Human whole-body biodistribution and dosimetry of a new PET tracer, [(11)C]ketoprofen methyl ester, for imagings of neuroinflammation.
BACKGROUND
Neuroinflammatory processes play an important role in the pathogenesis of Alzheimer's disease and other brain disorders, and nonsteroidal anti-inflammatory drugs (NSAIDs) are considered therapeutic candidates. As a biomarker of neuroinflammatory processes, (11)C-labeled ketoprofen methyl ester ([(11)C]KTP-Me) was designed to allow cerebral penetration of ketoprofen (KTP), an active form of a selective cyclooxygenase-1 inhibitor that acts as an NSAID. Rat neuroinflammation models indicate that [(11)C]KTP-Me enters the brain and is retained in inflammatory lesions, accumulating in activated microglia. [(11)C]KTP-Me is washed out from normal tissues, leading to the present first-in-human exploratory study.


METHODS
[(11)C]KTP-Me was synthesized by rapid C-[(11)C]methylation of [(11)C]CH3I and the corresponding arylacetate precursor, purified with high-performance liquid chromatography, and prepared as an injectable solution including PEG400, providing radiochemical purity of >99% and specific activity of >25GBq/μmol at injection. Six young healthy male humans were injected with [(11)C]KTP-Me and scanned with PET camera to determine the early-phase brain time course followed by three whole-body scans starting 8, 20, and 40 min post-injection, together with sequential blood sampling and labeled metabolite analysis.


RESULTS
No adverse effects were observed during PET scanning after [(11)C]KTP-Me injection. [(11)C]KTP-Me was rapidly metabolized to (11)C-labeled ketoprofen ([(11)C]KTP) within 2-3 min and was gradually cleared from blood. The radioactivity entered the brain with an average peak cortical SUV of 1.5 at 2 min. The cortical activity was gradually washed out. Whole-body images indicated that the urinary bladder was the major excretory pathway. The organ with the highest radiation dose was the urinary bladder (average dose of 41μGy/MBq, respectively). The mean effective dose was 4.7μSv/MBq, which was comparable to other (11)C-labeled radiopharmaceuticals.


CONCLUSIONS
[(11)C]KTP-Me demonstrated a favorable dosimetry, biodistribution, and safety profile. [(11)C]KTP-Me entered the human brain, and the radioactivity was washed out from cerebral tissue. These data warrant further exploratory studies on patients with neuroinflammation.
Division of Molecular Imaging, Institute of Biomedical Research and Innovation, Kobe, Hyogo, Japan.
Akihito
A
Ohnishi
Division of Molecular Imaging, Institute of Biomedical Research and Innovation, Kobe, Hyogo, Japan. Electronic address: senda@fbri.org.
Michio
M
Senda
Division of Molecular Imaging, Institute of Biomedical Research and Innovation, Kobe, Hyogo, Japan.
Tomohiko
T
Yamane
Division of Molecular Imaging, Institute of Biomedical Research and Innovation, Kobe, Hyogo, Japan.
Masahiro
M
Sasaki
Division of Molecular Imaging, Institute of Biomedical Research and Innovation, Kobe, Hyogo, Japan.
Tomoko
T
Mikami
Division of Molecular Imaging, Institute of Biomedical Research and Innovation, Kobe, Hyogo, Japan.
Tomoyuki
T
Nishio
Division of Molecular Imaging, Institute of Biomedical Research and Innovation, Kobe, Hyogo, Japan.
Yasuhiko
Y
Ikari
Division of Molecular Imaging, Institute of Biomedical Research and Innovation, Kobe, Hyogo, Japan.
Hiroyuki
H
Nishida
Division of Bio-function Dynamic Imaging, Center for Life Science Technologies RIKEN, Kobe, Hyogo, Japan.
Miho
M
Shukuri
Division of Bio-function Dynamic Imaging, Center for Life Science Technologies RIKEN, Kobe, Hyogo, Japan.
Tadayuki
T
Takashima
Division of Bio-function Dynamic Imaging, Center for Life Science Technologies RIKEN, Kobe, Hyogo, Japan.
Aya
A
Mawatari
Division of Bio-function Dynamic Imaging, Center for Life Science Technologies RIKEN, Kobe, Hyogo, Japan.
Hisashi
H
Doi
Division of Bio-function Dynamic Imaging, Center for Life Science Technologies RIKEN, Kobe, Hyogo, Japan.
Yasuyoshi
Y
Watanabe
Division of Bio-function Dynamic Imaging, Center for Life Science Technologies RIKEN, Kobe, Hyogo, Japan.
Hirotaka
H
Onoe
D000328:Adult; D000818:Animals; D001692:Biological Transport; D001921:Brain / Q000000981:diagnostic imaging*; D006801:Humans; D007249:Inflammation / Q000000981:diagnostic imaging; D007660:Ketoprofen / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics; D008297:Male; D049268:Positron-Emission Tomography / Q000379:methods*; D011849:Radioactive Tracers; D011874:Radiometry; D051381:Rats; D012449:Safety; D014018:Tissue Distribution
D011849:Radioactive Tracers; C560799:ketoprofen methyl ester; D007660:Ketoprofen
Biodistribution; Dosimetry; NSAIDs; Neuroinflammation; [(11)C]ketoprofen methyl ester