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Radiosynthesis and evaluation of [18F]FMTP, a COX-2 PET ligand

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Abstract

Background

The upregulation of cyclooxygenase-2 (COX-2) is involved in neuroinflammation associated with many neurological diseases as well as cancers of the brain. Outside the brain, inflammation and COX-2 induction contribute to the pathogenesis of pain, arthritis, acute allograft rejection, and in response to infections, tumors, autoimmune disorders, and injuries. Herein, we report the radiochemical synthesis and evaluation of [18F]6-fluoro-2-(4-(methylsulfonyl)phenyl)-N-(thiophen-2-ylmethyl)pyrimidin-4-amine ([18F]FMTP), a high-affinity COX-2 inhibitor, by cell uptake and PET imaging studies.

Methods

The radiochemical synthesis of [18F]FMTP was optimized using chlorine to fluorine displacement method, by reacting [18F]fluoride/K222/K2CO3 with the precursor molecule. Cellular uptake studies of [18F]FMTP was performed in COX-2 positive BxPC3 and COX-2 negative PANC-1 cell lines with unlabeled FMTP as well as celecoxib to define specific binding agents. Dynamic microPET image acquisitionwas performed in anesthetized nude mice (n = 3), lipopolysaccharide (LPS) induced neuroinflammation mice (n = 4), and phosphate-buffered saline (PBS) administered control mice (n = 4) using a Trifoil microPET/CT for a scan period of 60 min.

Results

A twofold higher binding of [18F]FMTP was found in COX-2 positive BxPC3 cells compared with COX-2 negative PANC-1 cells. The radioligand did not show specific binding to COX-2 negative PANC-1 cells. MicroPET imaging in wild-type mice indicated blood–brain barrier (BBB) penetration and fast washout of [18F]FMTP in the brain, likely due to the low constitutive COX-2 expression in the normal brain. In contrast, a ~ twofold higher uptake of the radioligand was found in LPS-induced mice brain than PBS treated control mice.

Conclusions

Specific binding to COX-2 in BxPC3 cell lines, BBB permeability, and increased brain uptake in neuroinflammation mice qualifies [18F]FMTP as a potential PET tracer for studying inflammation.

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Abbreviations

AD:

Alzheimer’s disease;

ALS:

Amyotrophic lateral sclerosis;

BBB:

Blood–brain barrier;

CNS:

Central nervous system;

COX2:

Cyclooxigenase-2;

COXIBs:

COX-2 inhibitors;

LPS:

Lipopolysaccharide;

NSAID:

Non-steroidal anti-inflammatory drugs;

MDD:

Major depressive disorders;

PBS:

Phosphate-buffered saline;

PD:

Parkinson’s disease;

PET:

Positron Emission Tomography;

RCY:

Radiochemical yield;

SUVs:

Standardized uptake values;

TACs:

Time-activity curves;

TBAF:

Tetra-n-butyl ammonium fluoride;

TBI:

Traumatic brain injury;

VOI:

Volume of interest

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Funding

This work was funded by Diane Goldberg Foundation (NYSPI/ CUMC) and NCATS UL1TR001873 (Reilly) Irving Institute/CTSA Translational Therapeutics Accelerator.

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Authors and Affiliations

  1. Molecular Imaging and Neuropathology Division, New York State Psychiatric Institute, Manhattan, NY, USA

    J. S. Dileep Kumar, Jaya Prabhakaran & J. John Mann

  2. Department of Psychiatry, Columbia University Medical Center, Manhattan, NY, USA

    Jaya Prabhakaran & J. John Mann

  3. Department of Radiology, Columbia University Medical Center, Manhattan, NY, USA

    Andrei Molotkov, Anirudh Sattiraju, Jongho Kim, Mikhail Doubrovin, J. John Mann & Akiva Mintz

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  1. J. S. Dileep Kumar
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  2. Jaya Prabhakaran
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  4. Anirudh Sattiraju
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  5. Jongho Kim
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  7. J. John Mann
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Correspondence to J. S. Dileep Kumar or Akiva Mintz.

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Dr. Mann receives royalties for commercial use of the C-SSRS from the Research Foundation for Mental Hygiene. The other authors declare no conflict of interest.

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Kumar, J.S.D., Prabhakaran, J., Molotkov, A. et al. Radiosynthesis and evaluation of [18F]FMTP, a COX-2 PET ligand. Pharmacol. Rep 72, 1433–1440 (2020). https://doi.org/10.1007/s43440-020-00124-z

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