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).
Highlights
Parkinson’s disease (PD) is a degenerative neurological disorder characterized by motor symptoms, it is known to be closely associated with dementia [1]
Α-Synuclein (α-syn) is a presynaptic terminal protein that consists of 140 amino acids; the aggregation of α-syn is considered the pathological hallmark of PD. α-Syn plays an important role in the central nervous system (CNS) in synaptic vesicle recycling; it regulates the synthesis, storage and release of neurotransmitters [4]
We report the radiosyntheses of [11C]2a and [18F]2b and their validation in animal studies to determine whether [11C]2a and [18F]2b can penetrate the blood-brain barrier (BBB), have sufficient brain uptake and fast washout from the brain
Summary
Parkinson’s disease (PD) is a degenerative neurological disorder characterized by motor symptoms, it is known to be closely associated with dementia [1]. Current diagnostic PET radioligands for PD target either the dopaminergic system (pre-synaptic and post-synaptic dopamine activity) or vesicular monoamine transporter type 2 (VMAT2) [12,13] Such imaging strategies have difficulty in distinguishing PD from other parkinsonian syndromes that result in the degeneration of nigrostriatal projections [14,15]. PET radiotracer with high affinity and selectivity to fibrillar α-syn protein could be used to quantify the level of α-syn aggregation non-invasively. This will improve the diagnostic accuracy of PD, and provide a tool to improve the understanding of disease progression and monitor the therapeutic efficacy in clinical trials. Results of ex vivo biodistribution of [11C]2a and [18F]2b in Sprague-Dawley rats and microPET CNS imaging in a cynomolgus macaque of [11C]2a suggest that further structure-activity relationship (SAR) study is necessary for identifying a highly specific PET radioligand targeting α-syn aggregation
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