Synthesis and radiolabeling of selective high-affinity ligands designed to target non-Hodgkin's lymphoma and leukemia

Selective high-affinity ligands (SHALs) were synthesized as molecular targeting agents for HLA-DR10, a cell surface receptor upregulated on malignant B-cell lymphocytes in non-Hodgkin's lymphoma and leukemia. SHALs are designed to mimic the affinity and selectivity of Lym-1, an antibody that binds to the beta-subunit of HLA-DR10. To bind selectively to HLA-DR10, SHALs were constructed to bind to two adjacent pockets on the surface of the beta-subunit of HLA-DR10 located within an epitope recognized by the Lym-1 antibody. A series of multivalent SHALs with molecular masses of 1500-3000 Da were synthesized using solid/polymer-supported synthesis on chlorotrityl chloride resin in 50-80% yield. To enable their use as radionuclide carriers in mouse studies, SHALs were conjugated to DOTA in a solution-phase reaction with 70-100% yield. 57Co/CoCl2 titrations revealed that 50-60% of the DOTA in the DOTA-conjugated SHALs was available for radiometal chelation. These DOTA-SHALs were labeled with 111In and used to carry out pharmacokinetic studies in mice. Radiolabeling reactions of DOTA-SHALs, with exactly one DOTA entity per targeting SHAL molecule, yielded products with greater than 90% radiochemical purity and specific activities ranging from 97 to 150 muCi/mug.