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

65 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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10.1007/s11307-014-0779-3

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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",

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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

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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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