Shanshan Cao1, Jie Tang2, Chunyi Liu2, Yi Fang2, Linyang Ji1, Yingjiao Xu2, Zhengping Chen3,4. 1. Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, School of Pharmacy, Xuzhou Medical University, Xuzhou, 221004, China. 2. NHC Key Laboratory of Nuclear Medicine, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, 214063, China. 3. Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, School of Pharmacy, Xuzhou Medical University, Xuzhou, 221004, China. chenzhengping@jsinm.org. 4. NHC Key Laboratory of Nuclear Medicine, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, 214063, China. chenzhengping@jsinm.org.
Abstract
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-[18F]-fluoroethyl)nortropane ([18F]FECNT), an 18F-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 [18F]FECNT. Deuterium-substituted analogues have presented better in vivo stability to reduce metabolites. This study aimed to synthesize a deuterium-substituted DAT radiotracer, [18F]FECNT-d4, and to make a preliminary investigation of its properties as a DAT tracer in vivo. PROCEDURES: The ligand [18F]FECNT-d4 was obtained by one-step radiolabelling reaction. The lipophilicity was measured by the shake-flask method. Binding properties of [18F]FECNT-d4 were estimated by in vitro binding assay, biodistribution, and microPET imaging in rats. In vivo stability of [18F]FECNT-d4 was estimated by radio-HPLC. RESULTS: [18F]FECNT-d4 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). [18F]FECNT-d4 displayed a high binding affinity for DAT comparable to that of [18F]FECNT in rat striatum homogenates. Biodistribution results in normal rats showed that [18F]FECNT-d4 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 [18F]FECNT-d4 vs [18F]FECNT). MicroPET imaging studies of [18F]FECNT-d4 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 [18F]FECNT-d4 remained ~4.02 in the striatum between 5 and 20 min, whereas that of [18F]FECNT fell rapidly from 4.11 to 2.95. Radio-HPLC analysis of the plasma demonstrated better in vivo stability of [18F]FECNT-d4 than [18F]FECNT. CONCLUSION: The deuterated compound [18F]FECNT-d4 may serve as a promising PET imaging agent to assess DAT-related disorders.
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-[18F]-fluoroethyl)nortropane ([18F]FECNT), an 18F-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 [18F]FECNT. Deuterium-substituted analogues have presented better in vivo stability to reduce metabolites. This study aimed to synthesize a deuterium-substituted DAT radiotracer, [18F]FECNT-d4, and to make a preliminary investigation of its properties as a DAT tracer in vivo. PROCEDURES: The ligand [18F]FECNT-d4 was obtained by one-step radiolabelling reaction. The lipophilicity was measured by the shake-flask method. Binding properties of [18F]FECNT-d4 were estimated by in vitro binding assay, biodistribution, and microPET imaging in rats. In vivo stability of [18F]FECNT-d4 was estimated by radio-HPLC. RESULTS: [18F]FECNT-d4 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). [18F]FECNT-d4 displayed a high binding affinity for DAT comparable to that of [18F]FECNT in rat striatum homogenates. Biodistribution results in normal rats showed that [18F]FECNT-d4 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 [18F]FECNT-d4 vs [18F]FECNT). MicroPET imaging studies of [18F]FECNT-d4 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 [18F]FECNT-d4 remained ~4.02 in the striatum between 5 and 20 min, whereas that of [18F]FECNT fell rapidly from 4.11 to 2.95. Radio-HPLC analysis of the plasma demonstrated better in vivo stability of [18F]FECNT-d4 than [18F]FECNT. CONCLUSION: The deuterated compound [18F]FECNT-d4 may serve as a promising PET imaging agent to assess DAT-related disorders.
Authors: Sami S Zoghbi; H Umesha Shetty; Masanori Ichise; Masahiro Fujita; Masao Imaizumi; Jeih-San Liow; Jay Shah; John L Musachio; Victor W Pike; Robert B Innis Journal: J Nucl Med Date: 2006-03 Impact factor: 10.057
Authors: Margaret R Davis; John R Votaw; J Douglas Bremner; Michael G Byas-Smith; Tracy L Faber; Ronald J Voll; John M Hoffman; Scott T Grafton; Clinton D Kilts; Mark M Goodman Journal: J Nucl Med Date: 2003-06 Impact factor: 10.057