4-(((4-Iodophenyl)methyl)-4H-1,2,4-triazol-4-ylamino)-benzonitrile: A Potential Imaging Agent for Aromatase.
Aromatase (CYP19) is a rate-limiting enzyme that catalyzes the biosynthesis of estrogens. Imaging agents based on aromatase inhibitors (AIs) have been developed for a PET/SPECT study. A series of compounds was synthesized based on YM511, which has previously been used for breast cancer treatment. Two examples of these derivatives, 4-(((4-iodophenyl)methyl)-4H-1,2,4-triazol-4-yl-amino)-benzonitrile (5) and 4-((1H-imidazol-1-yl)(4-iodobenzyl)amino)benzonitrile (11), displayed potent binding affinities to human aromatase (IC50= 0.17 and 0.04 nM, respectively). Biodistribution and autoradiographic studies revealed that [125I]5 and [125I]11 were highly accumulated in the stomach (16.21 and 10.88% dose/g, respectively) and ovaries (8.56 and 3.32% dose/g, respectively) of female rats. Log P of [125I]5 was 2.49, meaning good brain penetration. Autoradiograms of brain sections showed a high uptake in the bed nucleus of the stria terminalis and amygdala. These results suggest that [125I]5 and [125I]11 are potent probes for aromatase imaging in both the brain and peripheral organs.
Beijing Institute for Brain Disorders, Capital Medical University , Beijing 100069, China.|Department of Radiology, University of Pennsylvania , 3700 Market Street, Suite 305, Philadelphia, Pennsylvania 19104, United States.
Jin
J
Song
Beijing Institute for Brain Disorders, Capital Medical University , Beijing 100069, China.|Department of Radiology, University of Pennsylvania , 3700 Market Street, Suite 305, Philadelphia, Pennsylvania 19104, United States.
Zehui
Z
Wu
Department of Systems Pharmacology and Translational Therapeutics and the Center for Excellence in Environmental Toxicology, Perelman School of Medicine, University of Pennsylvania , 1315 BRBII/III, 421 Curie Boulevard, Philadelphia, Pennsylvania 19104-6160, United States.
Beau
B
Wangtrakuldee
Department of Radiology, University of Pennsylvania , 3700 Market Street, Suite 305, Philadelphia, Pennsylvania 19104, United States.|Five Eleven Pharma Inc. , Philadelphia, Pennsylvania 19104, United States.
Seok Rye
SR
Choi
Department of Radiology, University of Pennsylvania , 3700 Market Street, Suite 305, Philadelphia, Pennsylvania 19104, United States.
Zhihao
Z
Zha
Department of Radiology, University of Pennsylvania , 3700 Market Street, Suite 305, Philadelphia, Pennsylvania 19104, United States.|Five Eleven Pharma Inc. , Philadelphia, Pennsylvania 19104, United States.
Karl
K
Ploessl
Department of Radiology, University of Pennsylvania , 3700 Market Street, Suite 305, Philadelphia, Pennsylvania 19104, United States.
Robert H
RH
Mach
Beijing Institute for Brain Disorders, Capital Medical University , Beijing 100069, China.|Department of Radiology, University of Pennsylvania , 3700 Market Street, Suite 305, Philadelphia, Pennsylvania 19104, United States.|Five Eleven Pharma Inc. , Philadelphia, Pennsylvania 19104, United States.
Hank
H
Kung
D000814:Aniline Compounds / Q000032:analysis* / Q000138:chemical synthesis / Q000737:chemistry; D000818:Animals; D001141:Aromatase / Q000032:analysis* / Q000737:chemistry / Q000378:metabolism; D047072:Aromatase Inhibitors / Q000008:administration & dosage / Q000032:analysis* / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D049268:Positron-Emission Tomography; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D014018:Tissue Distribution; D014230:Triazoles / Q000032:analysis* / Q000138:chemical synthesis / Q000737:chemistry
C000619931:4-(((4-iodophenyl)methyl)-4H-1,2,4-triazol-4-ylamino)benzonitrile; D000814:Aniline Compounds; D047072:Aromatase Inhibitors; D014230:Triazoles; D001141:Aromatase; C561410:CYP19A1 protein, human