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Introduction: Nicotinic acetylcholine receptors located in extrathalamic brain regions (EN) are important therapeutic targets. The ability to image EN in the human brain has been hampered by the lack of suitable radiotracers. The radiotracers for imaging of the EN used previously in animals, display very slow brain kinetics requiring many hours of PET imaging. Here we present a novel high affinity radioligand [ 18 F]JHU86358 with improved brain kinetics and high regional binding potentials for imaging of EN.
Experimental: The in vitro inhibition binding assay of JHU86358, a novel fluorinated 5-aminoalkyl-3,3 -bipyridine synthesized in our lab, was performed in duplicate using rat cortical membranes and [ 3 H]epibatidine. [ 18 F]JHU86358, was prepared by radiofluorination of corresponding bromo precursor using GE box. Regional brain distribution of [ 18 F]JHU86358 was studied by baboon PET.
Results and Discussion: Inhibition binding affinity of JHU86358 was Ki = 51 pM, whereas epibatidine, a potent nAChR ligand, displayed a binding affinity of 43 pM in the same assay. [ 18 F]JHU86358 was obtained with radiochemical yield, radiochemical purity and the average specific activity of 50%, 99% and 580 GBq/ฮผmol, respectively. High radioligand uptake in the baboon brain was observed after injection of [ 18 F]JHU86358 using PET. The highest accumulation of radioactivity occurred in the thalamus. Intermediate uptake was observed in the cortex and pons. The lowest level of radioactivity was in the cerebellum. At 3 h after injection, region-to-cerebellum ratios values of 6.1, 2.4 and 2.1 in thalamus, frontal cortex and pons, respectively, were calculated. The time to reach a steady-state in the cortex and pons was about 2 h and it was more delayed in the thalamus. The distribution and kinetics of [ 18 F]JHU86358 in brain regions were similar to those of 2-[ 18 F]FA and 6-[ 18 F]FA but the tissue/cerebellum ratios of [ 18 F]JHU86358 were about 200-300% higher with the new radioligand. The brain kinetics of [ 18 F]JHU86358 were also faster than those of [ 18 F]NIDA52189 and [ 18 F]NIDA522131 since the latter two required at least 8 h to reach steady-state in the cortex. Scheme. Left: Time-uptake curves of [ 18 F]JHU86358 in baboon brain. Right: Region/verebellum ratios of [ 18 F]JHU86358 in 180 min after injection.
Conclusion: [ 18 F]JHU86358 holds promise as a radioligand for studying extrathalamic regions in human brain. It shows higher binding potential and shorter time to steady state than previously developed radioligands.
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