Auger Emitters in Radiotherapy: Novel Estrogen Receptor Radioligands

1. Auger Emitters in Radiotherapy: Novel Estrogen Receptor Radioligands M.C. Oliveira1, M. Videira1, A. Almeida1, L. Gano1, M. Watanabe2, T. Thiemann2, A.C. Santos3, F. Botelho3, C. Oliveira4 1Instituto Tecnológico e Nuclear, Estrada Nacional 10, 2686-953 Sacavém, Portugal; 2IMCE and Interdisciplinary Graduate School of Engineering Science, Kyushu University, Fukuoka, Japan3; Instituto de Biofísica/Biomatemática, CIMAGO, IBILI, FMUC, Coimbra, Portugal; 4Clínica Ginecológica, CIMAGO, FMUC Coimbra, Portugal Introduction Tumours over-expressing estrogen receptors (ER) have a great impact in women’s health and welfare since breast cancer still remains the leading cause of cancer mortality among women in Western countries. Since one-third of breast cancer patients respond to hormonal treatment, drugs based on ER ligands can be useful for diagnosis and oriented therapy of the disease. Radiopharmaceuticals based on Auger electron emitters(eg123I/125I) are anticipated to afford highly selective target radiotherapy since the emitted electrons deposit their low energy within the cell nucleus to cause double stranded DNA breaks and cell death with virtually no damage to the surrounding cells.1 As a part of our investigation on new specific ligands2 for targeted therapy and/ or nuclear imaging of ER rich tumours novel E-ring expanded estrane derivatives radiolabelled on the A aromatic ring (2- and 4-[125I]IMEBE) were synthesized. Biological behaviour was studied attempting to evaluate the effect of altering the position of radioiodination.3 Radioiodination Na125/127I Chloramine-T 2-IMEBE, 2-[125I]IMEBE: X=127I, 125I; Y=H 4-IMEBE, 4-[125I]IMEBE: X=H; Y= 127I,125I MEBE RP- HPLC purification EC 250/4 Nucleosil C18 1 mL/min 85% aq MeOH 2-[125I]IMEBE 4-[125I]IMEBE 42% 48% Biological Studies Sprague-Dawley immature female rat • high radiochemical purity • high specific activity (~ 2200Ci/ mmol) Human serum stability at 37ºC • high in vivo stability • hepatobiliary tract as main excretory pathway Target tissue selectivity 4-[125I]IMEBE 2-[125I]IMEBE In vivo ER binding specificity • high in vitro radiochemical stability 2-125IIMEBE • uterus and ovaries uptake via a receptor mediated process • high uterus to-non-targeting ratios at 24h Most promising biological profile References 1 - DeSombre ER et al.Acta Oncol 2000; 39:659-666. 2 - Melo e Silva, MC et al.Appl Rad Isotop 2001;54:227-239. 3 - Oliveira, MC et al. J Label Compd Radiopharm submitted • Concluding remarks • The favourable in vitro / in vivo stability and biodistribution profiles suggest these types of radioligands to be good candidates for further exploration of their potential therapeutic application. Acknowledgements This project has been partially supported by CIMAGO (09/05) and Fundação Luso-Americana para o Desenvolvimento (FLAD)