cancers Review PET Imaging Agents (FES, FFNP, and FDHT) for Estrogen, Androgen, and Progesterone Receptors to Improve Management of Breast and Prostate Cancers by Functional Imaging John A. Katzenellenbogen Department of Chemistry and Cancer Center at Illinois, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA; [email protected], Tel.: +1-217-333-6310; Fax: +1-217-333-7325 Received: 1 June 2020; Accepted: 17 July 2020; Published: 23 July 2020 Abstract: Many breast and prostate cancers are driven by the action of steroid hormones on their cognate receptors in primary tumors and in metastases, and endocrine therapies that inhibit hormone production or block the action of these receptors provide clinical benefit to many but not all of these cancer patients. Because it is difficult to predict which individuals will be helped by endocrine therapies and which will not, positron emission tomography (PET) imaging of estrogen receptor (ER) and progesterone receptor (PgR) in breast cancer, and androgen receptor (AR) in prostate cancer can provide useful, often functional, information on the likelihood of endocrine therapy response in individual patients. This review covers our development of three PET imaging agents, 16α-[18F]fluoroestradiol (FES) for ER, 21-[18F]fluoro-furanyl-nor-progesterone (FFNP) for PgR, and 16β-[18F]fluoro-5α-dihydrotestosterone (FDHT) for AR, and the evolution of their clinical use. For these agents, the pathway from concept through development tracks with an emerging understanding of critical performance criteria that is needed for successful PET imaging of these low-abundance receptor targets. Progress in the ongoing evaluation of what they can add to the clinical management of breast and prostate cancers reflects our increased understanding of these diseases and of optimal strategies for predicting the success of clinical endocrine therapies. Keywords: FES; FFNP; FDHT; receptor-targeting; PET imaging; radiopharmaceuticals; endocrine therapy; breast cancer; prostate cancer; hormone-challenge test 1. Introduction Steroid receptors are transcription factors that play major roles during development, and in both adult men and women, they control reproduction and regulate many other organ systems; they are also important regulators of the growth and spread of various hormone-dependent cancers. This review will cover principally the development of agents to image the estrogen receptor (ER) and the progesterone receptor (PgR) in breast cancer and the androgen receptor (AR) in prostate cancer. Imaging agents for these targets have been labeled with different radioisotopes (various radiohalogens, carbon-11, and radiometals) and have been developed for use with different tomographic imaging devices. Here, I will cover the development of three positron emission tomography (PET) imaging agents labeled with fluorine-18 that have reached the clinic and continue to be of great utility and actively investigated: 16α-[18F]fluoroestradiol (FES) and 21-[18F]fluoro-furanyl-nor-progesterone (FFNP) for breast cancer and 16β-[18F]fluoro-5α-dihydrotestosterone (FDHT) for prostate cancer (Figure1). Cancers 2020, 12, 2020; doi:10.3390/cancers12082020 www.mdpi.com/journal/cancers Cancers 2020, 12, 2020 2 of 32 CancersCancers 2020 2020, 12, 12, ,x x 22 of of 32 32 EstrogenEstrogen Receptor Receptor Breast Cancer Breast Cancer FESFES ProgesteroneProgesterone Receptor Receptor BreastBreast Cancer Cancer FFNPFFNP AndrogenAndrogen Receptor Receptor ProstateProstate Cancer Cancer FDHTFDHT FigureFigure 1. 1. Structures Structures of of 16 16 αα-[-[1818F]fluoroestradiolF]fluoroestradiolF]fluoroestradiol (FES), (FES), (FES), 21-[ 21-[ 21-[181818F]fluoro-furanyl-nor-progesteroneF]fluoro-furanyl-nor-progesteroneF]fluoro-furanyl-nor-progesterone (FFNP) (FFNP) andand 16 16ββ-[-[1818F]fluoro-5F]fluoro-5F]fluoro-5αα-dihydrotestosteroneα-dihydrotestosterone-dihydrotestosterone (FDHT), (FDHT), (FDHT), with with with thei thei theirr rhormone hormone hormone receptor receptor receptor targets targets and and use use in in cancercancer noted noted at at left. left. 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