N-(3-[18F]fluoropropyl)-spiperone: The preferred 18F labeled spiperone analog for positron emission tomographic studies of the dopamine receptor |
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| Affiliation: | 2. Division of Radiation Sciences, Washington University School of Medicine, 510 South Kingshighway, St Louis, MO 63110, U.S.A.;1. Department of Chemistry, University of Illinois, Urbana, Illinois, U.S.A.;1. Chemistry Division, Department of Biological and Chemical Sciences, Illinois Institute of Technology, 3101 S. Dearborn St, LS 182, Chicago, IL 60616, United States;2. Research Service, Harry S. Truman Memorial Veterans’ Hospital, Columbia, MO, United States;3. Department of Veterinary Medicine and Surgery, University of Missouri, Columbia, MO, United States;1. Neuroscience Medicinal Chemistry, Janssen Research and Development, Jarama 75A, 45007 Toledo, Spain;2. Neuroscience, Janssen Research and Development, Turnhoutseweg 30, B-2340 Beerse, Belgium;3. Discovery Sciences ADME/Tox, Janssen Research and Development, Turnhoutseweg 30, B-2340 Beerse, Belgium;4. Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA;5. Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA;1. Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, AL 36849, USA;2. Department of Medicinal Chemistry, Faculty of Pharmacy, Omar Al-Mukhtar University, El-Beida, Libya;3. Department of Pharmaceutical Analytical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt;1. Institute of Pharmaceutical Chemistry and University of Szeged, H-6720 Szeged, Eötvös u. 6, Hungary;2. Stereochemistry Research Group of the Hungarian Academy of Sciences, University of Szeged, H-6720 Szeged, Eötvös u. 6, Hungary;3. Department of Chemistry, University of Jyväskylä, FIN-40014 Jyväskylä, Finland;1. Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536, USA;2. Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA |
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| Abstract: | The ligands currently used for PET studies of the dopamine receptor are fluorine-18-labeled spiperone (FSp) and carbon-11 or fluorine-18-labeled N-methyl-spiperone. All three of these ligands have drawbacks in either their chemical preparation or their biological behavior. We have previously prepared a series of N-fluoroalkyl-spiperone derivatives which are simple to prepare in high radiochemical yield. N-[18F]fluoropropyl-spiperone (3-F-Pr-Sp) and N-[18F]fluoroethyl-spiperone (2-F-Et-Sp) were the most promising ligands. In vitro competitive binding studies showed affinities for the dopamine receptor of 3-F-Pr-Sp > FSp > 2-F-Et-Sp. Brain extraction studies in a primate model showed that FSp, 2-F-Et-Sp, and 3-F-Pr-Sp were not completely extracted by the brain. High bone uptake and kidney clearance was observed with 3-F-Pr-Sp, while 2-F-Et-Sp cleared through the intestine in rats. This is in contrast to FSp where clearance is through the kidney. Studies to evaluate the extraction of metabolites in the brain were carried out by administering large doses (10 mCi) of FSp, 2-F-Et-Sp and 3-F-Pr-Sp to rats and reinjecting the metabolites in blood into other rats. These experiments showed that < 0.02% of the metabolites from FSp and 3-F-Pr-Sp entered the brain, while 0.5% of the metabolites from 2-F-Et-Sp entered the brain. The majority of the activity present in the cerebellum after the administration of 2-F-Et-Sp is metabolites; therefore 2-F-Et-Sp is unsuitable for PET imaging studies. PET imaging studies in baboons and in one normal human volunteer with 3-F-Pr-Sp showed a high striatum-to-cerbellum ratio, showing that 3-F-Pr-Sp can replace ligands currently in use to study dopamine receptors. |
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