Developing Re(V)-based therapeutic agents, where the ReO3+ core is coordinated to a multidentate ligand, is of interest in the radiopharmaceutical sciences because of the desirable nuclear properties of 186Re/188Re. A reliable yet cost-effective computational method for evaluating the strength of each coordination bond while preserving the integrity of the metal–ligand complex would provide quantitative input for ligand design. A relaxed potential energy surface (PES) scan approach is assessed for trans-ReO(SH)2(NH2)(NH3), [ReO(SH)3(NH2)]1−, and [ReO(SH)3(N(H)CHO)]1− model complexes to calculate bond dissociation energies (BDEs) for ReNH3, ReNH2, ReN(H)CHO and ReSH bonds, common components of Re(V) coordination environments. The PES scans were performed using various combinations of DFT/coupled-cluster methods and basis sets, and the effect of bulk solvent was examined by using the integral equation formalism of the polarizable continuum model (IEF–PCM). BDEs obtained from the PES scans are compared to those obtained for infinite separation. In the gas phase, the BDE curves reach about 90% of the total BDE at 2Å and plateau by 3.0–3.5Å beyond the equilibrium bond length; in the presence of implicit solvent, the BDEwater curves plateau at a shorter distance and more than 90% of the total BDE is recovered at 2Å. The gas-phase PES scans follow the desired reaction coordinate for NH3, [N(H)CHO]1− and SH1−, but not for the poor leaving group NH21-. The desired heterolytic cleavage of the ReNH2 bond is achieved when the PES scans are performed in the presence of solvent. Elongating the ReS/N bonds in a rigid, multidentate trans-ReO-N2S2 complex yields BDE trends similar to those found for the model complexes (ReNH2>ReN(H)CHO>ReSH>ReNH3).