21-[18F]fluoro-16.alpha.-ethyl-19-norprogesterone. Synthesis and target tissue selective uptake of a progestin receptor-based radiotracer for positron emission tomography

Abstract

We have synthesized 21-[18F]fluoro-16 alpha-ethyl-19-norprogesterone (FENP), a high affinity ligand for the progesterone receptor, labeled with the positron-emitting radionuclide fluorine-18 (t1/2 = 110 min). The synthesis proceeds in two steps from 21-hydroxy-16 alpha-ethyl-19-norprogesterone and involves [18F]fluoride ion displacement of the 21-trifluoromethanesulfonate (21-triflate). This material is purified by HPLC and is obtained in 4-30% overall yield (decay corrected) within 40 min after the end of bombardment to produce [18F]fluoride ion. The effective specific activity, determined by competitive radioreceptor binding assays, is 700-1400 Ci/mmol. In vivo, [18F]FENP demonstrates highly selective, receptor-mediated uptake by the uterus of estrogen-primed rats; the uterus to blood and uterus to muscle ratios were respectively 26 and 16 at 1 h and 71 and 41 at 3 h after injection. The high target tissue selectivity of this uptake suggests that this compound may be useful for the in vivo imaging of progestin target tissues and receptor-rich tumors (such as human breast tumors) by positron emission tomography.

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).…”

PET and SPECT Imaging of Steroid Hormone Receptors

“…A few of them have even been successfully evaluated in rodents (Arterburn et al 2003 ;Nayak et al 2008 ;Ramesh et al 2006 ;Takahashi et al 2007a , b ;Yurt et al 2009 ;Zhu et al 2010 (Dehdashti et al 1991 ;Jonson and Welch 1998 ;Pomper et al 1988 ;Verhagen et al 1991a (Buckman et al 1995 ). […”

“…18 F]FENP showed highly selective PR-mediated uptake in the uterus of estrogen-primed rats (Pomper et al 1988 ) and in PR-positive carcinoma in mice (Verhagen et al 1991a ). In eight breast cancer patients, however, [ (Verhagen et al 1994 ).…”

Development of [F-18]Fluorine-Substituted Tanaproget as a Progesterone Receptor Imaging Agent for Positron Emission Tomography

“…In fact, because PR levels are increased by estrogen treatment, measurement of an increase in PR levels in breast tumors by PET, after a brief exposure to estrogen, might be useful in assessing whether the ER is functional and thus capable of mediating endocrine therapies (19,23). PR itself is also a target for endocrine therapy in breast cancer using antiprogestins (24).…”