This is a revised application to continue and extend our long-term objective to develop receptor-binding radiotracers for SPECT imaging of human brain. We propose a major new research direction by developing m2 subtype-selective receptor binding radioligands which can be applied to the in vivo study of regional concentrations of the m2 muscarinic receptor (mAChR) subtype in normal controls and in patients with CNS diseases. It is now apparent that quantitative detection of changes of cerebral concentrations of mAChR in Alzheimer's disease (AD) will require selectively imaging the m2 mAChR subtype, currently not possible with available radioligands. Therefore, we propose developing m2-selective radioligands based on the structure of AQ-RA 741, a potent m2-selective antagonist. Several alternative synthetic schemes are proposed to yield smaller and more lipophilic analogues of the parent compound that will be better able to cross the BBB. Each novel compound will be evaluated by apparent binding affinity and subtype-selectivity using a series of cell lines and tissues that each express a single mAChR subtype. Potent and subtype-selective compounds will be further evaluated for their ability to cross the BBB of mice using ex vivo binding studies, and if successful, will be radioiodinated and used further for biodistribution and pharmacokinetic studies in rats. We will perform pharmacokinetic modeling studies to determine whether the regional brain localization of the novel m2-selective radioligands will accurately reflect the regional brain m2 receptor concentration. This determination is required in order to validate that the regional m2 deficits expected in AD can be detectable in terms of a reduced regional radioligand localization. We will apply computer simulation studies of the SPECT, imaging process to a realistic model of the distribution of radioligand bound to m2 receptors in the brain. We will develop -an algorithm which can compensate for the distortions which we demonstrate in the SPECT imaging process, so that we will have the capability of performing quantitatively accurate SPECT neuroreceptor imaging. The proposed studies are designed to validate the quantitative potential of SPECT in studying CNS disorders, and to yield new information about disease states in living humans.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS022215-06A2
Application #
3404369
Study Section
Diagnostic Radiology Study Section (RNM)
Project Start
1986-01-01
Project End
1994-11-30
Budget Start
1991-12-01
Budget End
1992-11-30
Support Year
6
Fiscal Year
1992
Total Cost
Indirect Cost
Name
George Washington University
Department
Type
Schools of Medicine
DUNS #
City
Washington
State
DC
Country
United States
Zip Code
20052
Lai, Tina; Jabaudon, Denis; Molyneaux, Bradley J et al. (2008) SOX5 controls the sequential generation of distinct corticofugal neuron subtypes. Neuron 57:232-47
Cohen, V I; Jin, B; McRee, R C et al. (2000) In vitro and in vivo m2 muscarinic subtype selectivity of some dibenzodiazepinones and pyridobenzodiazepinones. Brain Res 861:305-15
Zeeberg, B R (1999) Pharmacokinetic computer simulations of the relationship between in vivo and in vitro neuroreceptor subtype selectivity of radioligands. Nucl Med Biol 26:803-9
Cohen, V I; Zeeberg, B R; Boulay, S F et al. (1998) In vivo competition studies of Z-(-,-)-[125I]IQNP against 3-quinuclidinyl 2-(5-bromothienyl)-2-thienylglycolate (BrQNT) demonstrating in vivo m2 muscarinic subtype selectivity for BrQNT. J Mol Neurosci 11:1-9
Zeeberg, B R; Boulay, S F; Gitler, M S et al. (1997) Correction of the stereochemical assignment of the benzilic acid center in (R)-(-)-3-quinuclidinyl (S)-(+)-4-iodobenzilate [(R,S)-4-IQNB] Appl Radiat Isot 48:463-7
Sood, V K; Lee, K S; Boulay, S F et al. (1997) In vivo autoradiography of radioiodinated (R)-3-quinuclidinyl (S)-4-iodobenzilate [(R, S)-IQNB] and (R)-3-quinuclidinyl (R)-4-iodobenzilate [(R,R)-IQNB]. Comparison of the radiolabelled products of a novel tributylstannyl precursor with those of the estab Appl Radiat Isot 48:27-35
Zeeberg, B R; Boulay, S F; Sood, V K et al. (1997) In vivo autoradiographic competition studies of isomers of [125I]IQNP against QNB demonstrating in vivo m2 muscarinic subtype selectivity for QNB. Recept Signal Transduct 7:45-54
Boulay, S F; Sood, V K; Rayeq, M R et al. (1996) Autoradiographic evidence that (R)-3-quinuclidinyl (S)-4-fluoromethylbenzilate ((R,S)-FMeQNB) displays in vivo selectivity for the muscarinic m2 subtype. Nucl Med Biol 23:889-96
Boulay, S F; McRee, R C; Cohen, V I et al. (1996) Specific binding component of the ""inactive"" stereoisomer (S,S)-[125I] IQNB to rat brain muscarinic receptors in vivo. Nucl Med Biol 23:211-9
Rayeq, M R; Boulay, S F; Sood, V K et al. (1996) In vivo autoradiographic and dissection evaluation of isomers of 125I-labeled 1-azabicyclo[2.2.2] oct-3-yl-alpha-(1-iodo-1-propen-3-yl)-alpha-phenylacetate (IQNP). Recept Signal Transduct 6:13-34

Showing the most recent 10 out of 43 publications