TECHNOLOGY BRIEF
HIGH YIELD SIMPLIFIED SYNTHESIS OF MACROCYCLIC POLYCARBOXYLATES AND FORMATION OF RADIOIMMUNOCONJUGATES FOR RADIOTHERAPY AND DIAGNOSTIC IMAGING
For further information, contact Christine Brakel
Description: These inventions provide a rapid, high yield, simplified synthetic route to the macrocyclic polycarboxylate chelators 1,4,7,10-tetraazacyclododecane N,N',N'',N'''- tetraacetic acid (DOTA) and 1,4,8,11-tetraazacyclotetradecane N,N',N'',N'''-tetraacetic acid (TETA). For formation of chelate-modified antibodies or other bioreactive molecules, the N-hydroxysuccinimide esters and methods for their synthesis are also disclosed. The formation of radiometal bioconjugates and their use in radioimmunoimaging and radioimmunotherapy procedures are also provided.
Commercial and Technical Merit: The utility of the macrocylic polycarboxylates commonly known as DOTA and TETA in Magnetic Resonance Imaging (MRI) with Gadolinium is well documented. These molecules are also effective chelators of radiometals useful in PET and SPECT imaging procedures and for systemic radiotherapy. When properly functionalized, the molecules can be linked to tumor-specific antibodies, antibody fragments, proteins, peptides and other biologically active compounds. As such, they may be useful tools for development of new radioimmunotherapies.
Competitive Advantage: Although the utility of these macrocylic polycarboxylate chelators, DOTA in particular, is well established, previous methods for synthesis and purification were cumbersome, requiring multistep procedures and chromatographic purification resulting in low yields of the chelators. Using the methods described in the present inventions a two step reaction procedure and purification by crystallization result in yields of material that exceed 90%. A method for functionalization to the activated ester makes the formation of antibody-chelator conjugates simple and free of drawbacks associated with procedures utilizing isothiocyanates or mixed anhydrides.
Development Status: In animal studies, radioimmunoconjugates prepared with DOTA and/or TETA showed excellent biodistribution and high in vivo stability.
Inventors: Ronnie C. Mease, Leonard F. Mausner, Suresh C. Srivastava
Patent Status: U.S. Patents 5,428,156 and 5,639,879
License Status: Available on a negotiable basis.
Literature References: Kolsky, K. L., et al., (1994) J. Nuc. Med. 35 259P; DeNardo, G. L., et al., (1993) J. Nuc. Med. 34 93P.