Evaluation of 1-Azabicyclo[2.2.2]oct-3-yl α-Fluoroalkyl-α-hydroxy-a-phenylacetates as potential ligands for the study of muscarinic receptor density by positron emission tomography

H. Luo; A. Hasan; V. Sood; R. C. McRee; B. Zeeberg; R. C. Reba; D. W. McPherson; F. F. Knapp

doi:10.1016/0969-8051(95)02066-7

Evaluation of 1-Azabicyclo[2.2.2]oct-3-yl α-Fluoroalkyl-α-hydroxy-a-phenylacetates as potential ligands for the study of muscarinic receptor density by positron emission tomography

H. Luo, A. Hasan, V. Sood, R. C. McRee, B. Zeeberg, R. C. Reba, D. W. McPherson, F. F. Knapp

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Abstract

Both 1-azabicyclo[2.2.2]oct-3-yl α-(1-fluoroeth-2-yl)-α-hydroxy-α-phenylacetate (FQNE, 5) and 1-azabicyclo[2.2.2]oct-3-yl α-(1-fluoropent-5-yl)-α-hydroxy-α-phenylacetate (FQNPe, 6) were prepared and evaluated as potential candidates for the determination of muscarinic cholinergic receptor (mAChR) density by positron emission tomography (PET). The results of in vitro binding assays demonstrated that although both 5 and 6 had high binding affinities for m₁ and m₂ mAChR subtypes, 6 displayed a higher affinity (nM, m₁; K_D, 0.45, m₂; K_D, 3.53) as compared to 5 (nM, m₁; K_D, 12.5, m₂; K_D, 62.8). It was observed that pretreatment of female Fisher rats with either 5 or 6 prior to the i.v. administration of Z-(-)(-)-[¹³¹I]-IQNP, a high-affinity muscarinic ligand, significantly blocked the uptake of radioactivity in the brain and heart measured 3 h postinjection of the radiolabeled ligand. These new fluoro QNB analogues represent important target ligands for evaluation as potential receptor imaging agents in conjunction with PET. NUCL MED BIOL 23;3:267-276, 1996.

Original language	English
Pages (from-to)	267-276
Number of pages	10
Journal	Nuclear Medicine and Biology
Volume	23
Issue number	3
DOIs	https://doi.org/10.1016/0969-8051(95)02066-7
State	Published - Apr 1996

Funding

Research was supported at Oak Ridge National Laboratory by the Office of Health and Environmental Research (OHER), U.S. Department of Energy (DOE), under contract DE-AC05-960R22464 with Lock-heed Martin Energy Research Corporation, and at the George Washington University Medical Center by NIH grant NS-22215 and DOE grant DE FG0588ER60649. The authors thank Dr. J. Baumgold for providing the transfected cell membranes, Ms. Carla R. Lambert for assisting with the tissue distribution studies, and Ms. S. Milligan for typing the manuscript. Huimin Luo, PhD, gratefully acknowledges support from the Alexander Hollaender Distinguished Postdoctoral Fellowship Program sponsored by the U.S. Department of Energy, Office of Health and Environmental Research, and administered by the Oak Ridge Institute for Science and Education.

Funders	Funder number
OHER
Office of Health and Environmental Research
National Institutes of Health	DE FG0588ER60649
U.S. Department of Energy	DE-AC05-960R22464
National Institute of Neurological Disorders and Stroke	R01NS022215
Oak Ridge National Laboratory
Oak Ridge Institute for Science and Education

Keywords

Fluorine-18
Fluoroalkyl group
Muscarinic receptor
PET
QNB analogues

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Luo, H., Hasan, A., Sood, V., McRee, R. C., Zeeberg, B., Reba, R. C., McPherson, D. W., & Knapp, F. F. (1996). Evaluation of 1-Azabicyclo[2.2.2]oct-3-yl α-Fluoroalkyl-α-hydroxy-a-phenylacetates as potential ligands for the study of muscarinic receptor density by positron emission tomography. Nuclear Medicine and Biology, 23(3), 267-276. https://doi.org/10.1016/0969-8051(95)02066-7

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title = "Evaluation of 1-Azabicyclo[2.2.2]oct-3-yl α-Fluoroalkyl-α-hydroxy-a-phenylacetates as potential ligands for the study of muscarinic receptor density by positron emission tomography",

abstract = "Both 1-azabicyclo[2.2.2]oct-3-yl α-(1-fluoroeth-2-yl)-α-hydroxy-α-phenylacetate (FQNE, 5) and 1-azabicyclo[2.2.2]oct-3-yl α-(1-fluoropent-5-yl)-α-hydroxy-α-phenylacetate (FQNPe, 6) were prepared and evaluated as potential candidates for the determination of muscarinic cholinergic receptor (mAChR) density by positron emission tomography (PET). The results of in vitro binding assays demonstrated that although both 5 and 6 had high binding affinities for m1 and m2 mAChR subtypes, 6 displayed a higher affinity (nM, m1; KD, 0.45, m2; KD, 3.53) as compared to 5 (nM, m1; KD, 12.5, m2; KD, 62.8). It was observed that pretreatment of female Fisher rats with either 5 or 6 prior to the i.v. administration of Z-(-)(-)-[131I]-IQNP, a high-affinity muscarinic ligand, significantly blocked the uptake of radioactivity in the brain and heart measured 3 h postinjection of the radiolabeled ligand. These new fluoro QNB analogues represent important target ligands for evaluation as potential receptor imaging agents in conjunction with PET. NUCL MED BIOL 23;3:267-276, 1996.",

keywords = "Fluorine-18, Fluoroalkyl group, Muscarinic receptor, PET, QNB analogues",

author = "H. Luo and A. Hasan and V. Sood and McRee, {R. C.} and B. Zeeberg and Reba, {R. C.} and McPherson, {D. W.} and Knapp, {F. F.}",

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Luo, H, Hasan, A, Sood, V, McRee, RC, Zeeberg, B, Reba, RC, McPherson, DW & Knapp, FF 1996, 'Evaluation of 1-Azabicyclo[2.2.2]oct-3-yl α-Fluoroalkyl-α-hydroxy-a-phenylacetates as potential ligands for the study of muscarinic receptor density by positron emission tomography', Nuclear Medicine and Biology, vol. 23, no. 3, pp. 267-276. https://doi.org/10.1016/0969-8051(95)02066-7

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T1 - Evaluation of 1-Azabicyclo[2.2.2]oct-3-yl α-Fluoroalkyl-α-hydroxy-a-phenylacetates as potential ligands for the study of muscarinic receptor density by positron emission tomography

AU - Luo, H.

AU - Hasan, A.

AU - Sood, V.

AU - McRee, R. C.

AU - Zeeberg, B.

AU - Reba, R. C.

AU - McPherson, D. W.

AU - Knapp, F. F.

PY - 1996/4

Y1 - 1996/4

N2 - Both 1-azabicyclo[2.2.2]oct-3-yl α-(1-fluoroeth-2-yl)-α-hydroxy-α-phenylacetate (FQNE, 5) and 1-azabicyclo[2.2.2]oct-3-yl α-(1-fluoropent-5-yl)-α-hydroxy-α-phenylacetate (FQNPe, 6) were prepared and evaluated as potential candidates for the determination of muscarinic cholinergic receptor (mAChR) density by positron emission tomography (PET). The results of in vitro binding assays demonstrated that although both 5 and 6 had high binding affinities for m1 and m2 mAChR subtypes, 6 displayed a higher affinity (nM, m1; KD, 0.45, m2; KD, 3.53) as compared to 5 (nM, m1; KD, 12.5, m2; KD, 62.8). It was observed that pretreatment of female Fisher rats with either 5 or 6 prior to the i.v. administration of Z-(-)(-)-[131I]-IQNP, a high-affinity muscarinic ligand, significantly blocked the uptake of radioactivity in the brain and heart measured 3 h postinjection of the radiolabeled ligand. These new fluoro QNB analogues represent important target ligands for evaluation as potential receptor imaging agents in conjunction with PET. NUCL MED BIOL 23;3:267-276, 1996.

AB - Both 1-azabicyclo[2.2.2]oct-3-yl α-(1-fluoroeth-2-yl)-α-hydroxy-α-phenylacetate (FQNE, 5) and 1-azabicyclo[2.2.2]oct-3-yl α-(1-fluoropent-5-yl)-α-hydroxy-α-phenylacetate (FQNPe, 6) were prepared and evaluated as potential candidates for the determination of muscarinic cholinergic receptor (mAChR) density by positron emission tomography (PET). The results of in vitro binding assays demonstrated that although both 5 and 6 had high binding affinities for m1 and m2 mAChR subtypes, 6 displayed a higher affinity (nM, m1; KD, 0.45, m2; KD, 3.53) as compared to 5 (nM, m1; KD, 12.5, m2; KD, 62.8). It was observed that pretreatment of female Fisher rats with either 5 or 6 prior to the i.v. administration of Z-(-)(-)-[131I]-IQNP, a high-affinity muscarinic ligand, significantly blocked the uptake of radioactivity in the brain and heart measured 3 h postinjection of the radiolabeled ligand. These new fluoro QNB analogues represent important target ligands for evaluation as potential receptor imaging agents in conjunction with PET. NUCL MED BIOL 23;3:267-276, 1996.

KW - Fluorine-18

KW - Fluoroalkyl group

KW - Muscarinic receptor

KW - PET

KW - QNB analogues

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SN - 0969-8051

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JO - Nuclear Medicine and Biology

JF - Nuclear Medicine and Biology

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ER -

Evaluation of 1-Azabicyclo[2.2.2]oct-3-yl α-Fluoroalkyl-α-hydroxy-a-phenylacetates as potential ligands for the study of muscarinic receptor density by positron emission tomography

Abstract

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Keywords

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