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. 2014 Mar 17;4(1):66-78.
doi: 10.3390/app4010066.

Radiosynthesis and in Vivo Evaluation of Two PET Radioligands for Imaging α-Synuclein

Xiang Zhang  1 , Hongjun Jin  1 , Prashanth K Padakanti  1 , Junfeng Li  1 , Hao Yang  1 , Jinda Fan  1 , Robert H Mach  1 , Paul Kotzbauer  2 , Zhude Tu  1
Affiliations

Radiosynthesis and in Vivo Evaluation of Two PET Radioligands for Imaging α-Synuclein

Xiang Zhang et al. Appl Sci (Basel). .

Abstract

Two α-synuclein ligands, 3-methoxy-7-nitro-10H-phenothiazine (2a, Ki = 32.1 ± 1.3 nM) and 3-(2-fluoroethoxy)-7-nitro-10H-phenothiazine (2b, Ki = 49.0 ± 4.9 nM), were radiolabeled as potential PET imaging agents by respectively introducing 11C and 18F. The syntheses of [11C]2a and [18F]2b were accomplished in a good yield with high specific activity. Ex vivo biodistribution studies in rats revealed that both [11C]2a and [18F]2b crossed the blood-brain barrier (BBB) and demonstrated good brain uptake 5 min post-injection. MicroPET imaging of [11C]2a in a non-human primate (NHP) confirmed that the tracer was able to cross the BBB with rapid washout kinetics from brain regions of a healthy macaque. The initial studies suggested that further structural optimization of [11C]2a and [18F]2b is necessary in order to identify a highly specific positron emission tomography (PET) radioligand for in vivo imaging of α-synuclein aggregation in the central nervous system (CNS).

Keywords: Lewy bodies; PET; Parkinson's disease; phenothiazine; radiosynthesis; α-synuclein.

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Conflict of interest statement

Conflicts of Interest: The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Potent tricyclic aromatic ring analogues. a Thioflavin T fluorescence assay; b 125I competitive binding assay; c 95% confidence intervals for Ki values are shown in parentheses.
Figure 2
Figure 2
Regional radioactivity uptake in male Sprague Dawley (SD) rat brain (n = 4). (A) Regional brain uptake of [11C]2a; (B) regional brain uptake of [18F]2b. Cb, cerebellum; Ctx, cortex; Str, striatum; Thal, thalamus; Hippo, hippocampus.
Figure 3
Figure 3
In vivo microPET brain imaging studies of [11C]2a in cynomolgus macaque. (A) PET image (left), co-registered with MRI (middle), MRI image (right); (B) time-activity curves. SUV, standardized uptake value.
Scheme 1
Scheme 1
Synthesis of phenol Precursor 4. rt, room temperature. Reagents and conditions: a AcCl, DCM, rt, overnight; b BBr3 in DCM (1.0 M), DCM, −78 °C–rt, overnight.
Scheme 2
Scheme 2
Synthesis of [11C]2a and [18F]2b. DMF, N,N-dimethylformamide; [18F]FEOTs, [18F]fluoroethyltosylate; DMSO, dimethyl sulfoxide; DBU, 1,8-diazabicyclo[5.4.0]undec-7-ene. Reagents and conditions: a [11C]CH3I/DMF, NaOH, 90 °C, 5 min; b DBU, 7 min; c [18F]F−, Kryptofix 2.2.2, K2CO3, CH3CN, 110 °C, 10 min; d [18F]FEOTs, Cs2CO3, DMSO, 90 °C, 15 min; e DBU, 15 min.
See this image and copyright information in PMC

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