The sigma-2 (σ2) receptor was discovered nearly 40 years ago and was recently identified as the Transmembrane Protein 97 (TMEM97, also known as MAC30 (Meningioma-associated protein). Aberrant σ2 activity has been linked to disease and conditions such as schizophrenia, Alzheimer’s disease, neuropathic pain, traumatic brain injury, and cancer. The utility of σ2 as a therapeutic target is currently under investigation in numerous laboratories. Herein, we report on the synthesis and evaluation of a series of novel, functionalized γ-butyrolactones that are potent σ2 receptor ligands.