Synthesis of an Estrogen Receptor β-Selective Radioligand:  5-[18F]Fluoro-(2R,3S)-2,3-bis(4-hydroxyphenyl)pentanenitrile and Comparison of in Vivo Distribution with 16α-[18F]Fluoro-17β-estradiol

• Published in: Journal of medicinal chemistry 2005-10, Vol.48 (20), p.6366-6378
• Main Authors: Yoo, Jeongsoo, Dence, Carmen S, Sharp, Terry L, Katzenellenbogen, John A, Welch, Michael J
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Contrast media. Radiopharmaceuticals; Medical sciences; Pharmacology. Drug treatments
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm050121f

Estrogen receptor β (ERβ), a less active ER subtype that appears to have a restraining effect on the more active ERα, could be a factor that determines the level of estrogen action in certain estrogen target tissues. ERβ is found in breast cancer, and its levels relative to ERα decline with disease progression. Thus, the independent quantification of ERα and ERβ levels in breast cancer by imaging might be predictive of responses to different hormone therapies. To develop an imaging agent for ERβ, we synthesized a fluoroethyl analogue of DPN (2,3-bis(4-hydroxyphenyl)propanonitrile), a known ERβ-selective ligand. This analogue, FEDPN (5-fluoro-(2R*,3S*)-2,3-bis(4-hydroxyphenyl)pentanenitrile), has an 8.3-fold absolute affinity preference for ERβ. [18F]Fluoride-labeled FEDPN was prepared from a toluenesulfonate precursor, which provided [18F]FEDPN with a specific activity greater than 3100 Ci/mmol after HPLC purification. Biodistribution studies in immature female rats using estradiol as a blocking agent revealed specific uptake of [18F]FEDPN in the uterus and ovaries. Experiments using ERα- and ERβ-knockout mice demonstrated the expected ERα-subtype dependence in the tissue uptake of the known 16α-[18F]fluoro-17β-estradiol ([18F]FES), which has a 6.3-fold preference for ERα. The tissue uptake of [18F]FEDPN in the ER knockout mice showed some evidence of mediation by ERβ, but the levels of specific uptake of this agent were relatively modest. Based on our results, imaging of ERα can be done effectively with [18F]FES, but imaging of ERβ will likely require agents with more optimized ERβ binding affinity and selectivity than [18F]FEDNP.