The long term objective of this project is to develop single-photon emitting receptor binding radiotracers and implement methods for quantitating SPECT images of receptors in the brains of patients suffering from a variety of disorders which have been shown to affect receptor systems in the CNS. We are currently investigating the muscarinic acetylcholine receptor (m-AChR) with respect to changes in Alzheimer's disease and related disorders. Although this is a new proposal, we have imaged m-AChR in man using (R,R) (123I) 3-quinuclidinyl 4-iodobenzilate (41QNB), a high affinity m-AChR antagonist which we developed for myocardial imaging. But it is better suited for use in the CNS because there is a need for diagnostic tools which which provide information on receptor concentrations in brain. The objectives of this current proposal are to prepare in large quantities the precursor for synthesis of (R,R) and (R,S) (123I) 41QNB for use in clinical and biochemical studies. The (R,S) diastereomer provides different kinetic properties from those of the (R,R) diastereomer which may be more beneficial for the clinical studies. The clinical studies are suggested for a five year period; the patient populations to be examined are those with Alzheimer's disease, multi infarct dementia and Parkinson's disease. Normal subjects, age and sex matched, will be recruited from the families of patients when possible. The biochemical studies are designed to demonstrate that receptor concentration changes can be measured by the in vivo distribution of 41QNB. Changes are effected by a variety of lesioning techniques and the demonstration mapping by autoradiography. We will also establish the metabolic fate of (125I) 41QNB and the effect of decay on the compound and its receptor. In addition, we will provide the synthetic route for the synthesis of (11C) 3-quinuclidinyl atrolactate, a positron emitting radiotracer with many of the same properties as 41QNB. We will compare and contrast the images obtained using the two different radionuclides and technologies for their detection. The long term results of our pursuit of these goals will be an agent or agents which will be used for determining the change of receptor concentration of receptors in the CNS related to disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS022215-04
Application #
3404372
Study Section
Diagnostic Radiology Study Section (RNM)
Project Start
1986-01-01
Project End
1990-12-31
Budget Start
1989-01-01
Budget End
1989-12-31
Support Year
4
Fiscal Year
1989
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

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