The project goal is to development novel positron emission (PET) and single photon emission computed tomography (SPECT) radiotracers that (1) label central nicotinic acetyl cholin receptors (nAChRs) in vivo, (2) can be administered in subpharmacologic doses with a high margin of safety, (3) can detect changes in nAChR binding site concentration (via emission tomography) non-invasively in non-human primate brain. There is a need for development and validation of such radiotracers since human tomographic imaging studies of central nAChRs have been hampered b an absence of radioligands that label nAChRs in vivo with high specificity. Th proposed radiotracers will ultimately prove useful as in vivo probes for the study of nAChRs in healthy people and in patients suffering from neurodegenerative disease such as Alzheimer's. Moreover, the ability to assess nAChR sites by tomography will also aid new drug discovery efforts in smoking cessation therapy and cholinergic replacement therapy. A focused, medicinal chemistry approach will be undertaken in the development efforts. Analogs of high affinity nAChR agonist, epibatidine, homoepibatidine, and A-85380 will be synthesized, characterized and labeled with positron emitting radionuclides (C-11, F-18) or with radioiodine (I-125, I-123). Preliminary results show that all three classes of compounds (in radiolabeled form) can label central anchors in vivo. The novel radioligands will be screened to define in vitro and in vivo binding profiles, metabolism, and radiation chemistry. Also, the applicants will demonstrate that the high specific activity radioligands can be administered in subpharmacologic doses with a high margin of safety. The most promising radioligands will be evaluate in imaging trials in baboons, and from these imaging experiments a lead PET radiotracer will be identified. This lead PET radioligand will be tested further via PET for its ability to detect changes in nAChR binding site concentration in the brains of baboons chronically treated with (-)-nicotine. This project will provide radioligands useful for in vitro and in vivo studies of nAChRs and will lay the foundation for PET and SPECT studies of nAChRs in humans

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29CA077349-04
Application #
6376680
Study Section
Diagnostic Radiology Study Section (RNM)
Program Officer
Menkens, Anne E
Project Start
1998-04-01
Project End
2002-03-31
Budget Start
2001-04-01
Budget End
2002-03-31
Support Year
4
Fiscal Year
2001
Total Cost
$188,428
Indirect Cost
Name
Johns Hopkins University
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218
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Kassiou, Michael; Bottlaender, Michel; Loc'h, Christian et al. (2002) Pharmacological evaluation of a Br-76 analog of epibatidine: a potent ligand for studying brain nicotinic acetylcholine receptors. Synapse 45:95-104
Perry, David C; Xiao, Yingxian; Nguyen, Henry N et al. (2002) Measuring nicotinic receptors with characteristics of alpha4beta2, alpha3beta2 and alpha3beta4 subtypes in rat tissues by autoradiography. J Neurochem 82:468-81
Kulak, Jennifer M; Sum, Jocelyn; Musachio, John L et al. (2002) 5-Iodo-A-85380 binds to alpha-conotoxin MII-sensitive nicotinic acetylcholine receptors (nAChRs) as well as alpha4beta2* subtypes. J Neurochem 81:403-6
Kassiou, M; Loc'h, C; Dolle, F et al. (2002) Preparation of a bromine-76 labelled analogue of epibatidine: a potent ligand for nicotinic acetylcholine receptor studies. Appl Radiat Isot 57:713-7
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Musachio, J L; Villemagne, V L; Scheffel, U A et al. (1999) Synthesis of an I-123 analog of A-85380 and preliminary SPECT imaging of nicotinic receptors in baboon. Nucl Med Biol 26:201-7
Mochizuki, T; Villemagne, V L; Scheffel, U et al. (1998) Nicotine induced up-regulation of nicotinic receptors in CD-1 mice demonstrated with an in vivo radiotracer: gender differences. Synapse 30:116-8