Synthesis and evaluation of aryl-substituted diarylpropionitriles, selective ligands for estrogen receptor beta, as positron-emission tomographic imaging agents.
We have investigated halogen-substituted non-steroidal estrogens with selective binding affinity for the estrogen receptor beta (ERbeta that might be used for imaging the levels of this ER-subtype in breast tumors by positron emission tomography (PET). Based on diarylpropionitrile (DPN, 1a), a compound previously reported that has a 72-fold binding selectivity for ERbeta, we developed a series of DPN analogs having methyl-, hydroxyl-, and halogen substituents, including fluoroethyl and fluoropropyl groups. In competitive radiometric binding assays with [(3)H]estradiol, all of these DPN analogs showed high ERbeta/ERalpha selectivity; while the selectivity varied, in some cases it reached nearly 300-fold (RBA: ERalpha, 0.023%; ERbeta, 6.25%). The absolute ERbeta binding affinities, however, were not sufficient to merit further consideration for developing these ligands as PET imaging agents.
Moon
Byung Seok
BS
Molecular Imaging Research Center, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea.
Carlson
Kathryn E
KE
Katzenellenbogen
John A
JA
Choi
Tae Hyun
TH
Chi
Dae Yoon
DY
Kim
Jung Young
JY
Cheon
Gi Jeong
GJ
Koh
Hun Yeong
HY
Lee
Kyo Chul
KC
An
Gwangil
G
D001667:Binding, Competitive; D047629:Estrogen Receptor beta / Q000737:chemistry / Q000378:metabolism*; D005462:Fluorine Radioisotopes / Q000737:chemistry; D006801:Humans; D007700:Kinetics; D008024:Ligands; D009570:Nitriles / Q000138:chemical synthesis* / Q000737:chemistry; D049268:Positron-Emission Tomography; D011422:Propionates / Q000138:chemical synthesis* / Q000737:chemistry; D011485:Protein Binding; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000737:chemistry; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
C486182:2,3-bis(4-hydroxyphenyl)-propionitrile; D047629:Estrogen Receptor beta; D005462:Fluorine Radioisotopes; D008024:Ligands; D009570:Nitriles; D011422:Propionates; D019275:Radiopharmaceuticals