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Background: Cross-modality image estimation can be performed using generative adversarial networks (GANs). To date, SPECT image estimation from another medical imaging modality using this technique has not been considered. We evaluate the estimation of SPECT from MRI and PET, and additionally assess the necessity for cross-modality image registration for GAN training., Methods: We estimated interictal SPECT from PET and MRI as a single-channel input, and as a multi-channel input to the GAN. We collected data from 48 individuals with epilepsy and converted them to 3D isotropic images for consistence across the modalities. Training and testing data were prepared in native and template spaces. The Pix2pix framework within the GAN network was adopted. We evaluated the addition of the structural similarity index metric to the loss function in the GAN implementation. Root-mean-square error, structural similarity index, and peak signal-to-noise ratio were used to assess how well SPECT images were able to be synthesised., Results: High quality SPECT images could be synthesised in each case. On average, the use of native space images resulted in a 5.4% percentage improvement in SSIM than the use of images registered to template space. The addition of structural similarity index metric to the GAN loss function did not result in improved synthetic SPECT images. Using PET in either the single channel or dual channel implementation led to the best results, however MRI could produce SPECT images close in quality., Conclusion: Synthesis of SPECT from MRI or PET can potentially reduce the number of scans needed for epilepsy patient evaluation and reduce patient exposure to radiation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Fard, Reutens, Ramsay, Goodman, Ghosh and Vegh.)