Longitudinal in vivo ( R )-[ 18 F]FBFP PET imaging for preclinical evaluation of cerebral sigma-1 receptor after ischemic stroke

Rationale: Sigma-1 receptor (sigma-1R) is a promising biomarker and therapeutic target for ischemic stroke. However, the real-time changes in the expression of sigma-1R post-stroke have not been elucidated. (R)-1-(4-[¹⁸F]Fluorobenzyl)-4-[(tetrahydrofuran-2-yl)methyl]piperazine ((R)-[¹⁸F]FBFP) has emerged as a novel radiotracer targeting sigma-1R. This study aimed to use (R)-[¹⁸F]FBFP PET imaging for the investigation of spatiotemporal alterations in sigma-1R expression in the rat brain following stroke and treatment, and to explore the correlation between the imaging findings and neurological outcomes. Methods: Sigma-1R levels were evaluated on days 1, 3, 7, 14, 21, and 28 after middle cerebral artery occlusion (MCAO) using (R)-[¹⁸F]FBFP PET/CT imaging. Ex vivo autoradiography and immunofluorescence (IF) staining were performed to corroborate the findings from PET/CT imaging. The cellular localization of sigma-1R during stroke progression was identified by co-labeling sigma-1R with neurons (NeuN), astrocytes (GFAP), and microglia (Iba1). Behavioral tests were conducted on MCAO rats at corresponding time points, and the correlation between PET signals and neurological outcomes was analyzed. The MCAO rats were then treated with recombinant tissue-type plasminogen activator (rtPA), and the therapeutic response was evaluated with (R)-[¹⁸F]FBFP to elucidate the impact of treatment on PET imaging. Results: Compared with the sham group, the ipsilateral-to-contralateral hemisphere uptake ratio of (R)-[¹⁸F]FBFP of the MCAO group significantly decreased in the acute phase (days 1 and 3), increased in the subacute phase (days 7 and 14), and then gradually declined in the chronic phase (days 21 and 28). The PET imaging findings were in agreement with the ex vivo autoradiography and IF staining. Changes in sigma-1R levels in ischemic lesions were influenced by the initial neuronal loss and the later accumulation of glial cells. Furthermore, there was a significant correlation between the uptake of (R)-[¹⁸F]FBFP and the neurological outcomes during stroke recovery. After rtPA treatment, the (R)-[¹⁸F]FBFP uptake in the affected hemisphere gradually returned to levels comparable to the contralateral hemisphere. Conclusions: (R)-[¹⁸F]FBFP PET imaging effectively visualized and accurately quantified the spatiotemporal alterations of sigma-1R in the rat brain during ischemic stroke progression. The (R)-[¹⁸F]FBFP uptake correlated with the neurological outcomes during stroke recovery, and (R)-[¹⁸F]FBFP PET imaging could be a valuable tool for predicting post-stroke recovery and evaluating the efficacy of rtPA treatment.