in the case of DTPA. Thereafter, the macrocyclic component will envelop the cation trapped in the acyclic donor groups by wrapping around the metal ion to achieve maximum complex stability by saturating the metal coordination sphere, as in the case of DOTA. NOTA is known to be an inadequate chelate for lanthanides by virtue of its cavity size, an insufficient number of donors to saturate the coordination sphere, and an inability to assume an optimal geometry for the six donor groups toward the metal ion.18The new bimodal ligandC-NETA is proposed to permit orientation for all donors to assume an optimal geometry.