18F-labeled difluoroestradiols: preparation and preclinical evaluation as estrogen receptor-binding radiopharmaceuticals.
A-ring fluorination of estradiol (ES) at position 2 or 4 decreases the rate of metabolism by blocking the formation of catechol estrogens, one of the major metabolic pathways of ES. We postulate that adding a 2- or 4-fluoro substituent to 16alpha-[18F]fluoroestradiol (FES), a positron emission tomography (PET) radiopharmaceutical used for estrogen receptor (ER) imaging, should prolong its blood circulation time, and thus, improve its localization in ER-rich target tissues. On such account, we prepared a series of FES derivatives substituted with a fluorine atom at C2 or C4, with or without an 11beta-OMe group, and we tested their binding affinities for the ER and different serum proteins including rat alphafetoprotein (AFP) and human sex hormone-binding globulin (SHBG). Labeling at the 16alpha-position was accomplished via nucleophilic substitution with [18F]F(-) on the reactive 16beta,17beta-cyclic sulfate intermediates. Decay corrected yields varied between 30 and 50% for a total synthesis time of 120 min, providing final products with specific activities >3000 Ci/mmol. The 18F-labeled analogs were evaluated for their biodistribution in immature female rats. Substitutions with the 4-F have little effect on binding affinities. Addition of the 2-F diminishes ER and AFP-binding affinities while augmenting the affinity for the SHBG. Addition of the 11beta-OMe decreases all binding affinities, particularly to AFP and SHBG. In contrast, biodistribution of the corresponding [16alpha-18F]fluoro analogs in immature female rats revealed that the presence of the 11beta-OMe group improves ER-mediated uterus uptake, with the 4,16alpha-[16alpha-18F]difluoro-11beta-methoxyestradiol showing the highest uptake values (15% ID at 1-h post-injection). These data suggest that the addition of both a 4-F and 11beta-OMe group onto FES may provide an improved radiopharmaceutical for PET imaging of ER densities in breast cancer patients.
Department of Nuclear Medicine and Radiobiology, Faculty of Medicine, Sherbrooke PET Center, Université de Sherbrooke, Sherbrooke, Que., Canada J1H 5N4.
Yann
Y
Seimbille
Jacques
J
Rousseau
François
F
Bénard
Catherine
C
Morin
Hasrat
H
Ali
George
G
Avvakumov
Geoffrey L
GL
Hammond
Johan E
JE
van Lier
D000818:Animals; D001943:Breast Neoplasms / Q000000981:diagnostic imaging; D004958:Estradiol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism*; D005260:Female; D005462:Fluorine Radioisotopes; D006801:Humans; D007553:Isotope Labeling; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011960:Receptors, Estrogen / Q000378:metabolism*; D012738:Sex Hormone-Binding Globulin / Q000378:metabolism; D013816:Thermodynamics; D014055:Tomography, Emission-Computed / Q000379:methods; D000509:alpha-Fetoproteins / Q000378:metabolism
D005462:Fluorine Radioisotopes; D019275:Radiopharmaceuticals; D011960:Receptors, Estrogen; D012738:Sex Hormone-Binding Globulin; D000509:alpha-Fetoproteins; D004958:Estradiol