Evaluation of a bromine-76-labeled progestin 16α,17α-dioxolane for breast tumor imaging and radiotherapy: in vivo biodistribution and metabolic stability studies

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• 作者：Dong Zhou ; Terry L. Sharp ; Nicole M. Fettig ; Hsiaoju Lee ; Jason S. Lewis ; John A. Katzenellenbogen ; Michael J. Welch
• 关键词：Progesterone receptor ; Br-76 radiolabeling ; PET breast tumor imaging ; Radiotherapy
• 刊名：Nuclear Medicine and Biology
• 出版年：2008
• 出版时间：August 2008
• 年：2008
• 卷：35
• 期：6
• 页码：655-663
• 全文大小：270 K

文摘

Introduction

Progesterone receptors (PRs) are present in many breast tumors, and their levels are increased by certain endocrine therapies. They can be used as targets for diagnostic imaging and radiotherapy.

Method

16α,17α-[(R)-1′-α-(5-[⁷⁶Br]Bromofurylmethylidene)dioxyl]-21-hydroxy-19-norpregn-4-ene-3,20-dione ([⁷⁶Br]16α,17α-[(R)-1′-α-(5-bromofurylmethylidene)dioxyl]-21-hydroxy-19-norpregn-4-ene-3,20-dione (3)), a PR ligand with relative binding affinity (RBA)=65 and log P_o/w=5.09±0.84, was synthesized via a two-step reaction, and its tissue biodistribution and metabolic stability were evaluated in estrogen-primed immature female Sprague-Dawley rats.

Results

[⁷⁶Br]16α,17α-[(R)-1′-α-(5-bromofurylmethylidene)dioxyl]-21-hydroxy-19-norpregn-4-ene-3,20-dione 3 was synthesized in 5 % overall yield with specific activity being 200–1250 Ci/mmol. [⁷⁶Br]16α,17α-[(R)-1′-α-(5-bromofurylmethylidene)dioxyl]-21-hydroxy-19-norpregn-4-ene-3,20-dione 3 demonstrated high PR-mediated uptake in the target tissue uterus (8.72±1.84 % ID/g at 1 h) that was reduced by a blocking dose of unlabeled progestin R5020, but the nonspecific uptake in blood and muscle (2.11±0.14 and 0.89±0.16 % ID/g at 1 h, respectively) was relatively high. [⁷⁶Br]16α,17α-[(R)-1′-α-(5-bromofurylmethylidene)dioxyl]-21-hydroxy-19-norpregn-4-ene-3,20-dione 3 was stable in whole rat blood in vitro, but it was not stable in vivo due to the fast metabolism that occurred in the liver, resulting in the formation of a more polar radioactive metabolite and free [⁷⁶Br]bromide. The level of free [⁷⁶Br]bromide in blood remained high during the experiment (2.11±0.14 % ID/g at 1 h and 1.52±0.24 % ID/g at 24 h). The tissue distribution of [⁷⁶Br]16α,17α-[(R)-1′-α-(5-bromofurylmethylidene)dioxyl]-21-hydroxy-19-norpregn-4-ene-3,20-dione 3 at 1 and 3 h was compared with that of the ¹⁸F analogs, [¹⁸F]FFNP fluoro furanyl norprogesterone (FFNP) 1 and ketal 2.

Conclusion

[⁷⁶Br]16α,17α-[(R)-1′-α-(5-bromofurylmethylidene)dioxyl]-21-hydroxy-19-norpregn-4-ene-3,20-dione 3 may have potential for imaging PR-positive breast tumors at early time points, but it is not suitable for imaging at later times or for radiotherapy.