Alzheimer's disease (AD) and vascular dementia (VaD) are the most frequent causes of cognitive impairment in the elderly. In the pathogenesis of cognitive impairment, the association of neurodegenerative and vascular factors indicates a major role of hemodynamic abnormalities including cerebral hypoperfusion. There is also ample evidence that oxidative stress of vascular origin leads to profound alterations in cerebrovascular regulation and is crucial to cerebrovascular dysfunction in a variety of conditions that result in chronic hypoperfusion of the brain. In rodents, experimental chronic cerebral hypoperfusion (CCH) can be initiated by occlusion of the major arterial supply. This way CCH brings about mitochondrial dysfunction and protein synthesis inhibition. These effects may destroy the balance of antioxidases and reactive oxygen species (ROS) and produce oxidative damage. At the same time, oxidative injury to vascular endothelial cell, glia, and neuron impairs vascular function and neurovascular coupling, which may result in a vicious cycle of further reduction of cerebral perfusion. In clinical cases of severe cognitive dysfunction, vascular risk factors are commonly present, while cerebral hypoperfusion is often associated with vascular oxidative damage. Thus we hypothesize that cerebral hypoperfusion is one of the key factors in the development of cognitive impairment, in which vascular oxidative stress plays a major role. The approaches against cerebrovascular dysfunction, combined with antioxidants and others, might make a promising contribution to the treatment of cognitive impairment.
Nine fluorine-containing vesicular acetylcholine transporter (VAChT) inhibitors were synthesized and screened as potential PET tracers for imaging the VAChT. Compound 18a was one of the most promising carbonyl-containing benzovesamicol analogues; the minus enantiomer, (-)-18a displayed high potency (VAChT Ki = 0.59 ± 0.06 nM) and high selectivity for VAChT versus receptors (> 10,000-fold). The radiosynthesis of (-)-[18F]18a was accomplished by a two-step procedure with 30 – 40% radiochemical yield. Preliminary biodistribution studies of (-)-[18F]18a in adult male Sprague–Dawley rats at 5, 30, 60 and 120 min post-injection (p.i.) were promising. The total brain uptake of (-)-[18F]18a was 0.684 ID%/g at 5 min p.i. and by 120 min p.i. slowly washed out to 0.409 %ID/g.; evaluation of regional brain uptake showed stable levels of ~0.800 %ID/g from 5 to 120 min p.i in the VAChT-enriched striatal tissue of rats, indicating the tracer had crossed the blood brain barrier and was retained in the striatum. Subsequent microPET brain imaging studies of (-)-[18F]18a in nonhuman primates (NHPs) showed high striatal accumulation in the NHP brain; the standardized uptake value (SUV) for striatum reached a maximum value of 5.1 at 15 min p.i. The time-activity curve for the target striatal region displayed a slow and gradual decreasing trend 15 min after injection, while clearance of the radioactivity from the cerebellar reference region was much more rapid. Pretreatment of NHPs with 0.25 mg/kg of the VAChT inhibitor (-)-vesamicol resulted in a ~90% decrease of striatal uptake compared to baseline studies. HPLC metabolite analysis of NHP plasma revealed that (-)-[18F]18a had a good in vivo stability. Together, these preliminary results suggest (-)-[18F]18a is a promising PET tracer candidate for imaging VAChT in the brain of living subjects.
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