Common anesthetic used in preclinical PET imaging inhibits metabolism of the PET tracer [18F]3F4AP

• Published in: Journal of neurochemistry Vol. 168; no. 9; pp. 2577 - 2586
• Main Authors: Ramos‐Torres, Karla, Sun, Yang, Takahashi, Kazue, Zhou, Yu‐Peng, Brugarolas, Pedro
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01.05.2024
• Subjects: [18F]3F4AP; Anesthesia; Animals; Brain; Cytochrome P450; Cytochromes P450; Disulfiram; Fluorine isotopes; Image acquisition; Isoflurane; Laboratory animals; Medical imaging; Metabolism; Neuroimaging; PET imaging; Positron emission; Positron emission tomography; Radioactive tracers; radiometabolites; radiotracer; metabolism; [18F]3F4AP; PET imaging; radiotracer; radiometabolites; anesthesia
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/jnc.16118

Positron emission tomography (PET) imaging studies in laboratory animals are almost always performed under isoflurane anesthesia to ensure that the subject stays still during the image acquisition. Isoflurane is effective, safe, and easy to use, and it is generally assumed to not have an impact on the imaging results. Motivated by marked differences observed in the brain uptake and metabolism of the PET tracer 3‐[18F]fluoro‐4‐aminopyridine [(18F]3F4AP) between human and nonhuman primate studies, this study investigates the possible effect of isoflurane on this process. Mice received [18F]3F4AP injection while awake or under anesthesia and the tracer brain uptake and metabolism was compared between groups. A separate group of mice received the known cytochrome P450 2E1 inhibitor disulfiram prior to tracer administration. Isoflurane was found to largely abolish tracer metabolism in mice (74.8 ± 1.6 vs. 17.7 ± 1.7% plasma parent fraction, % PF) resulting in a 4.0‐fold higher brain uptake in anesthetized mice at 35 min post‐radiotracer administration. Similar to anesthetized mice, animals that received disulfiram showed reduced metabolism (50.0 ± 6.9% PF) and a 2.2‐fold higher brain signal than control mice. The higher brain uptake and lower metabolism of [18F]3F4AP observed in anesthetized mice compared to awake mice are attributed to isoflurane's interference in the CYP2E1‐mediated breakdown of the tracer, which was confirmed by reproducing the effect upon treatment with the known CYP2E1 inhibitor disulfiram. These findings underscore the critical need to examine the effect of isoflurane in PET imaging studies before translating tracers to humans that will be scanned without anesthesia. Differences in the brain uptake and metabolism of demyelination PET tracer [18F]3F4AP have been observed while imaging anesthetized nonhuman primates and awake human subjects. Isoflurane anesthesia was found to enhance the brain uptake and in vivo stability of [18F]3F4AP in mice. These findings underscore the critical need to examine the effect of isoflurane in PET imaging studies before translating tracers to humans that will be scanned without anesthesia.