Synthesis and evaluation of a new series of 17α-[123I]iodovinyl estradiols

doi:10.1016/S0969-8051(99)00100-6

Nuclear Medicine and Biology

Volume 27, Issue 3, April 2000, Pages 279-287

https://doi.org/10.1016/S0969-8051(99)00100-6 Get rights and content

Abstract

A series of 17α-substituted estradiols was synthesized in which the stereochemical characteristics of carbons 20 and 21 were modified. It was found that the (Z)-isomer demonstrated more favorable receptor binding affinity than the corresponding (E)-isomer.

Introduction

Radioiodinated estrogens have been proposed as potential probes for the detection of estrogen dependent cancers 6, 21, 22, 30, 31. The development of a successful tumor imaging agent is dependent on devising rapid synthetic routes to materials with high receptor affinity. Additionally, the radiolabeled agent must be stable toward in vivo deiodination. We first reported the use of the iodovinyl group for stabilizing radioiodine in vivo in an estradiol (1) in 1981 (18). Since that time, a wide variety of iodovinyl radiopharmaceuticals have been developed 5, 8, 9, 10, 11, 12, 26, 28 including a number of related iodovinyl estradiols 4, 7, 13, 15, 16, 17, 23, 27, 29. Interestingly, both the nature of the estrogen derivative and the synthesis of the iodovinyl group have proven to be fruitful areas of research. We prepared the majority of our iodovinyl reagents via a hydroboration/iodination sequence that was developed in our laboratory due to the chemical and physical stability of the solid vinylboronic acid intermediates (Eq. 1) (18).

(1)

The stereochemistry of the 17α substituent in the 17α-iodovinyl estradiol agent has proven to be important in the receptor binding affinity of the agent. For example, it has been demonstrated that (Z)-isomers 1, 3 such as 2 and related steroid derivatives bind to receptors more effectively than the corresponding (E)-isomers 2, 7, 14, 15, 24, 25, 29. It has been postulated that, in molecules such as 2, the large iodine atom is directed at a different (and presumably less critical) portion of the receptor than the iodine in the corresponding (E)-isomer (1). It was further postulated that the results can be rationalized by permitting the steroid binding domain of the receptor to possess an additional hydrophobic pocket that could accommodate moderately sized lipophilic moieties in that region. In an effort to probe the limits of this proposed mechanism, we prepared a series of 17α-substituted estradiols in which the stereochemical characteristics of carbons 20 and 21 were modified systematically. The (Z)- and (E)-isomers (3 and 4) were prepared along with the related alkyl (5) and alkynyl (6) derivatives. The ¹²³I derivatives were prepared for preliminary animal uptake evaluations, which will be reported at a later date.

Section snippets

Chemistry

The synthetic strategy involved the preparation of an alkynyl estradiol derivative which could then be converted to the corresponding boronic acid. The boronic acid would then be iodinated to give the desired vinyl iodide 18, 19, 20. A stepwise approach to forming the alkynyl estradiol was used (Fig. 1). Estrone (7, R = H) was treated with excess 5-chloro-1-lithiopent-1-yne to provide the 17α-substituted-5-chloropent-1-yl estradiol 8 in 85% yield after hydrolysis. This approach allowed

Materials and methods

A 26-gauge intravenous pediatric catheter was placed into the lateral tail vein of 24 110–130 g Sprague-Dawley rats. The radiolabeled ligand was injected through the tail vein catheter and flushed with heparinized saline. At specific times, the rats were euthanized by an intravenous overdose of sodium pentobarbital. Blood samples were collected by cardiac puncture. The following organs or tissue samples were collected and weighed: heart, lung, liver, kidney, spleen, muscle, ovaries, uterus, and

Acknowledgements

We wish to thank Professor John Katzenellenbogen (University of Illinois) for graciously carrying out the binding efficiency determinations. We also wish to thank the Department of Energy and the Robert H. Cole Foundation for financial support.

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Original articlesSynthesis and evaluation of a new series of 17α-[123I]iodovinyl estradiols

Abstract

Introduction

Section snippets

Chemistry

Materials and methods

Acknowledgements

J. Steroid Biochem.

Steroids

Appl. Radiat. Isotopes

J. Steroid. Biochem.

Int. J. Rad. App. Instrum. [B]

Int. J. Rad. Appl. Instrum. Part B

Int. J. Rad. Appl. Instrum. Part B

Nucl. Med. Biol.

Tetrahedron

Int. J. Rad. Appl. Instrum. Part B

J. Steroid. Biochem.

Biochem. Pharmacol.

Int. J. Rad. Appl. Instrum. Part B

Synthesis receptor binding and tissue distribution of 7α- and 11β-substituted (17α,20 E) and (17α, 20Z)-21-[125I]iodo-19-norpregna-1,3,5(10), 20-tetraene-3,17-diols

J. Med. Chem.

Synthesis receptor binding and tissue distribution of (17α,20 E)- and (17α,20 Z)-21-[125]-iodo-19-norpregna-1,3,5(10),20 tetraene-3,17-diol

J. Med. Chem.

Original articles
Synthesis and evaluation of a new series of 17α-[¹²³I]iodovinyl estradiols

Synthesis receptor binding and tissue distribution of 7α- and 11β-substituted (17α,20 E) and (17α, 20Z)-21-[¹²⁵I]iodo-19-norpregna-1,3,5(10), 20-tetraene-3,17-diols

Synthesis receptor binding and tissue distribution of (17α,20 E)- and (17α,20 Z)-21-[¹²⁵]-iodo-19-norpregna-1,3,5(10),20 tetraene-3,17-diol