Radiochemical synthesis and tissue distribution of Tc-99m-labeled 7α-substituted estradiol complexes

Skaddan, Marc B.; Wüst, F.; Jonson, Stephanie D.; Syhre, R.; Welch, Michael J.; Spies, Hartmut; Katzenellenbogen, John A.

doi:10.1016/s0969-8051(00)00083-4

Cited by 59 publications

(46 citation statements)

References 42 publications

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“…Most of the previously described 99m Tc-labeled estradiol derivatives were modified at the 7a-and 17a-positions for incorporation of 99m Tc (18,19). None of these reported steroidal analogs was successful as ideal imaging agents, because of either low binding affinity or the difficulty in preparing 99m Tc-labeled derivatives with high specific activity and yields.…”

Section: Discussionmentioning

confidence: 99%

“…As an alternative to PET, we wanted to evaluate the utility of a 99m Tc(I)-estradiol-pyridin-2-yl hydrazine derivative in SPECT of breast and endometrial cancers. In previously published studies, problems encountered in developing a neutral Tc-estradiol derivative suitable for imaging of tumors were associated with excessive lipophilicity (i.e., logP values of .5 (23)) resulting in high liver and intestine uptake, low tumor-to-blood ratios, and relatively low uptake in the tumor compared with that in the background (17)(18)(19). In the present study, we encountered similar problems despite the fact that the logP value of our tracer was not significantly different from that previously reported for estradiol itself (3.9 vs. approximately 3.7 (23), respectively).…”

Section: Discussionmentioning

confidence: 99%

“…To determine nonspecific binding, the cells were incubated with 10 mM 17b-estradiol. To establish the affinity of the corresponding Re-labeled derivative (20), which serves as an isosteric nonradioactive surrogate for the 99m Tc-labeled derivative (19,23), cells were treated with a trace amount of the radioligand and competition was performed with increasing amounts of the Re-estradiol derivative. Binding data were analyzed with GraphPad Prism, Version 4 (GraphPad Software, Inc.).…”

Section: Receptor-binding Studiesmentioning

confidence: 99%

“…However, the agents described to date have demonstrated suboptimal target tissue selectivity in vivo, possibly as a result of the high lipophilicity or rapid metabolism of these agents. The complex chemistry involved in the radiosynthesis of these compounds to obtain high yields and purities has further hampered their development for clinical use (18,19).…”

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

Nayak

Hathaway²,

Ramesh³

et al. 2008

J Nucl Med

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Breast and endometrial cancers are the most common invasive malignancies in women, with more than 217,000 new diagnoses per year in the United States. These cancers are often classified into 2 subtypes based on the expression of the classical estrogen receptor. In this study, we describe a new structural class of neutral tridentate 99m Tc(I)-estradiol-pyridin-2-yl hydrazine derivatives for potential use in breast and endometrial cancer imaging. Methods: The 99m Tc(I)-estradiol-pyridin-2-yl hydrazine derivative was synthesized via the Sonogashira cross-coupling reaction and radiolabeled via the tricarbonyl approach. Radiochemical purity was assessed by high-performance liquid chromatography. Cell-binding studies were performed with human breast adenocarcinoma MCF-7 cells. The in vivo biodistribution of the 99m Tc(I) derivative was evaluated in virgin female C57BL/6 mice in defined phases of the estrous cycle. Biodistribution and SPECT/CT studies were performed with mice bearing MCF-7 and primary human endometrial tumors. Results: Radiochemical analysis demonstrated that the postpurification purity of the 99m Tc(I)-estradiol-pyridin-2-yl hydrazine derivative was $95%, with a specific activity of 99m Tc of 47.5 TBq/mmol. Cell-binding studies yielded a dissociation constant (mean 6 SEM) of 11 6 1.5 nM. In vivo studies revealed that receptor-mediated uptake was present in all phases of the estrous cycle in reproductive organs and mammary glands but was highest during the diestrous phase of the estrous cycle. Despite high nonspecific uptake in the liver, significant receptor-mediated uptake was observed in target tissues and estrogen receptor-expressing tumors (0.67% for MCF-7 tumors and 0.77% for endometrial tumors). Tumor uptake was reduced by approximately 50% on coinjection with 17b-estradiol. Conclusion: We have characterized a novel neutral tridentate 99m Tc(I)-estradiol-pyridin-2-yl hydrazine derivative for potential use in breast and endometrial cancer imaging. This study represents the first step on a path toward the design of estrogen-based Tc-labeled tracers with improved targeting and SPECT imaging characteristics. Over 250,000 new cases of breast, ovarian, and endometrial cancers were diagnosed in the United States in 2006 (1). Such cancers are often hormonally regulated and can be divided into 2 subtypes on the basis of whether or not tumor cells express the classical estrogen receptor (ER), ERa. Estrogen promotes cell proliferation and inhibits apoptosis through a complex signaling cascade resulting in transcriptional changes that may include the modulation of tumor suppressor function. The presence of ERa in approximately two thirds of breast cancers correlates with whether the tumors are estrogen dependent or independent (2) and represents one of the best prognostic factors in breast cancer because of the availability of antiestrogens such as tamoxifen and fulvestrant and, more recently, the aromatase inhibitors. With the recent characterization of a novel transmembrane ER, GPR30, in multiple cancer t...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Receptor-binding Studiesmentioning

confidence: 99%

mentioning

confidence: 99%

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

Nayak

Hathaway²,

Ramesh³

et al. 2008

J Nucl Med

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“…Because the current methodologies for screening estrogen and progesterone receptor require invasive biopsies, identification of an in vivo imaging agent could improve the diagnosis of the disease. Several PET imaging agents have been developed preclinically to evaluate the expression of these nuclear intracellular receptors such as 18 F-fluoroestradiol, 99 mTc, and 68 Ga-flutamate peptide-estradiol, and 18 F-16 a-ethyl-19-norprogesterone ( Jonson & Welch 1998, Hostetler et al 1999, Skaddan et al 2000. While many of these molecules have been plagued with metabolic inactivation, binding to serum hormone binding globulin, and poor chemical synthetic yield, positive results have been reported for .…”

Section: Intracellular Receptorsmentioning

confidence: 99%

In vivo imaging of molecular targets and their function in endocrinology

Burdette

2008

Journal of Molecular Endocrinology

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Imaging is one of the fastest growing fields of study. New technologies and multimodal approaches are increasing the application of imaging to determine molecular targets and functional processes in vivo. The identification of a specific target, transporter, or biological process using imaging has introduced major breakthroughs to the field of endocrinology primarily utilizing computed tomography, magnetic resonance imaging, ultrasonography, positron emission tomography, single-photon emission computed tomography, and optical imaging. This review provides a general background to the specific developments in imaging that pertains to in vivo function and target identification in endocrine-based diseases.

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New and Efficient Routes to Biomolecules Substituted with Cyclopentadienyltricarbonylrhenium and -Technetium Derivatives

et al. 2001

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The small, compact, robust, and nonpolar units of [CpM(CO)3] (M = Re, Tc) coupled with biomolecules may be considered as bioorganometallic entities of potential interest in the field of medicinal chemistry. However, the short half-life of useful radionuclides (186Re t1/2 = 3.7 d, 188Re t1/2 = 16.8 h, 99mTc t1/2 = 6 h), the risks inherent in their use, and their cost have led chemists to search for novel synthetic strategies that allow the rapid introduction of the [CpM(CO)3] moiety as a late step in the course of synthesizing the target molecule. The present paper describes different strategies recently reported in the literature to tackle this problem.

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Radiochemical synthesis and tissue distribution of Tc-99m-labeled 7α-substituted estradiol complexes

Cited by 59 publications

References 42 publications

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

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

In vivo imaging of molecular targets and their function in endocrinology

New and Efficient Routes to Biomolecules Substituted with Cyclopentadienyltricarbonylrhenium and -Technetium Derivatives

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Radiochemical synthesis and tissue distribution of Tc-99m-labeled 7α-substituted estradiol complexes

Cited by 59 publications

References 42 publications

Preclinical Development of a Neutral, Estrogen Receptor–Targeted, Tridentate99mTc(I)-Estradiol-Pyridin-2-yl Hydrazine Derivative for Imaging of Breast and Endometrial Cancers

Preclinical Development of a Neutral, Estrogen Receptor–Targeted, Tridentate99mTc(I)-Estradiol-Pyridin-2-yl Hydrazine Derivative for Imaging of Breast and Endometrial Cancers

In vivo imaging of molecular targets and their function in endocrinology

New and Efficient Routes to Biomolecules Substituted with Cyclopentadienyltricarbonylrhenium and -Technetium Derivatives

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Product

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

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