Abstract
Purpose
Using the α7-nAChR radiotracer, [18F]ASEM, we present the first successful human positron emission tomography (PET) studies. Rodent occupancy with three clinically employed α7-nAChR drugs confirms the specificity of the radiotracer.
Procedures
Five healthy male subjects were imaged for 90 min following IV [18F]ASEM. Two subjects were scanned for the second time (test/retest; TRV). Mouse biodistribution of [18F]ASEM was carried out in CD1 mice injected with using human equivalent doses of DMXB-A, EVP-6124, and varenicline to block specific binding.
Results
[18F]ASEM readily entered the brain and peaked at 15 min post-injection with reversible kinetics and a peak %SUV of about 400 %. The regional human brain distribution of [18F]ASEM matched previous in vitro data and baboon PET results. The precuneus, parietal, occipital, cingulate cortexes, putamen, and thalamus showed high values of distribution volume (>20 ml/ml) and binding potentials >1 with TRV averaged 10.8 ± 5.1 %. In mouse distribution studies, there was significant dose-dependent blockade in the mouse brain with DMXB-A as well as the other two α7-nAChR drugs.
Conclusions
The characteristics of [18F]ASEM are consistent with the ability to quantify α7-nAChR in the human brain. [18F]ASEM is suitable for imaging neuropsychiatric disorders and target engagement (receptor occupancy) of potential α7-nAChR drugs.
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Acknowledgments
The authors received NIH grants MH079017 and AG037298 and funds from the Department of Radiology. Special thanks to Ali Kargbo, MS; Rebecca Mellinger Pilgram, BS; and Anil Mathur, MD, MIS for the HPLC metabolite analysis; Paige Finley, BS for the mouse experiments; the JHU PET technologists and PET radiochemists and Andrew Crabb, MS and Arman Rahmim, PhD for the computer-related and HRRT PET assistance. Thanks to Michael Stabin, PhD for assisting in radiation dosimetry estimates and Julia Buchanan for the editorial assistance.
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The authors declare that they have no conflict of interest.
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Wong, D.F., Kuwabara, H., Pomper, M. et al. Human Brain Imaging of α7 nAChR with [18F]ASEM: a New PET Radiotracer for Neuropsychiatry and Determination of Drug Occupancy. Mol Imaging Biol 16, 730–738 (2014). https://doi.org/10.1007/s11307-014-0779-3
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DOI: https://doi.org/10.1007/s11307-014-0779-3