Abstract
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Introduction: Sigma-1 receptor (σ1R) is an intracellular chaperone protein that widely expressed in the central nervous system, have been investigated as a potential therapeutic target for several neuropsychiatric diseases over decades. Since the highly σ1R binding affinity and good selectivity, with the performance of blood‒brain barrier (BBB) penetration, the radio-labeled ligands with pyrimidine scaffold are of great potential. Herein we reported the radiosynthesis of two 11C-labeled pyrimidine derivatives, [11C]CNY-01 and [11C]CNY-02 and preliminary tested in mice PET/CT imaging and non-human primate (NHP) PET/MR.
Methods: Firstly, [11C]CNY-01 and [11C]CNY-02 were successfully achieved through a standard methylation reaction of corresponding precursor and [11C]CH3I, respectively. Then preliminary in vivo imaging studies were performed in rodents and NHP to study the potential of these two two 11C-labeled radioligands to serve as radiotracers for brain σ1R imaging. Initially, male Balb/c mice were administered [11C]CNY-01 and [11C]CNY-02 via intravenous bolus injection (100‒150 μCi per animal) and then followed a 60 minutes dynamic PET imaging and a 10 minutes CT scanning. After that, the followed NHPs study was implemented with a male rhesus macaque conducted a 90 minutes dynamic PET/MR scanning after radiotracer administrating.
Results: Both [11C]CNY-01 and [11C]CNY-02 could pass the BBB rapidly with high uptake in brain when administered by intravenous bolus injection (100‒150 μCi per animal). Based on a whole-brain analysis, the brain uptake of [11C]CNY-01 and [11C]CNY-02 reached the peak 14.5 %ID/cc and 12.2 %ID/cc within first few minutes after injection, and sustained binding over the scanning time(Figure 1 and 2). Then [11C]CNY-01 was selected as potential candidate to further NHP imaging study. [11C]CNY-01 exerted high brain uptake of 1.0-2.2 in standardized uptake value (SUV) based on PET/MR images. Relatively higher uptake was observed in brain regions such as midbrain and hypothalamus (Figure 3).
Conclusions: In summary, Both two 11C-labeled radioligands can bound to σ1R in the mice brain fast and efficiency, and their brain uptake could dose-dependent blockade by unlabeled compound, respectively. Of the two, [11C]CNY-01 was shown to possess more favorable pharmacokinetic property as its brain clearance was more rapidly. Using[11C]CNY-01 as a PET probe could great benefit to quantify σ1R expression in various neurological disorders, and would also be valuable for evaluation of potential drugs in living subjects. Acknowledgements: Support for this work includes a pilot funding from the Athinoula A. Martinos Center for Biomedical Imaging at the Massachusetts General Hospital (Changning Wang, USA), National Natural Science Foundation of China (Grant No.81602946, Yu Lan) and Natural Science Foundation of Hubei Province of China (Grant No. 2016CFB258, Yu Lan).