The coordination properties and photochemical responses of three fluorescent polyamine macrocycles, 9,12,15,24,25pentaaza-26-oxatetracyclo[21.2.1.0(2,7).0(17,22)]Thexaicosa -2,4,6,17,19,21,23,25(1)-octaene (L1), 9,12,15,18,27,28-hexaaza-29-oxatetracyclo[24,2.1.0(2.7).02(20,25)]enneic osa-2,4,6,20,22,24,26,28(1)-octaene (L2), and 9,12,15,18,21,30,31-heptaaza32-oxatetracyclo[27.2.1.0(2.7).0(23,28)]diat riconta-2,4,6,23,25,27,29,31(1)-octaene (L3), toward Cu(II), Zn(II), Cd(II), and Pb(II) are reported. Each ligand contains the 2,5-diphenyl[1,3,4]oxadiazole (PPD) moiety inserted in a polyamine macrocycle skeleton. The stability constants were determined by means of potentiometric measurements in aqueous solution. L1 forms mononuclear complexes only with Cu(II). L2 and L3 form stable mononuclear species with all of the metals, while L3 is able to form dinuclear Cu(II) species. The fluorescence of all ligands was totally quenched by the presence of Cu(II). L2 behaves as an OFF-ON sensor for Zn(I I) under physiological conditions, even in the presence of interfering species such as Cd(II) and Pb(II). This ligand combines selective binding of Zn(II) with a highly specific fluorescent response to Zn(I I) due to the chelating enhancement of fluorescence (CHEF) effect. The interaction of Zn(II), Cd(II), and Pb(II) with L3 does not produce an appreciable enhancement of fluorescence at the same pH. The different behavior is attributed to the cavity size of the macrocycle and to the number of amine functions. L2 possesses the best arrangement of these two characteristics, allowing a full participation of all of the amine functions in metal coordination, as shown by the crystal structures of [CuL2(CIO4)](CIO4)center dot H2O and [ZnL2BrIBr center dot H2O species; this prevents the PET effect and supplies the higher CHEF effect. The interaction between 12 and Zn(II) can also be observed with the naked eye as an intense sky blue emission.