Aryl cyclopentadienyl tricarbonyl rhenium complexes: novel ligands for the estrogen receptor with potential use as estrogen radiopharmaceuticals.
The need for imaging agents for estrogen receptor positive (ER+) tumors that are both cost effective and widely available, as well as the need for novel radiotherapeutic agents for the treatment of breast cancer, has prompted us to investigate cyclopentadienyl tricarbonyl metal [CpMet(CO)(3), Met=Re, Tc-99m] complexes that bind well to the ER. Thus, we have prepared a series of p-hydroxyphenyl-substituted CpRe(CO)(3) complexes and evaluated them (and, in some cases, their cyclopentadiene precursors) for binding to ER. These compounds constitute a new class of structurally integrated organometallic ligands for ER in which the CpMet(CO)(3 )organometallic unit forms the very structural core of these molecules and thus is necessarily intimately involved in their interaction with the receptor. The CpRe(CO)(3) compounds were prepared by reaction of the lithium salt of the arene-substituted cyclopentadiene with a suitable Re(CO)(3)(+) precursor, followed by deprotection of the methyl ether. The X-ray crystal structure of one of these analogues shows that it has the classical 'piano stool'-like geometry, with the alkyl groups directed upward, away from the tripodyl metal carbonyl base. The aryl-substituted CpRe(CO)(3) complexes that we have prepared all bind to the ER, some with affinity as great as 20% that of the native ligand, estradiol. In general, at least two p-hydroxyphenyl substituents and one to two alkyl groups attached to the organometallic cyclopentadienyl core are needed for high ER affinity. Where we have been able to make comparisons, the metal complexes bind to ER with an affinity greater than their cyclopentadiene precursors. The high affinity of some of these complexes indicates that the bulky Re(CO)(3) unit is able to exploit the considerable volume in the center of the ER ligand binding pocket that is not occupied by most ligands, a consideration that is supported by molecular modeling. The preparation of the best of these agents in technetium-99m labeled form is currently being investigated.
Mull
Eric S
ES
Department of Chemistry, University of Illinois, Urbana 61801, USA.
Sattigeri
Viswajanani J
VJ
Rodriguez
Alice L
AL
Katzenellenbogen
John A
JA
D001943:Breast Neoplasms / Q000175:diagnosis / Q000000981:diagnostic imaging; D004967:Estrogens / Q000737:chemistry; D005260:Female; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D009942:Organometallic Compounds / Q000138:chemical synthesis* / Q000737:chemistry; D011485:Protein Binding; D011868:Radioisotopes / Q000737:chemistry; D011869:Radioligand Assay; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000737:chemistry; D011960:Receptors, Estrogen / Q000378:metabolism*; D012211:Rhenium / Q000737:chemistry; D013329:Structure-Activity Relationship
D004967:Estrogens; D008024:Ligands; D009942:Organometallic Compounds; D011868:Radioisotopes; D019275:Radiopharmaceuticals; D011960:Receptors, Estrogen; C116454:cyclopentadienyl tricarbonyl rhenium; D012211:Rhenium