The syntheses of a new 1,4,7,10-tetraazacyclododecane (cyclen) derivative bearing a picolinate pendant arm (HL1), and its 1,4,8,11-tetraazacyclotetradecane (cyclam) analogue HL2, were achieved by using two different selective-protection methods involving the preparation of cyclen-bisaminal or phosphoryl cyclam derivatives. The acid–base properties of both compounds were investigated as well as their coordination chemistry, especially with Cu2+, in aqueous solution and in solid state. The copper(II) complexes were synthesized, and the single crystal X-ray diffraction structures of compounds of formula [Cu(HL)](ClO4)2·H2O (L = L1 or L2), [CuL1](ClO4) and [CuL2]Cl·2H2O, were determined. These studies revealed that protonation of the complexes occurs on the carboxylate group of the picolinate moiety. Stability constants of the complexes were determined at 25.0 °C and ionic strength 0.10 M in KNO3 using potentiometric titrations. Both ligands form complexes with Cu2+ that are thermodynamically very stable. Additionally, both HL1 and HL2 exhibit an important selectivity for Cu2+ over Zn2+. The kinetic inertness in acidic medium of both complexes of Cu2+ was evaluated by spectrophotometry revealing that [CuL2]+ is much more inert than [CuL1]+. The determined half-life values also demonstrate the very high kinetic inertness of [CuL2]+ when compared to a list of copper(II) complexes of other macrocyclic ligands. The coordination geometry of the copper center in the complexes was established in aqueous solution from UV–visible and electron paramagnetic resonance (EPR) spectroscopy, showing that the solution structures of both complexes are in excellent agreement with those of crystallographic data. Cyclic voltammetry experiments point to a good stability of the complexes with respect to metal ion dissociation upon reduction of the metal ion to Cu+ at about neutral pH. Our results revealed that the cyclam-based ligand HL2 is a very attractive receptor for copper(II), presenting a fast complexation process, a high kinetic inertness, and important thermodynamic and electrochemical stability.