Detecting cancerous lesions is a major clinical application in emission tomography. In previous work, we have studied penalized maximum-likelihood (PML) image reconstruction for the detection task and proposed a method to design a shift-invariant quadratic penalty function to maximize detectability of a lesion at a known location in a two dimensional image. Here we extend the regularization design to maximize detectability of lesions at unknown locations in fully 3D PET. We used a multiview channelized Hotelling observer (mvCHO) to assess the lesion detectability in 3D images to mimic the condition where a human observer examines three orthogonal views of a 3D image for lesion detection. We derived simplified theoretical expressions that allow fast prediction of the detectability of a 3D lesion. The theoretical results were used to design the regularization in PML reconstruction to improve lesion detectability. We conducted computer-based Monte Carlo simulations to compare the optimized penalty with the conventional penalty for detecting lesions of various sizes. Only true coincidence events were simulated. Lesion detectability was also assessed by two human observers, whose performances agree well with that of the mvCHO. Both the numerical observer and human observer results showed a statistically significant improvement in lesion detection by using the proposed penalty function compared to using the conventional penalty function.