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Copper diacetyl-bis(N⁴-methylthiosemicarbazone), Cu(II)ATSM, is a promising agent for imaging hypoxic tissue. Here we present results that provide insight into the chemical and electronic properties underlying previously observed structure−activity relationships. Density functional theory (DFT) calculations on the electronic structures and molecular orbitals of a series of 13 Cu(II)bis(thiosemicarbazone) analogues with different alkylation patterns and with fixed geometries based on the known structure of Cu(II)PTSM showed that the LUMO and the next lowest orbital were very close in energy, and their energy order was strikingly dependent on the ligand alkylation pattern in a way that correlated with hypoxia-selectivity and redox potentials. The LUMOs of Cu(II)ATSM and other hypoxia-selective analogues were predominantly metal-based (leading to a singlet reduced species) while the LUMOs of Cu(II)PTSM and …