Cao Shanshan,Tang Jie,Liu Chunyi,Fang Yi,Ji Linyang,Xu Yingjiao,Chen Zhengping
Purpose The dopamine transporter (DAT) is a marker of the occurrence and development of Parkinson’s disease (PD) and other diseases with nigrostriatal degeneration. 2β-Carbomethoxy-3β-(4-chlorophenyl)-8-(2-[ 18 F]-fluoroethyl)nortropane ([ 18 F]FECNT), an 18 F-labelled tropane derivative, was reported to be a useful positron-emitting probe for DAT. However, the rapid formation of brain-penetrating radioactive metabolites is an impediment to the proper quantitation of DAT in PET studies with [ 18 F]FECNT. Deuterium-substituted analogues have presented better in vivo stability to reduce metabolites. This study aimed to synthesize a deuterium-substituted DAT radiotracer, [ 18 F]FECNT- d 4 , and to make a preliminary investigation of its properties as a DAT tracer in vivo . Procedures The ligand [ 18 F]FECNT- d 4 was obtained by one-step radiolabelling reaction. The lipophilicity was measured by the shake-flask method. Binding properties of [ 18 F]FECNT- d 4 were estimated by in vitro binding assay, biodistribution, and microPET imaging in rats. In vivo stability of [ 18 F]FECNT- d 4 was estimated by radio-HPLC. Results [ 18 F]FECNT- d 4 was synthesized at an average activity yield of 46 ± 17 % ( n = 15) and the molar activity was 67 ± 12 GBq/μmol. The deuterated tracer showed suitable lipophilicity and the ability to penetrate the blood-brain barrier (brain uptake of 1.72 % ID at 5 min). [ 18 F]FECNT- d 4 displayed a high binding affinity for DAT comparable to that of [ 18 F]FECNT in rat striatum homogenates. Biodistribution results in normal rats showed that [ 18 F]FECNT- d 4 exhibited a higher ratio of the target to non-target (striatum/cerebellum) at 15 min post administration (5.00 ± 0.44 vs 3.84 ± 0.24 for [ 18 F]FECNT- d 4 vs [ 18 F]FECNT). MicroPET imaging studies of [ 18 F]FECNT- d 4 in normal rats showed that the ligand selectively localized to DAT-rich striatal regions and the accumulation could be blocked with DAT inhibitor. Furthermore, in the unilateral PD model rat, a significant reduction of the signal was found in the lesioned side relative to the unlesioned side. Striatal standardized uptake value of [ 18 F]FECNT- d 4 remained ~4.02 in the striatum between 5 and 20 min, whereas that of [ 18 F]FECNT fell rapidly from 4.11 to 2.95. Radio-HPLC analysis of the plasma demonstrated better in vivo stability of [ 18 F]FECNT- d 4 than [ 18 F]FECNT. Conclusion The deuterated compound [ 18 F]FECNT- d 4 may serve as a promising PET imaging agent to assess DAT-related disorders.
Background Parkinson’s disease (PD) is a prevalent neurodegenerative disorder worldwide, diagnosed based on classic symptoms like motor dysfunction and cognitive impairments. With the development of various radioactive ligands, positron emission tomography (PET) imaging combined with specific radiolabelling probes has proven to be effective in aiding clinical PD diagnosis. Among these probes, 2β-Carbomethoxy-3β-(4-chlorophenyl)-8-(2-[ 18 F]-fluoroethyl) nortropane ([ 18 F]FECNT) has been utilized as a PET tracer to image dopamine transporter (DAT) integrity in striatal presynaptic dopaminergic terminals. However, the presence of brain-penetrant radioactive metabolites produced by [ 18 F]FECNT may impact the accuracy of PET imaging. In previous research, we developed 2β-Carbomethoxy-3β-(4-chlorophenyl)-8-(2-[ 18 F]-fluoroethyl-1,1,2,2-d4) nortropane ([ 18 F]FECNT-d 4 ), a deuterated derivative with enhanced stability in plasma and the striatum, along with a slower washout rate. In this study, we further investigated the potential of [ 18 F]FECNT-d 4 to detect dopaminergic neuron degeneration in Parkinson’s disease. This involved PET imaging in unilaterally-lesioned PD model rats and in vitro autoradiography conducted on postmortem brain sections. Results PET images revealed reduced specific uptake in the ipsilateral striatum of rats stereotactically injected with 6-hydroxydopamine hydrochloride (6-OHDA). Compared to the sham group, the ratio of standardized uptake value (SUV) in the ipsilateral to contralateral striatum decreased by 13%, 23%, and 63% in the mild, moderate, and severe lesioned groups, respectively. Dopaminergic denervation observed in PET imaging was further supported by behavioral assessments, immunostaining, and monoamine concentration tests. Moreover, the microPET results exhibited positive correlations with these measurements, except for the apomorphine-induced rotational behavior test, which showed a negative correlation. Additionally, [ 18 F]FECNT-d 4 uptake was approximately 40% lower in the postmortem striatal sections of a PD patient compared to a healthy subject. Furthermore, estimated human dosimetry (effective dose equivalent: 5.06 E-03 mSv/MBq), extrapolated from rat biodistribution data, remained below the current Food and Drug Administration limit for radiation exposure. Conclusion Our findings demonstrate that [ 18 F]FECNT-d 4 accurately estimates levels of dopaminergic neuron degeneration in the 6-OHDA-induced PD rat model and effectively distinguishes between PD patients and healthy individuals. This highly sensitive and safe PET probe holds promising potential for clinical application in the diagnosis and monitoring of Parkinson’s disease.
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