Synthesis and evaluation of new radioligands [11C]A-833834 and [11C]A-752274 for positron-emission tomography of α7-nicotinic acetylcholine receptors

Andrew G. Horti; Hayden T Ravert; Yongjun Gao; Daniel P. Holt; William H. Bunnelle; Michael R. Schrimpf; Tao Li; Jianguo Ji; Heather Valentine; Ursula Scheffel; Hiroto Kuwabara; Dean Foster Wong; Robert F. Dannals

doi:10.1016/j.nucmedbio.2012.11.013

Synthesis and evaluation of new radioligands [¹¹C]A-833834 and [¹¹C]A-752274 for positron-emission tomography of α7-nicotinic acetylcholine receptors

Andrew G. Horti, Hayden T Ravert, Yongjun Gao, Daniel P. Holt, William H. Bunnelle, Michael R. Schrimpf, Tao Li, Jianguo Ji, Heather Valentine, Ursula Scheffel, Hiroto Kuwabara, Dean Foster Wong, Robert F. Dannals

School of Medicine

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

18 Scopus citations

Abstract

Introduction: α7-nicotinic acetylcholine receptor (α7-nAChR) is one of the major neuronal nAChR subtypes. α7-nAChR is involved in variety of neuronal processes and disorders including schizophrenia and Alzheimer's disease. A number of α7-nAChR PET radioligands have been developed, but a quality radiotracer remains to be discovered. Methods: High binding affinity α7-nAChR ligands A-833834 and A-752274 were radiolabeled with ¹¹C. Baseline and blockade biodistribution studies in the mouse brain of [¹¹C]A-833834 (5-(6-(5-[¹¹C]methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridazin-3-yl)-1H-indole) and [¹¹C]A-752274 (2-(6-[¹¹C]methyl-3,6-diazabicyclo[3.2.0]heptan-3-yl)-7-(6-methyl-3,6-diazabicyclo[3.2.0]heptan-3-yl)-9H-fluoren-9-one) were performed. [¹¹C]A-752274 was evaluated in a baseline baboon PET study. Results: [¹¹C]A-833834 and [¹¹C]A-752274 were synthesized by radiomethylation of corresponding des-methyl precursors. The radioligands were prepared with radiochemical yield of 12%-32%, high specific radioactivity (330-403GBq/μmol) and radiochemical purity>95%. Dissection studies with [¹¹C]A-833834 demonstrated low specific α7-nAChR binding in the mouse brain. [¹¹C]A-752274 specifically (~50%) labeled α7-nAChR in the mouse thalamus. However, [¹¹CA-752274 exhibited low brain uptake in baboon (%SUV<100). Conclusion: Two novel α7-nAChR ligands radioligands were synthesized and studied in animals. Specific binding of [¹¹C]A-833834 in the mouse brain is low due to the insufficient binding affinity of the radioligand. The very high binding affinity [¹¹C]A-752274 exhibited good specific binding in the α7-nAChR-rich mouse brain regions. The low uptake of [¹¹C]A-752274 in the baboon brain is due to its high hydrophilicity, rapid metabolism or other properties. Future development of α7-nAChR PET radioligands will be based on compounds with high binding affinities and good blood-brain barrier permeability.

Original language	English (US)
Pages (from-to)	395-402
Number of pages	8
Journal	Nuclear Medicine and Biology
Volume	40
Issue number	3
DOIs	https://doi.org/10.1016/j.nucmedbio.2012.11.013
State	Published - Apr 2013

Keywords

Nicotinic acetylcholine receptor
PET
Positron emission tomography
Radioligand
α7-nAChR

ASJC Scopus subject areas

Molecular Medicine
Radiology Nuclear Medicine and imaging
Cancer Research

Access to Document

10.1016/j.nucmedbio.2012.11.013

Cite this

Horti, A. G., Ravert, H. T., Gao, Y., Holt, D. P., Bunnelle, W. H., Schrimpf, M. R., Li, T., Ji, J., Valentine, H., Scheffel, U., Kuwabara, H., Wong, D. F., & Dannals, R. F. (2013). Synthesis and evaluation of new radioligands [¹¹C]A-833834 and [¹¹C]A-752274 for positron-emission tomography of α7-nicotinic acetylcholine receptors. Nuclear Medicine and Biology, 40(3), 395-402. https://doi.org/10.1016/j.nucmedbio.2012.11.013

Horti, AG, Ravert, HT, Gao, Y, Holt, DP, Bunnelle, WH, Schrimpf, MR, Li, T, Ji, J, Valentine, H, Scheffel, U, Kuwabara, H, Wong, DF & Dannals, RF 2013, 'Synthesis and evaluation of new radioligands [¹¹C]A-833834 and [¹¹C]A-752274 for positron-emission tomography of α7-nicotinic acetylcholine receptors', Nuclear Medicine and Biology, vol. 40, no. 3, pp. 395-402. https://doi.org/10.1016/j.nucmedbio.2012.11.013

@article{9f450084be344bb0aeb514d70694c101,

title = "Synthesis and evaluation of new radioligands [11C]A-833834 and [11C]A-752274 for positron-emission tomography of α7-nicotinic acetylcholine receptors",

abstract = "Introduction: α7-nicotinic acetylcholine receptor (α7-nAChR) is one of the major neuronal nAChR subtypes. α7-nAChR is involved in variety of neuronal processes and disorders including schizophrenia and Alzheimer's disease. A number of α7-nAChR PET radioligands have been developed, but a quality radiotracer remains to be discovered. Methods: High binding affinity α7-nAChR ligands A-833834 and A-752274 were radiolabeled with 11C. Baseline and blockade biodistribution studies in the mouse brain of [11C]A-833834 (5-(6-(5-[11C]methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridazin-3-yl)-1H-indole) and [11C]A-752274 (2-(6-[11C]methyl-3,6-diazabicyclo[3.2.0]heptan-3-yl)-7-(6-methyl-3,6-diazabicyclo[3.2.0]heptan-3-yl)-9H-fluoren-9-one) were performed. [11C]A-752274 was evaluated in a baseline baboon PET study. Results: [11C]A-833834 and [11C]A-752274 were synthesized by radiomethylation of corresponding des-methyl precursors. The radioligands were prepared with radiochemical yield of 12%-32%, high specific radioactivity (330-403GBq/μmol) and radiochemical purity>95%. Dissection studies with [11C]A-833834 demonstrated low specific α7-nAChR binding in the mouse brain. [11C]A-752274 specifically (~50%) labeled α7-nAChR in the mouse thalamus. However, [11CA-752274 exhibited low brain uptake in baboon (%SUV<100). Conclusion: Two novel α7-nAChR ligands radioligands were synthesized and studied in animals. Specific binding of [11C]A-833834 in the mouse brain is low due to the insufficient binding affinity of the radioligand. The very high binding affinity [11C]A-752274 exhibited good specific binding in the α7-nAChR-rich mouse brain regions. The low uptake of [11C]A-752274 in the baboon brain is due to its high hydrophilicity, rapid metabolism or other properties. Future development of α7-nAChR PET radioligands will be based on compounds with high binding affinities and good blood-brain barrier permeability.",

keywords = "Nicotinic acetylcholine receptor, PET, Positron emission tomography, Radioligand, α7-nAChR",

author = "Horti, {Andrew G.} and Ravert, {Hayden T} and Yongjun Gao and Holt, {Daniel P.} and Bunnelle, {William H.} and Schrimpf, {Michael R.} and Tao Li and Jianguo Ji and Heather Valentine and Ursula Scheffel and Hiroto Kuwabara and Wong, {Dean Foster} and Dannals, {Robert F.}",

note = "Funding Information: We are grateful to Robert C. Smoot for radiochemistry assistance, and David J. Clough and Karen Edmonds for PET scanner operation and Paige Finley for help with animal experiments. The authors thank Mrs. Judy Buchanan for her kind editorial assistance. This research was supported in part by the Division of Nuclear Medicine of Johns Hopkins University School of Medicine and by NIH Grants DA020777 and MH079017 (AGH).",

year = "2013",

month = apr,

doi = "10.1016/j.nucmedbio.2012.11.013",

language = "English (US)",

volume = "40",

pages = "395--402",

journal = "Nuclear Medicine and Biology",

issn = "0969-8051",

publisher = "Elsevier Inc.",

number = "3",

}

TY - JOUR

T1 - Synthesis and evaluation of new radioligands [11C]A-833834 and [11C]A-752274 for positron-emission tomography of α7-nicotinic acetylcholine receptors

AU - Horti, Andrew G.

AU - Ravert, Hayden T

AU - Gao, Yongjun

AU - Holt, Daniel P.

AU - Bunnelle, William H.

AU - Schrimpf, Michael R.

AU - Li, Tao

AU - Ji, Jianguo

AU - Valentine, Heather

AU - Scheffel, Ursula

AU - Kuwabara, Hiroto

AU - Wong, Dean Foster

AU - Dannals, Robert F.

N1 - Funding Information: We are grateful to Robert C. Smoot for radiochemistry assistance, and David J. Clough and Karen Edmonds for PET scanner operation and Paige Finley for help with animal experiments. The authors thank Mrs. Judy Buchanan for her kind editorial assistance. This research was supported in part by the Division of Nuclear Medicine of Johns Hopkins University School of Medicine and by NIH Grants DA020777 and MH079017 (AGH).

PY - 2013/4

Y1 - 2013/4

N2 - Introduction: α7-nicotinic acetylcholine receptor (α7-nAChR) is one of the major neuronal nAChR subtypes. α7-nAChR is involved in variety of neuronal processes and disorders including schizophrenia and Alzheimer's disease. A number of α7-nAChR PET radioligands have been developed, but a quality radiotracer remains to be discovered. Methods: High binding affinity α7-nAChR ligands A-833834 and A-752274 were radiolabeled with 11C. Baseline and blockade biodistribution studies in the mouse brain of [11C]A-833834 (5-(6-(5-[11C]methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridazin-3-yl)-1H-indole) and [11C]A-752274 (2-(6-[11C]methyl-3,6-diazabicyclo[3.2.0]heptan-3-yl)-7-(6-methyl-3,6-diazabicyclo[3.2.0]heptan-3-yl)-9H-fluoren-9-one) were performed. [11C]A-752274 was evaluated in a baseline baboon PET study. Results: [11C]A-833834 and [11C]A-752274 were synthesized by radiomethylation of corresponding des-methyl precursors. The radioligands were prepared with radiochemical yield of 12%-32%, high specific radioactivity (330-403GBq/μmol) and radiochemical purity>95%. Dissection studies with [11C]A-833834 demonstrated low specific α7-nAChR binding in the mouse brain. [11C]A-752274 specifically (~50%) labeled α7-nAChR in the mouse thalamus. However, [11CA-752274 exhibited low brain uptake in baboon (%SUV<100). Conclusion: Two novel α7-nAChR ligands radioligands were synthesized and studied in animals. Specific binding of [11C]A-833834 in the mouse brain is low due to the insufficient binding affinity of the radioligand. The very high binding affinity [11C]A-752274 exhibited good specific binding in the α7-nAChR-rich mouse brain regions. The low uptake of [11C]A-752274 in the baboon brain is due to its high hydrophilicity, rapid metabolism or other properties. Future development of α7-nAChR PET radioligands will be based on compounds with high binding affinities and good blood-brain barrier permeability.

AB - Introduction: α7-nicotinic acetylcholine receptor (α7-nAChR) is one of the major neuronal nAChR subtypes. α7-nAChR is involved in variety of neuronal processes and disorders including schizophrenia and Alzheimer's disease. A number of α7-nAChR PET radioligands have been developed, but a quality radiotracer remains to be discovered. Methods: High binding affinity α7-nAChR ligands A-833834 and A-752274 were radiolabeled with 11C. Baseline and blockade biodistribution studies in the mouse brain of [11C]A-833834 (5-(6-(5-[11C]methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridazin-3-yl)-1H-indole) and [11C]A-752274 (2-(6-[11C]methyl-3,6-diazabicyclo[3.2.0]heptan-3-yl)-7-(6-methyl-3,6-diazabicyclo[3.2.0]heptan-3-yl)-9H-fluoren-9-one) were performed. [11C]A-752274 was evaluated in a baseline baboon PET study. Results: [11C]A-833834 and [11C]A-752274 were synthesized by radiomethylation of corresponding des-methyl precursors. The radioligands were prepared with radiochemical yield of 12%-32%, high specific radioactivity (330-403GBq/μmol) and radiochemical purity>95%. Dissection studies with [11C]A-833834 demonstrated low specific α7-nAChR binding in the mouse brain. [11C]A-752274 specifically (~50%) labeled α7-nAChR in the mouse thalamus. However, [11CA-752274 exhibited low brain uptake in baboon (%SUV<100). Conclusion: Two novel α7-nAChR ligands radioligands were synthesized and studied in animals. Specific binding of [11C]A-833834 in the mouse brain is low due to the insufficient binding affinity of the radioligand. The very high binding affinity [11C]A-752274 exhibited good specific binding in the α7-nAChR-rich mouse brain regions. The low uptake of [11C]A-752274 in the baboon brain is due to its high hydrophilicity, rapid metabolism or other properties. Future development of α7-nAChR PET radioligands will be based on compounds with high binding affinities and good blood-brain barrier permeability.

KW - Nicotinic acetylcholine receptor

KW - PET

KW - Positron emission tomography

KW - Radioligand

KW - α7-nAChR

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