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

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

doi:10.1007/s11307-014-0779-3

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

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

Precision Radiotheranostics Translation Center (PRTC)

Research output: Contribution to journal › Article › peer-review

69 Scopus citations

Abstract

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.

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.

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.

Original language	English
Pages (from-to)	730-738
Number of pages	9
Journal	Molecular Imaging and Biology
Volume	16
Issue number	5
DOIs	https://doi.org/10.1007/s11307-014-0779-3
State	Published - Oct 2014

Keywords

Alpha-7
DMXB-A
GTS-21
Nicotinic acetylcholine receptor
PET brain imaging
Radiotracer kinetic modeling
Receptor occupancy
Schizophrenia

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Wong, D. F., Kuwabara, H., Pomper, M., Holt, D. P., Brasic, J. R., George, N., Frolov, B., Willis, W., Gao, Y., Valentine, H., Nandi, A., Gapasin, L., Dannals, R. F., & Horti, A. G. (2014). Human Brain Imaging of α7 nAChR with [¹⁸F]ASEM: a New PET Radiotracer for Neuropsychiatry and Determination of Drug Occupancy. Molecular Imaging and Biology, 16(5), 730-738. https://doi.org/10.1007/s11307-014-0779-3

@article{5a14106698014f42849e82ce99aa137b,

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

abstract = "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.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.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.",

keywords = "Alpha-7, DMXB-A, GTS-21, Nicotinic acetylcholine receptor, PET brain imaging, Radiotracer kinetic modeling, Receptor occupancy, Schizophrenia",

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

note = "Publisher Copyright: {\textcopyright} 2014, Academy of Molecular Imaging and Society for Molecular Imaging.",

year = "2014",

month = oct,

doi = "10.1007/s11307-014-0779-3",

language = "English",

volume = "16",

pages = "730--738",

journal = "Molecular Imaging and Biology",

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Wong, DF, Kuwabara, H, Pomper, M, Holt, DP, Brasic, JR, George, N, Frolov, B, Willis, W, Gao, Y, Valentine, H, Nandi, A, Gapasin, L, Dannals, RF & Horti, AG 2014, 'Human Brain Imaging of α7 nAChR with [¹⁸F]ASEM: a New PET Radiotracer for Neuropsychiatry and Determination of Drug Occupancy', Molecular Imaging and Biology, vol. 16, no. 5, pp. 730-738. https://doi.org/10.1007/s11307-014-0779-3

TY - JOUR

T1 - Human Brain Imaging of α7 nAChR with [18F]ASEM

T2 - a New PET Radiotracer for Neuropsychiatry and Determination of Drug Occupancy

AU - Wong, Dean F.

AU - Kuwabara, Hiroto

AU - Pomper, Martin

AU - Holt, Daniel P.

AU - Brasic, James R.

AU - George, Noble

AU - Frolov, Boris

AU - Willis, William

AU - Gao, Yongjun

AU - Valentine, Heather

AU - Nandi, Ayon

AU - Gapasin, Lorena

AU - Dannals, Robert F.

AU - Horti, Andrew G.

PY - 2014/10

Y1 - 2014/10

N2 - 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.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.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.

AB - 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.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.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.

KW - Alpha-7

KW - DMXB-A

KW - GTS-21

KW - Nicotinic acetylcholine receptor

KW - PET brain imaging

KW - Radiotracer kinetic modeling

KW - Receptor occupancy

KW - Schizophrenia

UR - https://www.scopus.com/pages/publications/84919919769

U2 - 10.1007/s11307-014-0779-3

DO - 10.1007/s11307-014-0779-3

M3 - Article

C2 - 25145965

AN - SCOPUS:84919919769

SN - 1536-1632

VL - 16

SP - 730

EP - 738

JO - Molecular Imaging and Biology

JF - Molecular Imaging and Biology

IS - 5

ER -

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

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Keywords

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