Fluorine-18-labeled progestin 16.alpha.,17.alpha.-dioxolanes: development of high-affinity ligands for the progesterone receptor with high in vivo target site selectivity

Abstract

We describe the synthesis and tissue biodistribution of two 21-[fluoro-18F]progestin 16 alpha, 17 alpha-furanyl ketals, potential agents for imaging progesterone receptor (PR)-positive breast tumors in humans, using positron emission tomography. 21-Fluro-16 alpha, 17 alpha-[(R)-(1'-alpha-furylmethylidene)dioxy]-19- norpregn-4-ene-3,20-dione (endo-10a) and 21-fluoro-16 alpha, 17 alpha-[(R)-(1'-alpha-furylethylidene)dioxy]-19- norpregn-4-ene-3,20-dione (endo-10b) were chosen for radiochemical synthesis from a series of seven novel progestin 16 alpha, 17 alpha-(furanyldioxolanes) on the basis of their high relative binding affinity to PR (190% and 173%, respectively, relative to R5020 = 100%), their low nonspecific binding (NSB) (log P o/w = 3.87 and 4.13, respectively), and their resulting high binding selectivity indices (BSI; i.e., the ratio of their PR binding affinity to nonspecific binding). Radiochemical synthesis of these two species in high radiochemical purity and at high effective specific activity was accomplished by treatment of the corresponding diastereomerically pure 21-trifluoromethanesulfonates with fluorine-18 anion. In tissue biodistribution studies in estrogen-primed immature female Sprague-Dawley rats, both [18F]-endo-10a and [18F]endo-10b demonstrated high PR-selective uptake in the principal target tissues, the uterus and the ovaries, and relatively low uptake in fat and bone. The metabolism at the 21-position in these progestins (as monitored by in vivo defluorination) appears to be less than that in other 21-fluoroprogestins; this may reflect steric inhibition of metabolism at this site due to the bulk of the furan-substituted dioxolane ring at the 16 alpha, 17 alpha-position. Comparison with other fluorine-18-labeled progestins shows that the PR-specific uptake in uterine tissue correlates with the BSI of the ligand and that the fat uptake correlates with the NSB of the ligand at high levels of statistical significance. These two dioxolanes may prove to be useful as breast tumor-imaging agents in humans.

Evaluation of a bromine-76-labeled progestin 16α,17α-dioxolane for breast tumor imaging and radiotherapy: in vivo biodistribution and metabolic stability studies

“…Nevertheless, the most promising PR ligand for PET imaging of breast cancer reported so far is fluoro furanyl norprogesterone (FFNP, 1), the 18 F-labeled form of which is undergoing clinical imaging investigations at Washington University, School of Medicine. FFNP has a high relative binding affinity to PR, low nonspecific binding, and a high binding selectivity index [35,40]. In tissue biodistribution studies, [ 18 F]FFNP demonstrated high PR-selective uptake in the principal PR target organs, uterus and ovaries, and relatively low uptake in non-PR target tissues, such as fat and bone [35].…”

“…FFNP has a high relative binding affinity to PR, low nonspecific binding, and a high binding selectivity index [35,40]. In tissue biodistribution studies, [ 18 F]FFNP demonstrated high PR-selective uptake in the principal PR target organs, uterus and ovaries, and relatively low uptake in non-PR target tissues, such as fat and bone [35]. In addition, FFNP is expected to be more stable towards the metabolism of the C-20 ketone by steroid dehydrogenases, because it is protected by the bulk of the 16α, 17α-furanyl group, a group onto which a bromine can be introduced easily.…”

“…A series of bromine-and iodine-substituted 16α,17α-dioxolane progestins have been synthesized [34] based on the very promising PR ligand, fluoro furanyl norprogesterone (FFNP) 1 [35] and its analog 2 [36]. Among this series, 16α,17α-[(R)-1'-α-(5-bromofurylmethylidene)dioxyl]-21-hydroxy-19-norpregn-4-ene-3,20-dione (3) appeared to be the most promising one with good relative binding affinity to PR (RBA = 65, relative to R5020) and moderate lipophilicity (log P o/w = 5.09 ± 0.84) [34].…”

Synthesis and pre-clinical evaluation of a [18F]fluoromethyl-tanaproget derivative for imaging of progesterone receptor expression

“…23 Tanaproget derivatives have previously been investigated for use as radioligands where derivatization at the R2-position provided racemic Figure 1A. [24][25][26][27] The relative binding affinities (RBA) of Tanaproget and related 18 F-labelled scaffolds are shown in Figure 1B. were synthesized and evaluated for PR binding affinity (data summarized in Figure 1B).…”

A Structure Based, Solid Phase Synthesis Approach to the Development of Novel Selective Estrogen Receptor Modulatory Steroids

“…7). In particular the work with the 16a, 17a-dioxolanes provides opportunities to synthesize the corresponding iodinated analogs of the fluorinated compounds [26][27][28]. Conversion to the corresponding tributylstannyl derivatives followed by radioiododestannylation should yield target radiochemicals for in vitro and in vivo evaluation.…”