Synthesis, characterization, and evaluation of a novel bifunctional chelating agent for the lead isotopes ²⁰³Pb and ²¹²Pb

Radioisotopes of Pb(II) have been of some interest in radioimmunotherapy and radioimmunoimaging (RII). However, the absence of a kinetically stable bifunctional chelating agent for Pb(II) has hampered its use for these applications. ²⁰³Pb (T(1/2) = 52.02 h) has application potential in RII, with a γ-emission that is ideal for single photon emission computerized tomography, whereas ²¹²Pb (T(1/2) = 10 h) is a source of highly cytotoxic α-particles via its decay to its ²¹²Bi (T(1/2) = 60 min) daughter. The synthesis of the novel bifunctional chelating agent 2-(4-isothiocyanotobenzyl)-1,4,7,10-tetraaza-1,4,7,10-tetra-(2-carbamoyl methyl)-cyclododecane (4-NCS-Bz-TCMC) is reported herein. The Pb[TCMC]²⁺ complex was less labile to metal ion release than Pb[DOTA]^2- at pH 3.5 and below in isotopic exchange experiments. In addition to increased stability to Pb²⁺ ion release at low pH, the bifunctional TCMC ligand was found to have many other advantages over the bifunctional 1,4,7,10-tetraazacyclodocane-1,4,7,10-tetraacetic acid (DOTA) ligand. These include a shorter and more straightforward synthetic route, a more efficient conjugation reaction to a monoclonal antibody (mAb), with a higher chelate to protein ratio, a higher percent immuroreactivity, and a more efficient radiolabeling reaction of the mAb-ligand conjugate with ²⁰³Pb. Copyright (C) 2000 Elsevier Science Inc.