Synthesis and Evaluation of Two 18F-Labeled 6-Iodo-2-(4′ -N,N-dimethylamino)phenylimidazo[1,2-a]pyridine Derivatives as Prospective Radioligands for β-Amyloid in Alzheimer's Disease

Lisheng Cai, Frederick T. Chin, Victor W. Pike, Hiroshi Toyama, Jeih San Liow, Sami S. Zoghbi, Kendra Modell, Emmanuelle Briard, H. Umesha Shetty, Kathryn Sinclair, Sean Donohue, Dnyanesh Tipre, Mei Ping Kung, Claudio Dagostin, David A. Widdowson, Michael Green, Weiyi Gao, Mary M. Herman, Masanori Ichise, Robert B. Innis

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Abstract

This study evaluated 18F-labeled IMPY [6-iodo-2-(4′ -N,N-dimethylamino)phenylimidazo[1,2-a]pyridine] derivatives as agents for imaging β-amyloid plaque with positron emission tomography (PET). The precursor for radiolabeling and reference compounds was synthesized in up to five steps from commercially accessible starting materials. One of the two N-methyl groups of IMPY was substituted with either a 3-fluoropropyl (FPM-IMPY) or a 2-fluoroethyl (FEM-IMPY) group. FPM-IMPY and FEM-IMPY were found to have moderate affinity for Aβ-aggregates with Ki = 27 ± 8 and 40 ± 5 nM, respectively. A "one-pot" method for 18F-2-fluoroethylation and 18F-3-fluoropropylation of the precursor was developed. The overall decay-corrected radiochemical yields were 26-51%. In PET experiments with normal mouse, high uptake of activity was obtained in the brain after iv injection of each probe: 6.4% ID/g for [ 18F]FEM-IMPY at 1.2 min, and 5.7% ID/g for [18F]FPM-IMPY at 0.8 min. These values were similar to those of [123I/ 125I]IMPY (7.2% ID/g at 2 min). Polar and nonpolar radioactive metabolites were observed in both plasma and brain homogenates after injection of [18F]FEM or [18F]FPM-IMPY. In contrast to the single-exponential washout of [123I/125I]IMPY, the washouts of brain activity for the two fluorinated analogues were biphasic, with an initial rapid phase over 20 min and a subsequent much slower phase. Residual brain activity at 2 h, which may represent polar metabolites trapped in the brain, was 4.5% ID/g for [18F]FEM-IMPY and 2.1% ID/g for [18F]FPM-IMPY. Substantial skull uptake of [18F]fluoride was also clearly observed. With a view to slow the metabolism of [ 18F]FEM-IMPY, an analogue was prepared with deuteriums substituted for the four ethyl hydrogens. However, D4-[18F]FEM-IMPY showed the same brain uptake and clearance as the protio analogue. Metabolism of the [18F]FEM-IMPY was appreciably slower in rhesus monkey than in mouse. Autoradiography of postmortem brain sections of human Alzheimer's disease patients with [18F]FEM-IMPY showed high displaceable uptake in gray matter and low nonspecific binding in the white matter. This study demonstrates that the IMPY derivatives have favorable in vivo brain pharmacokinetics and a moderate affinity for imaging β-amyloid plaques; however, further improvements are needed to reduce radioactive metabolites, increase binding affinity, and reduce lipophilicity.

Original languageEnglish
Pages (from-to)2208-2218
Number of pages11
JournalJournal of Medicinal Chemistry
Volume47
Issue number9
DOIs
Publication statusPublished - 22-04-2004
Externally publishedYes

Fingerprint

Amyloid
Alzheimer Disease
Brain
Amyloid Plaques
Positron-Emission Tomography
Injections
pyridine
6-iodo-2-(4'-N-(2-fluoroethyl)methylamino)phenylimidazo(1,2-a)pyridine
Macaca mulatta
Autoradiography
Fluorides
Skull
Hydrogen
Pharmacokinetics
6-iodo-2-(4'-N-(2-fluoropropyl)methylamino)phenylimidazo(1,2-a)pyridine
2,3-dihydro-1H-imidazo(1,2-b)pyrazole

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

Cite this

Cai, Lisheng ; Chin, Frederick T. ; Pike, Victor W. ; Toyama, Hiroshi ; Liow, Jeih San ; Zoghbi, Sami S. ; Modell, Kendra ; Briard, Emmanuelle ; Shetty, H. Umesha ; Sinclair, Kathryn ; Donohue, Sean ; Tipre, Dnyanesh ; Kung, Mei Ping ; Dagostin, Claudio ; Widdowson, David A. ; Green, Michael ; Gao, Weiyi ; Herman, Mary M. ; Ichise, Masanori ; Innis, Robert B. / Synthesis and Evaluation of Two 18F-Labeled 6-Iodo-2-(4′ -N,N-dimethylamino)phenylimidazo[1,2-a]pyridine Derivatives as Prospective Radioligands for β-Amyloid in Alzheimer's Disease. In: Journal of Medicinal Chemistry. 2004 ; Vol. 47, No. 9. pp. 2208-2218.
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title = "Synthesis and Evaluation of Two 18F-Labeled 6-Iodo-2-(4′ -N,N-dimethylamino)phenylimidazo[1,2-a]pyridine Derivatives as Prospective Radioligands for β-Amyloid in Alzheimer's Disease",
abstract = "This study evaluated 18F-labeled IMPY [6-iodo-2-(4′ -N,N-dimethylamino)phenylimidazo[1,2-a]pyridine] derivatives as agents for imaging β-amyloid plaque with positron emission tomography (PET). The precursor for radiolabeling and reference compounds was synthesized in up to five steps from commercially accessible starting materials. One of the two N-methyl groups of IMPY was substituted with either a 3-fluoropropyl (FPM-IMPY) or a 2-fluoroethyl (FEM-IMPY) group. FPM-IMPY and FEM-IMPY were found to have moderate affinity for Aβ-aggregates with Ki = 27 ± 8 and 40 ± 5 nM, respectively. A {"}one-pot{"} method for 18F-2-fluoroethylation and 18F-3-fluoropropylation of the precursor was developed. The overall decay-corrected radiochemical yields were 26-51{\%}. In PET experiments with normal mouse, high uptake of activity was obtained in the brain after iv injection of each probe: 6.4{\%} ID/g for [ 18F]FEM-IMPY at 1.2 min, and 5.7{\%} ID/g for [18F]FPM-IMPY at 0.8 min. These values were similar to those of [123I/ 125I]IMPY (7.2{\%} ID/g at 2 min). Polar and nonpolar radioactive metabolites were observed in both plasma and brain homogenates after injection of [18F]FEM or [18F]FPM-IMPY. In contrast to the single-exponential washout of [123I/125I]IMPY, the washouts of brain activity for the two fluorinated analogues were biphasic, with an initial rapid phase over 20 min and a subsequent much slower phase. Residual brain activity at 2 h, which may represent polar metabolites trapped in the brain, was 4.5{\%} ID/g for [18F]FEM-IMPY and 2.1{\%} ID/g for [18F]FPM-IMPY. Substantial skull uptake of [18F]fluoride was also clearly observed. With a view to slow the metabolism of [ 18F]FEM-IMPY, an analogue was prepared with deuteriums substituted for the four ethyl hydrogens. However, D4-[18F]FEM-IMPY showed the same brain uptake and clearance as the protio analogue. Metabolism of the [18F]FEM-IMPY was appreciably slower in rhesus monkey than in mouse. Autoradiography of postmortem brain sections of human Alzheimer's disease patients with [18F]FEM-IMPY showed high displaceable uptake in gray matter and low nonspecific binding in the white matter. This study demonstrates that the IMPY derivatives have favorable in vivo brain pharmacokinetics and a moderate affinity for imaging β-amyloid plaques; however, further improvements are needed to reduce radioactive metabolites, increase binding affinity, and reduce lipophilicity.",
author = "Lisheng Cai and Chin, {Frederick T.} and Pike, {Victor W.} and Hiroshi Toyama and Liow, {Jeih San} and Zoghbi, {Sami S.} and Kendra Modell and Emmanuelle Briard and Shetty, {H. Umesha} and Kathryn Sinclair and Sean Donohue and Dnyanesh Tipre and Kung, {Mei Ping} and Claudio Dagostin and Widdowson, {David A.} and Michael Green and Weiyi Gao and Herman, {Mary M.} and Masanori Ichise and Innis, {Robert B.}",
year = "2004",
month = "4",
day = "22",
doi = "10.1021/jm030477w",
language = "English",
volume = "47",
pages = "2208--2218",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
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}

Cai, L, Chin, FT, Pike, VW, Toyama, H, Liow, JS, Zoghbi, SS, Modell, K, Briard, E, Shetty, HU, Sinclair, K, Donohue, S, Tipre, D, Kung, MP, Dagostin, C, Widdowson, DA, Green, M, Gao, W, Herman, MM, Ichise, M & Innis, RB 2004, 'Synthesis and Evaluation of Two 18F-Labeled 6-Iodo-2-(4′ -N,N-dimethylamino)phenylimidazo[1,2-a]pyridine Derivatives as Prospective Radioligands for β-Amyloid in Alzheimer's Disease', Journal of Medicinal Chemistry, vol. 47, no. 9, pp. 2208-2218. https://doi.org/10.1021/jm030477w

Synthesis and Evaluation of Two 18F-Labeled 6-Iodo-2-(4′ -N,N-dimethylamino)phenylimidazo[1,2-a]pyridine Derivatives as Prospective Radioligands for β-Amyloid in Alzheimer's Disease. / Cai, Lisheng; Chin, Frederick T.; Pike, Victor W.; Toyama, Hiroshi; Liow, Jeih San; Zoghbi, Sami S.; Modell, Kendra; Briard, Emmanuelle; Shetty, H. Umesha; Sinclair, Kathryn; Donohue, Sean; Tipre, Dnyanesh; Kung, Mei Ping; Dagostin, Claudio; Widdowson, David A.; Green, Michael; Gao, Weiyi; Herman, Mary M.; Ichise, Masanori; Innis, Robert B.

In: Journal of Medicinal Chemistry, Vol. 47, No. 9, 22.04.2004, p. 2208-2218.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Synthesis and Evaluation of Two 18F-Labeled 6-Iodo-2-(4′ -N,N-dimethylamino)phenylimidazo[1,2-a]pyridine Derivatives as Prospective Radioligands for β-Amyloid in Alzheimer's Disease

AU - Cai, Lisheng

AU - Chin, Frederick T.

AU - Pike, Victor W.

AU - Toyama, Hiroshi

AU - Liow, Jeih San

AU - Zoghbi, Sami S.

AU - Modell, Kendra

AU - Briard, Emmanuelle

AU - Shetty, H. Umesha

AU - Sinclair, Kathryn

AU - Donohue, Sean

AU - Tipre, Dnyanesh

AU - Kung, Mei Ping

AU - Dagostin, Claudio

AU - Widdowson, David A.

AU - Green, Michael

AU - Gao, Weiyi

AU - Herman, Mary M.

AU - Ichise, Masanori

AU - Innis, Robert B.

PY - 2004/4/22

Y1 - 2004/4/22

N2 - This study evaluated 18F-labeled IMPY [6-iodo-2-(4′ -N,N-dimethylamino)phenylimidazo[1,2-a]pyridine] derivatives as agents for imaging β-amyloid plaque with positron emission tomography (PET). The precursor for radiolabeling and reference compounds was synthesized in up to five steps from commercially accessible starting materials. One of the two N-methyl groups of IMPY was substituted with either a 3-fluoropropyl (FPM-IMPY) or a 2-fluoroethyl (FEM-IMPY) group. FPM-IMPY and FEM-IMPY were found to have moderate affinity for Aβ-aggregates with Ki = 27 ± 8 and 40 ± 5 nM, respectively. A "one-pot" method for 18F-2-fluoroethylation and 18F-3-fluoropropylation of the precursor was developed. The overall decay-corrected radiochemical yields were 26-51%. In PET experiments with normal mouse, high uptake of activity was obtained in the brain after iv injection of each probe: 6.4% ID/g for [ 18F]FEM-IMPY at 1.2 min, and 5.7% ID/g for [18F]FPM-IMPY at 0.8 min. These values were similar to those of [123I/ 125I]IMPY (7.2% ID/g at 2 min). Polar and nonpolar radioactive metabolites were observed in both plasma and brain homogenates after injection of [18F]FEM or [18F]FPM-IMPY. In contrast to the single-exponential washout of [123I/125I]IMPY, the washouts of brain activity for the two fluorinated analogues were biphasic, with an initial rapid phase over 20 min and a subsequent much slower phase. Residual brain activity at 2 h, which may represent polar metabolites trapped in the brain, was 4.5% ID/g for [18F]FEM-IMPY and 2.1% ID/g for [18F]FPM-IMPY. Substantial skull uptake of [18F]fluoride was also clearly observed. With a view to slow the metabolism of [ 18F]FEM-IMPY, an analogue was prepared with deuteriums substituted for the four ethyl hydrogens. However, D4-[18F]FEM-IMPY showed the same brain uptake and clearance as the protio analogue. Metabolism of the [18F]FEM-IMPY was appreciably slower in rhesus monkey than in mouse. Autoradiography of postmortem brain sections of human Alzheimer's disease patients with [18F]FEM-IMPY showed high displaceable uptake in gray matter and low nonspecific binding in the white matter. This study demonstrates that the IMPY derivatives have favorable in vivo brain pharmacokinetics and a moderate affinity for imaging β-amyloid plaques; however, further improvements are needed to reduce radioactive metabolites, increase binding affinity, and reduce lipophilicity.

AB - This study evaluated 18F-labeled IMPY [6-iodo-2-(4′ -N,N-dimethylamino)phenylimidazo[1,2-a]pyridine] derivatives as agents for imaging β-amyloid plaque with positron emission tomography (PET). The precursor for radiolabeling and reference compounds was synthesized in up to five steps from commercially accessible starting materials. One of the two N-methyl groups of IMPY was substituted with either a 3-fluoropropyl (FPM-IMPY) or a 2-fluoroethyl (FEM-IMPY) group. FPM-IMPY and FEM-IMPY were found to have moderate affinity for Aβ-aggregates with Ki = 27 ± 8 and 40 ± 5 nM, respectively. A "one-pot" method for 18F-2-fluoroethylation and 18F-3-fluoropropylation of the precursor was developed. The overall decay-corrected radiochemical yields were 26-51%. In PET experiments with normal mouse, high uptake of activity was obtained in the brain after iv injection of each probe: 6.4% ID/g for [ 18F]FEM-IMPY at 1.2 min, and 5.7% ID/g for [18F]FPM-IMPY at 0.8 min. These values were similar to those of [123I/ 125I]IMPY (7.2% ID/g at 2 min). Polar and nonpolar radioactive metabolites were observed in both plasma and brain homogenates after injection of [18F]FEM or [18F]FPM-IMPY. In contrast to the single-exponential washout of [123I/125I]IMPY, the washouts of brain activity for the two fluorinated analogues were biphasic, with an initial rapid phase over 20 min and a subsequent much slower phase. Residual brain activity at 2 h, which may represent polar metabolites trapped in the brain, was 4.5% ID/g for [18F]FEM-IMPY and 2.1% ID/g for [18F]FPM-IMPY. Substantial skull uptake of [18F]fluoride was also clearly observed. With a view to slow the metabolism of [ 18F]FEM-IMPY, an analogue was prepared with deuteriums substituted for the four ethyl hydrogens. However, D4-[18F]FEM-IMPY showed the same brain uptake and clearance as the protio analogue. Metabolism of the [18F]FEM-IMPY was appreciably slower in rhesus monkey than in mouse. Autoradiography of postmortem brain sections of human Alzheimer's disease patients with [18F]FEM-IMPY showed high displaceable uptake in gray matter and low nonspecific binding in the white matter. This study demonstrates that the IMPY derivatives have favorable in vivo brain pharmacokinetics and a moderate affinity for imaging β-amyloid plaques; however, further improvements are needed to reduce radioactive metabolites, increase binding affinity, and reduce lipophilicity.

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