A reduction of nicotine receptors is reported in Alzheimer's disease (AD) and, conversely, an increase in the number of these receptors is reported in smokers. Imaging these receptors will therefore offer diagnostic capabilities for the study of both AD as well as nicotine dependency. At University of California-Irvine (UCI), we have two major programs: one in AD within the Center for Aging and Dementia and the other a program on studies related to nicotine dependence. The goal of this application is to develop selective alpha4beta2 nicotine acetylcholinergic receptor (a4b2 nAChR) radiopharmaceuticals for use in human PET imaging at the Brain Imaging Center at UCI. This will support collaborative research studies in the above two areas of interest at UCI. This research will also support investigations on other disorders such as Parkinson's disease and schizophrenia. Over the three-year period, our goal is to design and develop quantitative methods for a4b2 nAChR PET imaging studies using an agonist and an antagonist. We have successfully identified structural features in the pyridylether class of compounds that enable development of an antagonist and enhance the binding kinetics of agonists. Our preliminary efforts in developing agents with these properties have been promising. In this application developmental studies of 3 compounds will be carried out. These are putative agonist 2-18F-fluoro-3-[2-(3-(S)-pyrrolinylmethoxy)]pyridine (18F-nifene), and putative antagonists 5-(3 -18F-fluoropropyl)-(3-[2-(S)-pyrrolidinyl)methoxy]pyridine (18F-nifrolidine) and 5-(3 -18F-fluoropropyl)-(3-[2-(3-(S)-pyrrolinylmethoxy)]pyridine (18F-nifrolene). We hypothesize that 18F- nifrolene will have similar, faster kinetics like 18F-nifene. We propose to carry out pharmacological characterization of these compounds, optimize radiosynthesis, evaluate feasibility of quantitative PET studies and conduct test-retest studies. Based on these results radiation dosimetry measures in male and female rats with 18F-nifene as the agonist and either 18F-nifrolidine or 18F-nifrolene as the antagonist will be carried out. Upon complete characterization toxicity data of two agents will be obtained in order to file for an expedited investigational new drug application. Thus the outcome of this 3-year application would be to have an agonist and an antagonist for PET human imaging studies of the a4b2 receptor system. Continuation of this application will then study the role of these receptors in AD and nicotine dependency. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG029479-02
Application #
7433190
Study Section
Clinical Neuroscience and Disease Study Section (CND)
Program Officer
Petanceska, Suzana
Project Start
2007-06-01
Project End
2010-05-31
Budget Start
2008-06-01
Budget End
2009-05-31
Support Year
2
Fiscal Year
2008
Total Cost
$245,098
Indirect Cost
Name
University of California Irvine
Department
Psychiatry
Type
Schools of Medicine
DUNS #
046705849
City
Irvine
State
CA
Country
United States
Zip Code
92697
Mukherjee, Jogeshwar; Lao, Patrick J; Betthauser, Tobey J et al. (2018) Human brain imaging of nicotinic acetylcholine ?4?2* receptors using [18 F]Nifene: Selectivity, functional activity, toxicity, aging effects, gender effects, and extrathalamic pathways. J Comp Neurol 526:80-95
Samra, Gurleen K; Dang, Kenneth; Ho, Heather et al. (2018) Dual targeting agents for A? plaque/P-glycoprotein and A? plaque/nicotinic acetylcholine ?4?2* receptors-potential approaches to facilitate A? plaque removal in Alzheimer's disease brain. Med Chem Res 27:1634-1646
Samra, Gurleen K; Intskirveli, Irakli; Govind, Anitha P et al. (2017) Development of fluorescence imaging probes for nicotinic acetylcholine ?4?2? receptors. Bioorg Med Chem Lett :
Coleman, Robert A; Liang, Christopher; Patel, Rima et al. (2017) Brain and Brown Adipose Tissue Metabolism in Transgenic Tg2576 Mice Models of Alzheimer Disease Assessed Using 18F-FDG PET Imaging. Mol Imaging 16:1536012117704557
Betthauser, Tobey J; Hillmer, Ansel T; Lao, Patrick J et al. (2017) Human biodistribution and dosimetry of [18F]nifene, an ?4?2* nicotinic acetylcholine receptor PET tracer. Nucl Med Biol 55:7-11
Lao, Patrick J; Betthauser, Tobey J; Tudorascu, Dana L et al. (2017) [18 F]Nifene test-retest reproducibility in first-in-human imaging of ?4?2* nicotinic acetylcholine receptors. Synapse 71:
Pan, Min-Liang; Mukherjee, Meenakshi T; Patel, Himika H et al. (2016) Evaluation of [11C]TAZA for amyloid ? plaque imaging in postmortem human Alzheimer's disease brain region and whole body distribution in rodent PET/CT. Synapse 70:163-76
Pithia, Neema K; Liang, Christopher; Pan, Xiang-Zuo et al. (2016) Synthesis and evaluation of (S)-[(18)F]fesetron in the rat brain as a potential PET imaging agent for serotonin 5-HT3 receptors. Bioorg Med Chem Lett 26:1919-24
Mirbolooki, M Reza; Schade, Kimberly N; Constantinescu, Cristian C et al. (2015) Enhancement of 18F-fluorodeoxyglucose metabolism in rat brain frontal cortex using a ?3 adrenoceptor agonist. Synapse 69:96-8
Baranwal, Aparna; Mukherjee, Jogeshwar (2015) (18)F-Fluorodeoxyglucamines: Reductive amination of hydrophilic (18)F-fluoro-2-deoxyglucose with lipophilic amines for the development of potential PET imaging agents. Bioorg Med Chem Lett 25:2902-6

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