N-(3-[ 18F]fluoropropyl)-spiperone: The preferred 18F labeled spiperone analog for positron emission tomographic studies of the dopamine receptor

• Published in: International journal of radiation applications and instrumentation. Part B, Nuclear medicine and biology Vol. 15; no. 1; pp. 83,95 - 93,97
• Main Authors: Welch, M.J., Katzenellenbogen, J.A., Mathias, C.J., Brodack, J.W., Carlson, K.E., Chi, D.Y., Dence, C.S., Kilbourn, M.R., Perlmutter, J.S., Raichle, M.E., Ter-Pogossian, M.M.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 1988
• Subjects: Animals; Blood-Brain Barrier; Brain - diagnostic imaging; Brain - metabolism; Female; Humans; Papio; Rats; Rats, Inbred Strains; Receptors, Dopamine - analysis; Spiperone - analogs & derivatives; Spiperone - pharmacokinetics; Tomography, Emission-Computed
• ISSN: 0883-2897
• DOI: 10.1016/0883-2897(88)90164-X

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.