Novel polar single amino acid chelates for technetium-99m tricarbonyl-based radiopharmaceuticals with enhanced renal clearance: application to octreotide.

Single amino acid chelate (SAAC) systems for the incorporation of the M(CO)(3) moiety (M = Tc/Re) have been successfully incorporated into novel synthetic strategies for radiopharmaceuticals and evaluated in a variety of biological applications. However, the lipophilicity of the first generation Tc(CO)(3)-dipyridyl complexes has resulted in substantial hepatobiliary uptake when either examined as lysine derivatives or integrated into biologically active small molecules and peptides. Here we designed, synthesized, and evaluated novel SAAC systems that have been chemically modified to promote overall Tc(CO)(3)L-3 complex hydrophilicity with the intent of enhancing renal clearance. A series of lysine derived SAAC systems containing functionalized polar imidazole rings and/or carboxylic acids were synthesized via reductive alkylation of the epsilon amino group of lysine. The SAAC systems were radiolabeled with Tc-99m, purified, and evaluated for radiochemical stability, lipophilicity, and tissue distribution in rats. The log P values of the Tc-99m complexes were determined experimentally and ranged from -0.91 to -2.33. The resulting complexes were stable (>90%) for at least 24 h. Tissue distribution in normal rats of the lead Tc-99m complexes demonstrated decreased liver (<1 %1D/g) and gastrointestinal clearance (<1.5%1D/g) and increased kidney clearance (>15 %1D/g) at 2 h after injection compared to the dipyridyl lysine complex (DpK). One of the new SAAC ligands, [Tc-99m]bis-carboxymethylimidazole lysine, was conjugated to the N-terminus of Tyr-3 octreotide and evaluated for localization in nude mice bearing AR42J xenografts to examine tissue distribution, tumor uptake and retention, clearance, and route of excretion for comparison to In-111-DOTA-Tyr-3-octreotide and Tc-99m-DpK-Tyr-3-octreotide. Tc-99m-bis-(carboxymethylimidazole)-lysine-Tyr-3-octreotide exhibited significantly less liver uptake and gastrointestinal clearance compared to Tc-99m-DpK-Tyr-3-octreotide while maintaining tumor uptake in the same mouse model. These novel chelators demonstrate that lipophilicity can be controlled and organ distribution significantly altered, opening up broad application of these novel SAAC systems for radiopharmaceutical design.