Preclinical Development of a Neutral, Estrogen Receptor-Targeted, Tridentate 99mTc(I)-Estradiol-Pyridin-2-yl Hydrazine Derivative for Imaging of Breast and Endometrial Cancers

doi:10.2967/jnumed.107.048546

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Basic Science Investigation

Preclinical Development of a Neutral, Estrogen Receptor–Targeted, Tridentate ^99mTc(I)-Estradiol-Pyridin-2-yl Hydrazine Derivative for Imaging of Breast and Endometrial Cancers

Tapan K. Nayak¹^,2, Helen J. Hathaway¹^,3, Chinnasamy Ramesh⁴, Jeffrey B. Arterburn³^,4, Donghai Dai³^,5, Larry A. Sklar²^,3^,6, Jeffrey P. Norenberg²^,3 and Eric R. Prossnitz¹^,3

¹ Department of Cell Biology and Physiology, School of Medicine, University of New Mexico Health Science Center, Albuquerque, New Mexico; ² College of Pharmacy, University of New Mexico Health Science Center, Albuquerque, New Mexico; ³ Cancer Research and Treatment Center, University of New Mexico Health Science Center, Albuquerque, New Mexico; ⁴ Department of Chemistry and Biochemistry, New Mexico State University, Las Cruces, New Mexico; ⁵ Department of Obstetrics and Gynecology, School of Medicine, University of New Mexico Health Science Center, Albuquerque, New Mexico; and ⁶ Department of Pathology, School of Medicine, University of New Mexico Health Science Center, Albuquerque, New Mexico

Correspondence: For correspondence or reprints contact: Eric R. Prossnitz, Department of Cell Biology and Physiology, University of New Mexico, Albuquerque, NM 87131. E-mail: eprossnitz{at}salud.unm.edu

Breast and endometrial cancers are the most common invasivemalignancies in women, with more than 217,000 new diagnosesper year in the United States. These cancers are often classifiedinto 2 subtypes based on the expression of the classical estrogenreceptor. In this study, we describe a new structural classof neutral tridentate ^99mTc(I)-estradiol-pyridin-2-yl hydrazinederivatives for potential use in breast and endometrial cancerimaging. Methods: The ^99mTc(I)-estradiol-pyridin-2-yl hydrazinederivative was synthesized via the Sonogashira cross-couplingreaction and radiolabeled via the tricarbonyl approach. Radiochemicalpurity was assessed by high-performance liquid chromatography.Cell-binding studies were performed with human breast adenocarcinomaMCF-7 cells. The in vivo biodistribution of the ^99mTc(I) derivativewas evaluated in virgin female C57BL/6 mice in defined phasesof the estrous cycle. Biodistribution and SPECT/CT studies wereperformed with mice bearing MCF-7 and primary human endometrialtumors. Results: Radiochemical analysis demonstrated that thepostpurification purity of the ^99mTc(I)-estradiol-pyridin-2-ylhydrazine derivative was $≥$ 95%, with a specific activity of ^99mTcof 47.5 TBq/mmol. Cell-binding studies yielded a dissociationconstant (mean ± SEM) of 11 ± 1.5 nM. In vivostudies revealed that receptor-mediated uptake was present inall phases of the estrous cycle in reproductive organs and mammaryglands but was highest during the diestrous phase of the estrouscycle. Despite high nonspecific uptake in the liver, significantreceptor-mediated uptake was observed in target tissues andestrogen receptor–expressing tumors (0.67% for MCF-7 tumorsand 0.77% for endometrial tumors). Tumor uptake was reducedby approximately 50% on coinjection with 17β-estradiol.Conclusion: We have characterized a novel neutral tridentate^99mTc(I)-estradiol-pyridin-2-yl hydrazine derivative for potentialuse in breast and endometrial cancer imaging. This study representsthe first step on a path toward the design of estrogen-basedTc-labeled tracers with improved targeting and SPECT imagingcharacteristics.

Key Words: estrogen receptor • small-animal SPECT imaging • estrous cycle • breast cancer • endometrial cancer • ^99mTc-tricarbonyl

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