Nicotinic a4?2 receptors have been implicated in neurodegeneration and are being studied extensively. At University of California-Irvine (UCI), we have several major programs that would gain from imaging nicotinic receptors. These include: 1) Alzheimer's Disease Research Center (ADRC) at the institute for Mental Impairments and Neurological Disorders (MIND);2) Program on studies related to nicotine dependence;3) Program in the early detection of lung cancer, and 4) Neurobiology of learning and memory. During the previous funding period we have successfully completed preclinical evaluation of a new imaging agent, 18F-Nifene which has high affinity for a4?2 receptors and requires an imaging time of less than 60 minutes. In animal PET studies selective binding of 18F-Nifene in thalamus, lateral geniculate, cortex and other brain regions was observed with limited binding in the cerebellum, resulting in specific binding ratios of ~3. Plasma analysis indicated the presence of 18F-Nifene and no observed defluorination. The high ratios in specific brain regions and short scan time suggest that 18F-Nifene to be amongst the most suitable agonist that has good potential as a PET imaging agent for a4?2 receptors in humans. Our toxicity results of Nifene suggest that a radiotracer injection of 18F-Nifene is suitable for human use. Therefore, one goal in this NIH application is to carry out first human studies with 18F-Nifene. Human radiation dosimetry studies will be carried out using a PET/CT scanner on 6 subjects. Brain distribution of 18F-Nifene will be evaluated in normal volunteers in a test-retest paradigm to establish reproducibility and imaging methodology for quantitative analysis. A second goal of the proposal is to complete the preclinical development of 18F-Nifrolene which is a putative antagonist for this receptor. Animal studies show high binding in receptor-rich brain areas with a scan time of approx. 90 mins, with specific binding ratios ~4. We propose to complete animal imaging, toxicity testing and radiation dosimetry of 18F-Nifrolene during this funding period. The availability of an agonist and antagonist will allow comparative studies of this receptor system in various disorders. The third goal of this application is to evaluate if 18F-Nifene is able to detect changes in the level of the neurotransmitter, acetylcholine in PET studies. This will be of great value to evaluate efficacy of acetylcholinesterase inhibitors used in AD. The overall proposed research in this application will also support investigations in other disorders such as Parkinson's disease and schizophrenia.

Public Health Relevance

Development of human imaging methods for nicotine receptors will help understand several brain disorders, such as Alzheimer's disease, Parkinson's disease, learning and cognition as well as tobacco dependence and lung cancer. This grant application will specifically have implications in the potential diagnosis, treatment planning and therapeutics development for Alzheimer's disease.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG029479-06
Application #
8516925
Study Section
Clinical Neuroscience and Neurodegeneration Study Section (CNN)
Program Officer
Petanceska, Suzana
Project Start
2007-06-01
Project End
2014-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
6
Fiscal Year
2013
Total Cost
$298,498
Indirect Cost
$104,773
Name
University of California Irvine
Department
Psychiatry
Type
Schools of Medicine
DUNS #
046705849
City
Irvine
State
CA
Country
United States
Zip Code
92697
Baranwal, Aparna; Patel, Himika H; Mukherjee, Jogeshwar (2014) 18F-Fluorodeoxyglycosylamines: Maillard reaction of 18F-fluorodeoxyglucose with biological amines. J Labelled Comp Radiopharm 57:86-91
Constantinescu, Cristian C; Garcia, Adriana; Mirbolooki, M Reza et al. (2013) Evaluation of [18F]Nifene biodistribution and dosimetry based on whole-body PET imaging of mice. Nucl Med Biol 40:289-94
Hillmer, Ansel T; Wooten, Dustin W; Slesarev, Maxim S et al. (2013) Measuring *4*2* nicotinic acetylcholine receptor density in vivo with [(18)F]nifene PET in the nonhuman primate. J Cereb Blood Flow Metab 33:1806-14
Pichika, Rama; Kuruvilla, Sharon A; Patel, Narmisha et al. (2013) Nicotinic *4*2 receptor imaging agents. Part IV. Synthesis and biological evaluation of 3-(2-(S)-3,4-dehydropyrrolinyl methoxy)-5-(3'-ýýýýýF-fluoropropyl)pyridine (ýýýýýF-Nifrolene) using PET. Nucl Med Biol 40:117-25
Bieszczad, Kasia M; Kant, Ritu; Constantinescu, Cristian C et al. (2012) Nicotinic acetylcholine receptors in rat forebrain that bind ýýýýýF-nifene: relating PET imaging, autoradiography, and behavior. Synapse 66:418-34
Kant, Ritu; Constantinescu, Cristian C; Parekh, Puja et al. (2011) Evaluation of F-nifene binding to *4*2 nicotinic receptors in the rat brain using microPET imaging. EJNMMI Res 1:
Pichika, Rama; Easwaramoorthy, Balu; Christian, Bradley T et al. (2011) Nicotinic ýý4ýý2 receptor imaging agents. Part III. Synthesis and biological evaluation of 3-(2-(S)-azetidinylmethoxy)-5-(3'-18F-fluoropropyl)pyridine (18F-nifzetidine). Nucl Med Biol 38:1183-92