Synthesis and characterization of tricarbonyl-Re/Tc(I) chelate probes targeting the G protein-coupled estrogen receptor GPER/GPR30.
The discovery of the G protein-coupled estrogen receptor GPER (also GPR30) and the resulting development of selective chemical probes have revealed new aspects of estrogen receptor biology. The potential clinical relevance of this receptor has been suggested from numerous studies that have identified GPER expression in breast, endometrial, ovarian and other cancers. Thus GPER can be considered a candidate biomarker and target for non-invasive imaging and therapy. We have designed and synthesized a series of organometallic tricarbonyl-rhenium complexes conjugated to a GPER-selective small molecule derived from tetrahydro-3H-cyclopenta[c]quinoline. The activity and selectivity of these chelates in GPER-mediated signaling pathways were evaluated. These results demonstrate that GPER targeting characteristics depend strongly on the structure of the chelate and linkage. Ethanone conjugates functioned as agonists, a 1,2,3-triazole spacer yielded an antagonist, and derivatives with increased steric volume exhibited decreased activities. Promising GPER selectivity was observed, as none of the complexes interacted with the nuclear estrogen receptors. Radiolabeling with technetium-99m in aqueous media was efficient and gave radioligands with high radiochemical yields and purity. These chelates have favorable physicochemical properties, show excellent stability in biologically relevant media, exhibit receptor specificity and are promising candidates for continuing development as diagnostic imaging agents targeting GPER expression in cancer.
Department of Chemistry and Biochemistry, New Mexico State University, Las Cruces, New Mexico, USA.
Ritwik
R
Burai
Chinnasamy
C
Ramesh
Tapan K
TK
Nayak
Megan K
MK
Dennis
Bj K
BK
Bryant
Eric R
ER
Prossnitz
Jeffrey B
JB
Arterburn
D000818:Animals; D019556:COS Cells; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D056831:Coordination Complexes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000378:metabolism; D006801:Humans; D011804:Quinolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011960:Receptors, Estrogen / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012211:Rhenium / Q000737:chemistry / Q000494:pharmacology*; D013667:Technetium / Q000737:chemistry / Q000494:pharmacology*
D056831:Coordination Complexes; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; C109584:GPER1 protein, human; D011804:Quinolines; D011960:Receptors, Estrogen; D043562:Receptors, G-Protein-Coupled; D012211:Rhenium; D013667:Technetium