PET radiotracer [¹⁸F]-P6 selectively targeting COX-1 as a novel biomarker in ovarian cancer: preliminary investigation.
Cyclooxygenase-1 (COX-1), but not COX-2, is expressed at high levels in the early stages of human epithelial ovarian cancer where it seems to play a key role in cancer onset and progression. As a consequence, COX-1 is an ideal biomarker for early ovarian cancer detection. A series of novel fluorinated COX-1-targeted imaging agents derived from P6 was developed by using a highly selective COX-1 inhibitor as a lead compound. Among these new compounds, designed by structural modification of P6, 3-(5-chlorofuran-2-yl)-5-(fluoromethyl)-4-phenylisoxazole ([(18/19)F]-P6) is the most promising derivative [IC50 = 2.0 μM (purified oCOX-1) and 1.37 μM (hOVCAR-3 cell COX-1)]. Its tosylate precursor was also prepared and, a method for radio[(18)F]chemistry was developed and optimized. The radiochemistry was carried out using a carrier-free K(18)F/Kryptofix 2.2.2 complex, that afforded [(18)F]-P6 in good radiochemical yield (18%) and high purity (>95%). In vivo PET/CT imaging data showed that the radiotracer [(18)F]-P6 was selectively taken up by COX-1-expressing ovarian carcinoma (OVCAR 3) tumor xenografts as compared with the normal leg muscle. Our results suggest that [(18)F]-P6 might be an useful radiotracer in preclinical and clinical settings for in vivo PET-CT imaging of tissues that express elevated levels of COX-1.
Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari "A. Moro", Via E. Orabona 4, 70125 Bari, Italy.
Maria Grazia
MG
Perrone
Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari "A. Moro", Via E. Orabona 4, 70125 Bari, Italy.
Paola
P
Malerba
A.B. Hancock, Jr., Memorial Laboratory for Cancer Research, Department of Biochemistry, Chemistry and Pharmacology, Vanderbilt Institute of Chemical Biology, Nashville, TN 37232-0146, USA.
Jashim
J
Uddin
Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari "A. Moro", Via E. Orabona 4, 70125 Bari, Italy.
Paola
P
Vitale
Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari "A. Moro", Via E. Orabona 4, 70125 Bari, Italy.
Andrea
A
Panella
A.B. Hancock, Jr., Memorial Laboratory for Cancer Research, Department of Biochemistry, Chemistry and Pharmacology, Vanderbilt Institute of Chemical Biology, Nashville, TN 37232-0146, USA.
Brenda C
BC
Crews
A.B. Hancock, Jr., Memorial Laboratory for Cancer Research, Department of Biochemistry, Chemistry and Pharmacology, Vanderbilt Institute of Chemical Biology, Nashville, TN 37232-0146, USA.
Cristina K
CK
Daniel
A.B. Hancock, Jr., Memorial Laboratory for Cancer Research, Department of Biochemistry, Chemistry and Pharmacology, Vanderbilt Institute of Chemical Biology, Nashville, TN 37232-0146, USA.
Kebreab
K
Ghebreselasie
Department of Radiology and Radiological Sciences, Vanderbilt Institute of Imaging Sciences, Vanderbilt University School of Medicine, Nashville, TN 37232-0146, USA.
Mike
M
Nickels
Department of Radiology and Radiological Sciences, Vanderbilt Institute of Imaging Sciences, Vanderbilt University School of Medicine, Nashville, TN 37232-0146, USA.
Mohammed N
MN
Tantawy
Department of Radiology and Radiological Sciences, Vanderbilt Institute of Imaging Sciences, Vanderbilt University School of Medicine, Nashville, TN 37232-0146, USA.
H Charles
HC
Manning
A.B. Hancock, Jr., Memorial Laboratory for Cancer Research, Department of Biochemistry, Chemistry and Pharmacology, Vanderbilt Institute of Chemical Biology, Nashville, TN 37232-0146, USA.
Lawrence J
LJ
Marnett
Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari "A. Moro", Via E. Orabona 4, 70125 Bari, Italy.
Antonio
A
Scilimati
D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism*; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D051545:Cyclooxygenase 1 / Q000378:metabolism*; D016861:Cyclooxygenase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D005260:Female; D005462:Fluorine Radioisotopes; D005663:Furans / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007555:Isoxazoles / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D010051:Ovarian Neoplasms / Q000000981:diagnostic imaging* / Q000378:metabolism* / Q000473:pathology; D049268:Positron-Emission Tomography / Q000379:methods*; D011849:Radioactive Tracers; D011854:Radiochemistry; D014057:Tomography, X-Ray Computed
C582911:3-(5-chlorofuran-2-yl)-4-phenyl-5-(trifluoromethyl)isoxazole; D014408:Biomarkers, Tumor; D016861:Cyclooxygenase Inhibitors; D005462:Fluorine Radioisotopes; D005663:Furans; D007555:Isoxazoles; D011849:Radioactive Tracers; D051545:Cyclooxygenase 1
Biomarker; Cyclooxygenase (COX)-1; OVCAR-3 cell; Ovarian cancer; PET-CT imaging; [(18)F]-P6 radiotracer