Non-β-oxidizable ω-[18F]fluoro long chain fatty acid analogs show cytochrome P-450-mediated defluorination

Implications for the design of PET tracers of myocardial fatty acid utilization

Timothy R DeGrado, Detlef C. Moka

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

The nature of the in vivo defluorination of non-β-oxidizable no-carrier-added ω-[18F]fluoro long chain fatty acid (LCFA) analogs was studied with the aim of developing PET tracers of LCFA utilization. Extensive defluorination of 15-[18F]fluoro-3-thia-pentadecanoic acid (FTPA) in mouse was evidenced by radioactivity uptake by bone. [18F]Fluoride in the blood was verified analytically. Incubations of FTPA in rat-liver homogenates and subcellular fractions thereof showed a strong defluorination process in microsomes which was O2- and NADPH-dependent. In contrast, defluorination of FTPA was relatively slow in Langendorff perfused rat heart. High bone uptake in mouse was also observed with 14-[18F]fluoro-13, 13-dimethyl-3-thia-tetradecanoic acid, where gem-dimethyl substitution precludes direct elimination of H18F. These data indicate that the defluorination of non-β-oxidizable ω-[18F]fluoro LCFA analogs is primarily governed by cytochrome P-450-mediated ω-oxidation. Therefore, labeling at the (ω-3) carbon was proposed to provide a more stabile 18F-label. Defluorination of the (ω-3)-labeled 13 (R,S)-[18F]fluoro-3-thia-hexadecanoic acid was lower than that of FTPA in mouse and was independent of O2 and NADPH in vitro. Thus, (ω-3) labeling with 18F is preferable to ω labeling of non-β-oxidizable LCFA analogs.

Original languageEnglish (US)
Pages (from-to)389-397
Number of pages9
JournalInternational Journal of Radiation Applications and Instrumentation.
Volume19
Issue number3
DOIs
StatePublished - 1992
Externally publishedYes

Fingerprint

Cytochrome P-450 Enzyme System
Fatty Acids
NADP
Bone and Bones
Subcellular Fractions
Palmitic Acid
Myristic Acid
Microsomes
Fluorides
Radioactivity
Carbon
pentadecanoic acid
Liver

Cite this

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title = "Non-β-oxidizable ω-[18F]fluoro long chain fatty acid analogs show cytochrome P-450-mediated defluorination: Implications for the design of PET tracers of myocardial fatty acid utilization",
abstract = "The nature of the in vivo defluorination of non-β-oxidizable no-carrier-added ω-[18F]fluoro long chain fatty acid (LCFA) analogs was studied with the aim of developing PET tracers of LCFA utilization. Extensive defluorination of 15-[18F]fluoro-3-thia-pentadecanoic acid (FTPA) in mouse was evidenced by radioactivity uptake by bone. [18F]Fluoride in the blood was verified analytically. Incubations of FTPA in rat-liver homogenates and subcellular fractions thereof showed a strong defluorination process in microsomes which was O2- and NADPH-dependent. In contrast, defluorination of FTPA was relatively slow in Langendorff perfused rat heart. High bone uptake in mouse was also observed with 14-[18F]fluoro-13, 13-dimethyl-3-thia-tetradecanoic acid, where gem-dimethyl substitution precludes direct elimination of H18F. These data indicate that the defluorination of non-β-oxidizable ω-[18F]fluoro LCFA analogs is primarily governed by cytochrome P-450-mediated ω-oxidation. Therefore, labeling at the (ω-3) carbon was proposed to provide a more stabile 18F-label. Defluorination of the (ω-3)-labeled 13 (R,S)-[18F]fluoro-3-thia-hexadecanoic acid was lower than that of FTPA in mouse and was independent of O2 and NADPH in vitro. Thus, (ω-3) labeling with 18F is preferable to ω labeling of non-β-oxidizable LCFA analogs.",
author = "DeGrado, {Timothy R} and Moka, {Detlef C.}",
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T1 - Non-β-oxidizable ω-[18F]fluoro long chain fatty acid analogs show cytochrome P-450-mediated defluorination

T2 - Implications for the design of PET tracers of myocardial fatty acid utilization

AU - DeGrado, Timothy R

AU - Moka, Detlef C.

PY - 1992

Y1 - 1992

N2 - The nature of the in vivo defluorination of non-β-oxidizable no-carrier-added ω-[18F]fluoro long chain fatty acid (LCFA) analogs was studied with the aim of developing PET tracers of LCFA utilization. Extensive defluorination of 15-[18F]fluoro-3-thia-pentadecanoic acid (FTPA) in mouse was evidenced by radioactivity uptake by bone. [18F]Fluoride in the blood was verified analytically. Incubations of FTPA in rat-liver homogenates and subcellular fractions thereof showed a strong defluorination process in microsomes which was O2- and NADPH-dependent. In contrast, defluorination of FTPA was relatively slow in Langendorff perfused rat heart. High bone uptake in mouse was also observed with 14-[18F]fluoro-13, 13-dimethyl-3-thia-tetradecanoic acid, where gem-dimethyl substitution precludes direct elimination of H18F. These data indicate that the defluorination of non-β-oxidizable ω-[18F]fluoro LCFA analogs is primarily governed by cytochrome P-450-mediated ω-oxidation. Therefore, labeling at the (ω-3) carbon was proposed to provide a more stabile 18F-label. Defluorination of the (ω-3)-labeled 13 (R,S)-[18F]fluoro-3-thia-hexadecanoic acid was lower than that of FTPA in mouse and was independent of O2 and NADPH in vitro. Thus, (ω-3) labeling with 18F is preferable to ω labeling of non-β-oxidizable LCFA analogs.

AB - The nature of the in vivo defluorination of non-β-oxidizable no-carrier-added ω-[18F]fluoro long chain fatty acid (LCFA) analogs was studied with the aim of developing PET tracers of LCFA utilization. Extensive defluorination of 15-[18F]fluoro-3-thia-pentadecanoic acid (FTPA) in mouse was evidenced by radioactivity uptake by bone. [18F]Fluoride in the blood was verified analytically. Incubations of FTPA in rat-liver homogenates and subcellular fractions thereof showed a strong defluorination process in microsomes which was O2- and NADPH-dependent. In contrast, defluorination of FTPA was relatively slow in Langendorff perfused rat heart. High bone uptake in mouse was also observed with 14-[18F]fluoro-13, 13-dimethyl-3-thia-tetradecanoic acid, where gem-dimethyl substitution precludes direct elimination of H18F. These data indicate that the defluorination of non-β-oxidizable ω-[18F]fluoro LCFA analogs is primarily governed by cytochrome P-450-mediated ω-oxidation. Therefore, labeling at the (ω-3) carbon was proposed to provide a more stabile 18F-label. Defluorination of the (ω-3)-labeled 13 (R,S)-[18F]fluoro-3-thia-hexadecanoic acid was lower than that of FTPA in mouse and was independent of O2 and NADPH in vitro. Thus, (ω-3) labeling with 18F is preferable to ω labeling of non-β-oxidizable LCFA analogs.

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