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Scorpionate-Like Pendant Macrocyclic Ligands, Complexes and Compositions Thereof, and Methods of Using Same

Posted Apr 01 2012 8:00pm

Description of Invention:
Monoclonal antibodies (mAbs) have been employed as targeting biomolecules for the delivery of radionuclides into tumor cells in radioimmunotherapy (RIT). Numerous clinical trials have been performed to validate this modality of cancer therapy. Several useful ß--emitting radionuclides, including 131I, 90Y, 177Lu, and 153Sm, have been employed for labeling mAbs for RIT applications. The pure ß--emitting radionuclide 90Y has been extensively studied in RIT due to its physical properties. The macrocyclic chelating agent 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid ("DOTA") is well-known to be an effective chelator of Y(III) and lanthanides. In general, DOTA conjugated to mAbs displays relatively slow and inefficient radiolabeling with Y(III) isotopes under mild conditions. This is contrary to the rapid and high-yield radiolabeling (> 90%) of mAbs conjugated with bifunctional derivatives of the acyclic chelating agent diethylenetriaminepentaacetic acid (DTPA). Thus, there is still a need for a compound that possesses complex stability comparable to that of DOTA, the excellent practical complexation kinetics of DTPA, and increased stability in vitro and in vivo. The subject invention provides such a compound.

The invention provides substituted 1,4,7-triazacyclononane-N,N',N''-triacetic acid compounds with a pendant donor amino group, metal complexes thereof, compositions thereof and methods of using same. The compounds of the present invention possess the same octadentate coordinating groups as DOTA and DTPA; however, these compounds have a combined macrocyclic and acyclic character. The macrocyclic component chosen is based upon 1,4,7-triazacyclononane-N,N',N''-triacetic acid ("NOTA"), while the acyclic component is a pendant bis(carboxymethyl)amino donor group that is connected by an alkylene bridge that is optionally substituted with an aralkyl group. The cooperative binding of the pendant donor groups coupled with the pre-organization and macrocyclic effect of the NOTA sub-structure accelerates complexation with metal ions and isotopes (e.g., Y(III), Gd(III); etc.) while maintaining a high level of stability of the complexes.

Martin W Brechbiel (NCI)
Hyun-soon Chong (NCI)

Patent Status:
HHS, Reference No. E-063-2002/0
US, , Patent No. 7,081,452, Issued 25 Jul 2006
US, , Patent No. 7,163,935, Issued 16 Jan 2007

For Licensing Information Please Contact:
Surekha Vathyam Ph.D.
NIH Office of Technology Transfer
6011 Executive Blvd. Suite 325,
Rockville, MD 20852
United States
Phone: 301-435-4076
Fax: 301-402-0220

Ref No: 720

Updated: 04/2012

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