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Estrogen Receptor Ligands for Targeting Breast Tumours: a Brief Outlook on Radioiodination Strategies

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Estrogen Receptor Ligands for Targeting Breast Tumours: a Brief Outlook on Radioiodination Strategies 124 Current Radiopharmaceuticals, 2012, 5, 124-141 Estrogen Receptor Ligands for Targeting Breast Tumours: A Brief Outlook on Radioiodination Strategies Maria Cristina Oliveira*,1,2, Carina Neto1,2, Lurdes Gano1,2, Fernanda Marques1,2, Isabel Santos1,2, Thies Thiemann2,3, Ana Cristina Santos2,4, Filomena Botelho2,4 and Carlos F. Oliveira2,5 1Unidade de Ciências Químicas e Radiofarmacêuticas, Instituto Tecnológico e Nuclear, Sacavém, Portugal; 2Centro de Investigação em Meio Ambiente Genética e Oncobiologia (CIMAGO); 3Faculty of Science, United Arab Emirates University, United Arab Emirates; 4Instituto de Biofísica/Biomatemática, IBILI, FMUC, Coimbra, Portugal; 5Clínica Ginecológica, FMUC, Coimbra, Portugal Abstract: The design and development of radiolabelled estradiol derivatives has been an important area of research due to their recognized value in breast cancer management. The estrogen receptor (ER) is a relevant biomarker in the diagnosis, prognosis and prediction of the therapeutic response in estrogen receptor positive breast tumours. Hence, many radioligands based on estradiol derivatives have been proposed for targeted functional ER imaging. The main focus of this review is to survey the current knowledge on estradiol-based radioiodinated receptor ligands synthesis for breast tumour functional imaging. The main preclinical and clinical achievements in the field will also be briefly presented to make the manuscript more comprehensive. Keywords: Breast cancer, estradiol, estrogen receptor, radioiodination, SPECT, tumor targeting. expressed primarily in the brain, bone and vascular 1. INTRODUCTION epithelium. Breast cancer is the most malignant type of diagnosed Given the broad clinical application in women welfare of cancer among women and still remains a major cause of ligands that modulate the ER, several classes of ER targeting death in the western world. Owing to its tendency to meta- compounds that might be useful as chemotherapeutic/ stasize, even before the disease can be clinically detected, chemopreventive agents and as radioimaging agents have early diagnosis is essential for breast cancer patients' welfare been designed and evaluated all over the years. Non-invasive and survival. A majority of breast cancers express estrogen imaging of breast tumours based on their hormonal recep- receptors (ER) in the primary tumour and in many cases tor’s status can be used for hormone therapy follow-up by respond successfully to tamoxifen or to a selective estrogen single photon emission computed tomography (SPECT) or receptor modulator (SERM) such as raloxifene. positron emission tomography (PET) [4-7]. While PET imaging gives better resolution, SPECT still remains the The estrogen receptor (ER) is a ligand-regulated trans- more practical approach for routine diagnostics in nuclear cription factor whose activity as an inducer or repressor of medicine due to the use of medium to long-lived radionuc- gene transcription depends on the nature of the ligand with lides such as radioiodine isotopes. During the last years which it is bound, as well as the nature of the associated several efforts have been made to synthesize estradiol deri- corregulator. Estrogen action is important in many tissues vatives that could be labelled with γ-emitting radionuclides, and ER is involved in the development and function of the such as with radioisotopes of iodine, with high specific acti- reproductive system and plays a role in bone density main- vity, for imaging and monitoring estrogen-receptor (ER) tenance and brain function. Thus, ER is an important target positive breast cancers by SPECT modalities. Such a for the discovery of new drugs for treating or regulating a radiodiagnostic agent with a convenient half-life would have variety of hormone-related conditions and modulation of the advantage of being non-invasive. The search for selective estrogen receptor function is of paramount importance for a agents to image in vivo receptor densities in steroid-sensitive variety of diseases including breast cancer and osteoporosis. tumours, as well as the need for probes to study hormone The discovery of a second ER subtype, termed ERβ [1, 2] action, has led to the synthesis and evaluation of a series of has increased the level complexity of estrogen signalling. halogenated derivatives of estradiol over the last 30 years [4, The two receptor subtypes (ERα and ERβ) show significant 7]. These include estradiol derivatives labelled with bromine sequence homology in their DNA and binding domains but [8, 9], fluorine [10-14] and iodine [15-24]. However, few of exhibit differences in their tissue distribution patterns, ligand these agents have reached the clinical stage [12, 25-28]. selectivity and transcriptional activities [3]. ERα is found Additionally, due to the growing interest in Auger electron mainly in breast and uterine tissues whereas ERβ is emitters for potential radiotherapy of ER-positive breast cancers steroid carriers are needed that exhibit high selec- tivity and uptake in the target tissue [29, 30]. Such clinical *Address correspondence to this author at the Unidade de Ciências approach would require a receptor-ligand labelled with a Químicas e Radiofarmacêuticas, Instituto Tecnológico e Nuclear, Estrada Nacional 10, 2686-953 Sacavém, Portugal; Tel: 351 219946195; radionuclide suitable for radiotherapy, with high affinity for Fax: 351 219946185; E-mail: [email protected] 1874-4729/12 $58.00+.00 © 2012 Bentham Science Publishers Estrogen Receptor Ligands for Targeting Breast Tumours Current Radiopharmaceuticals, 2012, Vol. 5, No. 2 125 the estrogen receptor, low affinity for non-specific binding product 123I. Nevertheless, 123I is the most appropriate for in sites and good in vivo metabolic stability [31]. vivo diagnostic procedures because of its convenient half-life (13.2 h) and emitted photon energy of 159 keV, which is Herein, we will review the chemistry, radiochemistry and highly compatible with current detector technologies. 123I where available the in vitro/in vivo biological activity of estradiol analogues that have been studied as potential appears to be the best radiohalogen based on nuclear pro- perties and absorbed radiation to the patient. The 125I isotope probes for diagnostic purposes in breast cancer research. To with its long half-life of 60 days and the low energy (27-35 be fair, viewing the great amount of literature in this field, keV) of the emitted photons is the most commonly used for more than a few pages should be written. Therefore, we have the radiolabelling of compounds for in vitro biological and tried to focus on the area of radioiodinated estradiol-based preliminary in vivo animal studies. The 131I isotope has been ligands for ER targeting, and have inevitably done so with a radiochemist’s eye, giving special attention to the radio- routinely used for clinical applications. Its properties include an acceptable half-life of 8 days and an emitted radiation of iodination methods used in their preparation. Several radio- both 364 keV photons suitable for scintigraphic applications iodinated non-steroidal estrogens (e.g. hexestrol) [32-36] and and low energy β- particles suitable for in situ radiotherapy non-steroidal antiestrogens [37-44] have also been reported [46]. in the literature for ER imaging purposes, but will not be considered within the scope of this review. In spite of its adequate nuclear properties, the positron emitter 124I has not been yet extensively explored in PET The first part of the review covers the radioiodination of imaging because of a complex decay scheme, which includes estradiol-based ligands for ER molecular targeting. In the several high energy gamma rays. However, the favourable second part, a brief overview concerning the biological eva- 4.2 day half-life added to the ease of production on cyclo- luation of ER expression with estradiol-based ligands, trons makes this radiohalogen a promising radiotracer for the including structure-activity relationship (SAR) studies and pre-clinical/clinical studies of the most relevant radioligands, development of novel probes for molecular imaging [47]. will also be presented. The review concludes with a summary and an outlook on 3. METHODS OF RADIOIODINATION the future perspectives of the application of radioiodinated Numerous classical radio-iodination methods can be estradiol-based radioligands for ER SPECT molecular readily applied to the labelling of steroidal ligands for the imaging. estrogen receptor. Beyond the key parameters to be taken into account when dealing with any radiotracer such as half- 2. IODINE RADIONUCLIDES USED IN THE life, reaction time, radiochemical purity and specific activity, SYNTHESIS OF ESTROGEN RECEPTOR IMAGING careful attention must also be paid to the labelling site. Any AGENTS structural changes on the original molecule may have an effect on the binding affinity to the target, affecting its bio- Radioisotopes of iodine provide a nice combination of logical behaviour. Only radioiodination techniques that convenient nuclear properties and high specific activity and require minimal structural modifications to maintain the versatile chemistry. They are relatively easy to use and com- specific bioactivity exhibited by the unlabelled compounds mercially available at nominal cost. Three of the radio- should be realistically considered [48-50]. isotopes (123/125/131I) have found wide use for the labelling of The stability of the carbon-iodine bond at the particular small molecules such as steroidal ligands for
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