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. 2008 Aug;35(6):655-63.
doi: 10.1016/j.nucmedbio.2008.05.001. Epub 2008 Jun 30.

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

Dong Zhou  1 , Terry L Sharp, Nicole M Fettig, Hsiaoju Lee, Jason S Lewis, John A Katzenellenbogen, Michael J Welch
Affiliations

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

Dong Zhou et al. Nucl Med Biol. 2008 Aug.

Abstract

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: 16alpha,17alpha-[(R)-1'-alpha-(5-[(76)Br]Bromofurylmethylidene)dioxyl]-21-hydroxy-19-norpregn-4-ene-3,20-dione ([(76)Br]16alpha,17alpha-[(R)-1'-alpha-(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: [(76)Br]16alpha,17alpha-[(R)-1'-alpha-(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. [(76)Br]16alpha,17alpha-[(R)-1'-alpha-(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. [(76)Br]16alpha,17alpha-[(R)-1'-alpha-(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 [(76)Br]bromide. The level of free [(76)Br]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 [(76)Br]16alpha,17alpha-[(R)-1'-alpha-(5-bromofurylmethylidene)dioxyl]-21-hydroxy-19-norpregn-4-ene-3,20-dione 3 at 1 and 3 h was compared with that of the (18)F analogs, [(18)F]FFNP fluoro furanyl norprogesterone (FFNP) 1 and ketal 2.

Conclusion: [(76)Br]16alpha,17alpha-[(R)-1'-alpha-(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.

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Figures

Figure 1
Figure 1
Comparison of the tissue biodistribution of [18F]1, [18F]2, and [76Br]3 at 1 h post-injection
Scheme 1
Scheme 1
Progestin 16α,17α-dioxolanes
Scheme 2
Scheme 2
Scheme for the radiolabeling of [76Br]3
See this image and copyright information in PMC

References

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