Stability and structure of activated macrocycles. Ligands with biological applications

Single p-toluic acid pendant groups were attached to 1,4,7,10,13-pentaazacyclopentadecane (15aneN5) and 1,4,8,11-tetraazacyclotetradecane (cyclam) to prepare bifunctional reagents for radiolabeling monoclonal antibodies with ^64,67Cu. The ligands are 1,4,7,10,13-pentaazacyclopentadecane-l-(α-1,4-toluic acid) (PCBA) and 1,4,8,11-tetraazacyclotetradecane-l-(α-1,4-toluic acid) (CPTA). For the parent macrocycles and their pendant arm derivatives, the 1:1 Cu²⁺ complexes dissociate only below pH 2. At pH 0.0 and 25 °C the CPTA-Cu complex has a half-life toward complete dissociation of 24 days. A new approach was developed for the estimation of the Cu²⁺ stability constant for the kinetically robust CPTA. All other formation constants were determined at 25.0 °C with batch spectrophotometric techniques. Potentiometric titrations were used to determine the protonation constants of the macrocyclic ligands as well as of the metal chelates. The protonation constants, stability constants, and pM's are discussed in terms of both molecular mechanics calculations and the ligands' potential applicability as copper(II) radiopharmaceuticals.