Prev. Article Next Article Table of Contents

Article

Synthesis and Evaluation of N-Methyl and S-Methyl ¹¹C-Labeled 6-Methylthio-2-(4′-N,N-dimethylamino)phenylimidazo[1,2-a]pyridines as Radioligands for Imaging β-Amyloid Plaques in Alzheimer’s Disease

Supporting Info

Lisheng Cai*^†, Jeih-San Liow^†, Sami S. Zoghbi^†, Jessica Cuevas^†, Cesar Baetas^†, Jinsoo Hong^†, H. Umesha Shetty^†, Nicholas M. Seneca^†, Amira K. Brown^†, Robert Gladding^†, Sebastian S. Temme^†, Mary M. Herman^‡, Robert B. Innis^† and Victor W. Pike^†

Molecular Imaging Branch and Clinical Brain Disorders Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892

J. Med. Chem., 2008, 51 (1), pp 148–158

DOI: 10.1021/jm700970s

Publication Date (Web): December 14, 2007

* To whom correspondence should be addressed. Address: Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, 10 Center Drive, Building 10, Room B3 C346, Bethesda, MD 20892. Phone: (301) 451-3905 . Fax: (301) 480-5112. E-mail: cail@intra.nimh.nih.gov.

†

Molecular Imaging Branch.

‡

Clinical Brain Disorders Branch.

Abstract

6-Thiolato-substituted 2-(4′-N,N-dimethylamino)phenylimidazo[1,2-a]pyridines (RS-IMPYs; 1−4) were synthesized as candidates for labeling with carbon-11 (t_1/2 = 20.4 min) and imaging of A_β plaques in living human brain using positron emission tomography (PET). K_i values for binding of these ligands to Alzheimer’s disease brain homogenates were measured in vitro against tritium-labeled 6 (Pittsburgh compound B). MeS-IMPY (3, K_i = 7.93 nM) was labeled with carbon-11 at its S- or N-methyl position to give [¹¹C]7 or [¹¹C]8, respectively. After injection into rats, [¹¹C]7 or [¹¹C]8 gave moderately high brain uptakes of radioactivity followed by rapid washout to low levels. The ratio of radioactivity at maximal uptake to that at 60 min reached 18.7 for [¹¹C]7. [¹¹C]7 behaved similarly in mouse and monkey. [¹¹C]7 also bound selectively to A_β plaques in post mortem human Alzheimer’s disease brain. Although rapidly metabolized in rat by N-demethylation, [¹¹C]7 was stable in rat brain homogenates. The ex vivo brain radiometabolites observed in rats have a peripheral origin. Overall, [¹¹C]7 merits further evaluation in human subjects.

View: Full Text HTML | Hi-Res PDF | PDF w/ Links

Tools

SciFinder Links

History

Published In Issue January 10, 2008
Article ASAPDecember 14, 2007
Received: August 04, 2007

Recommend & Share

Related Content

Synthesis and Structure−Affinity Relationships of New 4-(6-Iodo-H-imidazo[1,2-a]pyridin-2-yl)-N-dimethylbenzeneamine Derivatives as Ligands for Human β-Amyloid PlaquesJournal of Medicinal Chemistry
- Synthesis and Structure−Affinity Relationships of New 4-(6-Iodo-H-imidazo[1,2-a]pyridin-2-yl)-N-dimethylbenzeneamine Derivatives as Ligands for Human β-Amyloid Plaques
  Lisheng Cai, Jessica Cuevas, Sebastian Temme, Mary M. Herman, Claudio Dagostin, David A. Widdowson, Robert B. Innis, and Victor W. Pike
  Journal of Medicinal Chemistry 2007 50 (19), pp 4746–4758
  Abstract: A new and extensive set of 4-(6-iodo-H-imidazo[1,2-a]pyridin-2-yl)-N-dimethylbenzeneamine (IMPY) derivatives was synthesized and assayed for affinity toward human Aβ plaques. 6-Ethylthio- (12h), 6-cyano- (12e), 6-nitro- (12f), and 6-p-methoxybenzylthio- (...
  Abstract | Full Text HTML | Hi-Res PDF
Design, Synthesis, and Anti-inflammatory Properties of Orally Active 4-(Phenylamino)-pyrrolo[2,1-f][1,2,4]triazine p38α Mitogen-Activated Protein Kinase InhibitorsJournal of Medicinal Chemistry
- Design, Synthesis, and Anti-inflammatory Properties of Orally Active 4-(Phenylamino)-pyrrolo[2,1-f][1,2,4]triazine p38α Mitogen-Activated Protein Kinase Inhibitors
  John Hynes, Jr., Alaric J. Dyckman, Shuqun Lin, Stephen T. Wrobleski, Hong Wu, Kathleen M. Gillooly, Steven B. Kanner, Herinder Lonial, Derek Loo, Kim W. McIntyre, Sidney Pitt, Ding Ren Shen, David J. Shuster, XiaoXia Yang, Rosemary Zhang, Kamelia Behnia, Hongjian Zhang, Punit H. Marathe, Arthur M. Doweyko, John S. Tokarski, John S. Sack, Matthew Pokross, Susan E. Kiefer, John A. Newitt, Joel C. Barrish, John Dodd, Gary L. Schieven and Katerina Leftheris
  Journal of Medicinal Chemistry 2008 51 (1), pp 4–16
  Abstract: A novel structural class of p38 mitogen-activated protein (MAP) kinase inhibitors consisting of substituted 4-(phenylamino)-pyrrolo[2,1-f][1,2,4]triazines has been discovered. An initial subdeck screen revealed that the oxindole-pyrrolo[2,1-f][1,2,4]...
  Abstract | Full Text HTML | PDF w/ Links | Hi-Res PDF
Design, Synthesis, and Biological Evaluation of Classical and Nonclassical 2-Amino-4-oxo-5-substituted-6-methylpyrrolo[3,2-d]pyrimidines as Dual Thymidylate Synthase and Dihydrofolate Reductase InhibitorsJournal of Medicinal Chemistry
- Design, Synthesis, and Biological Evaluation of Classical and Nonclassical 2-Amino-4-oxo-5-substituted-6-methylpyrrolo[3,2-d]pyrimidines as Dual Thymidylate Synthase and Dihydrofolate Reductase Inhibitors
  Aleem Gangjee, Wei Li, Jie Yang and Roy L. Kisliuk
  Journal of Medicinal Chemistry 2008 51 (1), pp 68–76
  Abstract: We designed and synthesized a classical antifolate N-{4-[(2-amino-6-methyl-4-oxo-3,4-dihydro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)methyl]benzoyl}-l-glutamic acid 4 and 11 nonclassical analogues 5–15 as potential dual thymidylate synthase (TS) and dihydrofolate ...
  Abstract | Full Text HTML | PDF w/ Links | Hi-Res PDF

Article

Synthesis and Evaluation of N-Methyl and S-Methyl ¹¹C-Labeled 6-Methylthio-2-(4′-N,N-dimethylamino)phenylimidazo[1,2-a]pyridines as Radioligands for Imaging β-Amyloid Plaques in Alzheimer’s Disease