Preparation and biological evaluation of a 99mTc labelled fibroblast activation protein inhibitor

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, 11C-labeled ketoprofen methyl ester ([11C]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 [11C]KTP-Me enters the brain and is retained in inflammatory lesions, accumulating in activated microglia. [11C]KTP-Me is washed out from normal tissues, leading to the present first-in-human exploratory study.[11C]KTP-Me was synthesized by rapid C-[11C]methylation of [11C]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 > 25 GBq/μmol at injection. Six young healthy male humans were injected with [11C]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.No adverse effects were observed during PET scanning after [11C]KTP-Me injection. [11C]KTP-Me was rapidly metabolized to 11C-labeled ketoprofen ([11C]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 4.7 μSv/MBq, which was comparable to other 11C-labeled radiopharmaceuticals.[11C]KTP-Me demonstrated a favorable dosimetry, biodistribution, and safety profile. [11C]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.