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

Abstract

The estrogen receptor (ER) and progesterone receptor (PR) are over-expressed in ~50% of breast cancer lesions, and used as biomarkers to stratify patients to endocrine therapy. Currently,

PET Imaging Agents (FES, FFNP, and FDHT) for Estrogen, Androgen, and Progesterone Receptors to Improve Management of Breast and Prostate Cancers by Functional Imaging

“…So, FPTP is an obvious candidate for clinical translation, but given that FFNP was already being advanced into clinical studies by our groups (NCT02455453) [ 4 ], we made no further efforts to develop FPTP. Other fluorine-18 tanaproget derivatives have been investigated, but showed limited promise for imaging PgR in vivo [ 92 , 93 ]. Hence, at this point, FFNP is the most advanced PET imaging agent for PgR in breast cancer patients, where it appears to have good selectivity for PgR (see Section 5.2 ).…”

Fluorine-18 labelled building blocks for PET tracer synthesis

“…Thus, 27 was synthesised from [ 18 F]fluoromethyl tosylate in 30 minutes with a radiochemical yield of 15 AE 4% (ndc). 56 Since 2010 only one case of P-alkylation with [ 18 F]fluoromethyl tosylate has been reported. [ 18 F]Fluoromethyl triphenylphosphonium cation 29 was synthesised in a one-pot reaction from [ 18 F]fluoromethyl tosylate 14 and triphenylphosphine 28 with an overall radiochemical yield of 30-34% dc (Scheme 14).…”

Synthesis of a benzoxazinthione derivative of tanaproget and pharmacological evaluation for PET imaging of PR expression

“…In silico evidence suggested that R- and S- enantiomers may display different binding affinities and therefore further study would be required to evaluate the enantiomerically pure species. [ 18 F]Fluoromethyl-Tanaproget ([ 18 F]FMTP) bears a fluoromethyl-substituent at the 1 N -pyrrole position of Tanaproget and was shown to maintain a high binding affinity to PR in accordance with structure-activity relationship (SAR) data (Merchant et al, 2016). Larger substituents at this position resulted in an inverse relationship between alkyl chain length and relative binding affinity (RBA), limiting substitution to moieties no larger than a single methyl group (Merchant et al, 2016, Zhou et al, 2010).…”

“…[ 18 F]Fluoromethyl-Tanaproget ([ 18 F]FMTP) bears a fluoromethyl-substituent at the 1 N -pyrrole position of Tanaproget and was shown to maintain a high binding affinity to PR in accordance with structure-activity relationship (SAR) data (Merchant et al, 2016). Larger substituents at this position resulted in an inverse relationship between alkyl chain length and relative binding affinity (RBA), limiting substitution to moieties no larger than a single methyl group (Merchant et al, 2016, Zhou et al, 2010). [ 18 F]FMTP was radiolabelled using the [ 18 F]fluoromethyltosylate prosthetic group and showed promising in vitro cell uptake but poor in vivo metabolic stability.…”

“…[ 18 F]FMTP was radiolabelled using the [ 18 F]fluoromethyltosylate prosthetic group and showed promising in vitro cell uptake but poor in vivo metabolic stability. The development of novel radiochemistry methodology to access carbon-11 thiocarbamates allowed the synthesis of [ 11 C]Tanaproget from an acyclic precursor; however, in vitro cell studies were unsuccessful due to uptake modulation by multi-drug resistance proteins (MDR) (Haywood et al, 2015, Merchant et al, 2016). The poor performance of [ 11 C]Tanaproget and the limited exploration of fluorine-18 radiolabelled non-steroidal PR ligands in the literature prompted further investigation of suitable ligands for imaging PR with PET (Merchant et al, 2016).…”