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Human Brain Imaging of α7 nAChR with [18F]ASEM: a New PET Radiotracer for Neuropsychiatry and Determination of Drug Occupancy

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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.

Conflict of Interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Radiology, School of Medicine, The Johns Hopkins University, Baltimore, MD, USA

    Dean F. Wong, Hiroto Kuwabara, Martin Pomper, Daniel P. Holt, James R. Brasic, Noble George, Boris Frolov, William Willis, Yongjun Gao, Heather Valentine, Ayon Nandi, Lorena Gapasin, Robert F. Dannals & Andrew G. Horti

  2. Department of Psychiatry, School of Medicine, The Johns Hopkins University, Baltimore, MD, USA

    Dean F. Wong & Martin Pomper

  3. Department of Neuroscience, School of Medicine, The Johns Hopkins University, Baltimore, MD, USA

    Dean F. Wong

  4. Department of Environmental Health Sciences, Bloomberg School of Public Health, The Johns Hopkins University, Baltimore, MD, USA

    Dean F. Wong, Martin Pomper & Robert F. Dannals

  5. Johns Hopkins Medical Institutions, JHOC Bldg. Room 3245, 601 N. Caroline St., Baltimore, MD, 21287, USA

    Dean F. Wong

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  1. Dean F. Wong
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Correspondence to Dean F. Wong.

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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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