SIMPLIFIED SYNTHESIS OF THE BIFUNCTIONAL CHELATING AGENT 10-TETRAAZACYCLODODECANE-N,N',N'',N'''-TETRAACETIC ACID

The attachment of metal ions to antibodies by means of bifunctional ch elating agents (BCA) for medical applications requires extremely high stability under physiological conditions, with no significant release of metals. Chelators that bind strongly with radiometals like In-111, Ga-67, Y-90, and Sm-153, giving complexes that are highly stable under these conditions are essential for effective radioimmunotherapy, for tumor imaging or immunoscintigraphy. 7,10-tetraazacyclodecane-N,N',N'' ,N'''-tetraacetic acid (nitrobenzyl-DOTA) is one of the most promising BCA. A convenient synthesis of 4-nitrobenzyl-substituted DOTA and its conversion to bifunctional chelating agents is described here. The pr ocess involves the reaction of a bis-bromoamide with a p-nitrobenzyl e thylenediamine followed by reduction of the cyclic diamide. The bis-br omoamide resembles a crab with two reactive organobromide groups poise d and ready to react, hence the term ''crab-like'' cyclization. The ov erall yield for the six-step synthesis sequence starting from p-nitrob enzyl ethylenediamine is 21.27%.