TY - JOUR
T1 - PET radiotracer [18F]-P6 selectively targeting COX-1 as a novel biomarker in ovarian cancer
T2 - Preliminary investigation
AU - Perrone, Maria Grazia
AU - Malerba, Paola
AU - Uddin, Md Jashim
AU - Vitale, Paola
AU - Panella, Andrea
AU - Crews, Brenda C.
AU - Daniel, Cristina K.
AU - Ghebreselasie, Kebreab
AU - Nickels, Mike
AU - Tantawy, Mohammed N.
AU - Manning, H. Charles
AU - Marnett, Lawrence J.
AU - Scilimati, Antonio
N1 - Funding Information:
This work has been supported by a grant from the National Institutes of Health, USA ( CA128323 ) and Ministero dell'Istruzione dell’Università e della Ricerca (Italy, PRIN 20097FJHPZ_001 ), and a graduate scholarship to PM from University of Bari (Italy). Authors are grateful to Mr. Donel of the Department of Radiology and Radiological Sciences for radio-HPLC analysis optimization condition assistance.
PY - 2014/6/10
Y1 - 2014/6/10
N2 - 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 ([18/19F]-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[18F]chemistry was developed and optimized. The radiochemistry was carried out using a carrier-free K18F/Kryptofix 2.2.2 complex, that afforded [18F]-P6 in good radiochemical yield (18%) and high purity (>95%). In vivo PET/CT imaging data showed that the radiotracer [18F]-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 [18F]-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.
AB - 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 ([18/19F]-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[18F]chemistry was developed and optimized. The radiochemistry was carried out using a carrier-free K18F/Kryptofix 2.2.2 complex, that afforded [18F]-P6 in good radiochemical yield (18%) and high purity (>95%). In vivo PET/CT imaging data showed that the radiotracer [18F]-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 [18F]-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.
KW - Biomarker
KW - Cyclooxygenase (COX)-1
KW - OVCAR-3 cell
KW - Ovarian cancer
KW - PET-CT imaging
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U2 - 10.1016/j.ejmech.2014.04.074
DO - 10.1016/j.ejmech.2014.04.074
M3 - Article
C2 - 24832612
AN - SCOPUS:84900565740
SN - 0223-5234
VL - 80
SP - 562
EP - 568
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
ER -