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Published on: April 11, 2018
Prokineticin receptor 1 antagonist PC-10 as a biomarker for imaging inflammatory pain
Orit Jacobson1, Ido D Weiss, Gang Niu
1Laboratory of Molecular Imaging and Nanomedicine, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, Maryland 20892, USA.
Unlabelled:
Prokineticin receptor 1 (PKR1) and its ligand Bv8 were shown to be expressed in inflammation-induced pain and by tumor-supporting fibroblasts. Blocking this receptor might prove useful for reducing pain and for cancer therapy. However, there is no method to quantify the levels of these receptors in vivo.
Methods:
A nonpeptidic PKR1 antagonist, N-{2-[5-(4-fluoro-benzyl)-1-(4-methoxy-benzyl)-4,6-dioxo-1,4,5,6-tetrahydro-[1,3,5]triazin-2-ylamino]-ethyl}-guanidine, which contains a free guanidine group, was labeled with (18)F by reacting the guanidine function with N-succinimidyl-4-(18)F-fluorobenzoate to give the guanidinyl amide N-(4-(18)F-fluoro-benzoyl)-N'-{2-[5-(4-fluoro-benzyl)-1-(4-methoxy-benzyl)-4,6-dioxo-1,4,5,6-tetrahydro-[1,3,5]triazin-2-ylamino]-ethyl}-guanidine ((18)F-PC-10). Inflammation was induced in C57BL/6 mice by subcutaneous injection of complete Freund adjuvant in the paw. The mice were imaged with (18)F-PC-10, (18)F-FDG, and (64)Cu-pyruvaldehyde bis(4-methyl-3-thiosemicarbazone) ((64)Cu-PTSM) at 24 h after complete Freund adjuvant injection using a small-animal PET device.
Results:
(18)F-PC-10 was synthesized with a radiochemical yield of 16% ± 3% (decay-corrected). (18)F-PC-10 accumulated specifically in the inflamed paw 4- to 5-fold more than in the control paw. Compared with (18)F-PC-10, (18)F-FDG and (64)Cu-PTSM displayed higher accumulation in the inflamed paw but also had higher accumulation in the control paw, demonstrating a reduced signal-to-background ratio. (18)F-PC-10 also accumulated in PKR1-expressing organs, such as the salivary gland and gastrointestinal tract.
Conclusion:
(18)F-PC-10 can be used to image PKR1, a biomarker of the inflammation process. However, the high uptake of (18)F-PC-10 in the gastrointestinal tract, due to specific uptake and the metabolic processing of this highly lipophilic molecule, would restrict its utility.
Insights
A novel radiotracer, (18)F-PC-10, allows in vivo imaging of prokineticin receptor 1 (PKR1) in inflammation. While effective in inflamed tissues, its utility is limited by gastrointestinal uptake.
Area of Science:
- Biochemistry
- Molecular Biology
- Radiochemistry
Background:
- Prokineticin receptor 1 (PKR1) and its ligand Bv8 are implicated in pain and cancer.
- Targeting PKR1 offers potential for pain management and cancer therapy.
- A method for in vivo quantification of PKR1 levels is currently lacking.
Purpose of the Study:
- To develop and evaluate a novel radiotracer for in vivo imaging of PKR1.
- To assess the efficacy of (18)F-PC-10 in a mouse model of inflammation.
Main Methods:
- Synthesis of a novel nonpeptidic PKR1 antagonist, (18)F-PC-10, by labeling with fluorine-18.
- Induction of inflammation in mice using complete Freund adjuvant.
- Small-animal PET imaging using (18)F-PC-10, (18)F-FDG, and (64)Cu-PTSM to compare tracer uptake.
Main Results:
- (18)F-PC-10 was synthesized with a 16% radiochemical yield.
- (18)F-PC-10 showed specific accumulation in inflamed paws (4-5 fold increase) compared to control paws.
- (18)F-PC-10 demonstrated a superior signal-to-background ratio compared to (18)F-FDG and (64)Cu-PTSM in inflamed tissue.
Conclusions:
- (18)F-PC-10 serves as a viable imaging agent for PKR1, a biomarker for inflammation.
- High uptake in the gastrointestinal tract may limit the clinical utility of (18)F-PC-10.
- Further research is needed to optimize the tracer for broader applications.
