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

• Published in: Nuclear medicine and biology 2008-08, Vol.35 (6), p.655-663
• Main Authors: Zhou, D, Sharp, T L, Fettig, N M, Lee, H, Lewis, J S, Katzenellenbogen, JA, Welch, MJ
• Format: Article
• Language: English
• ISSN: 0969-8051
• DOI: 10.1016/j.nucmedbio.2008.05.001

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. 16 alpha , 17 alpha -[(R)-1'- alpha -(5- [ super(76)Br]Bromofurylmethylidene)dioxyl] similar to 21-hydroxy-19-norpregn-4-ene-3, 20-dione ([ super(76)Br]16 alpha , 17 alpha -[(R)-1'- alpha -(5-bromofuryhnethylidene)dioxyl]- 21-hydroxy-19-norpregn-4-ene-3, 20-dione (3)), a PR ligand with relative binding affinity (RBA)=65 and log P sub(o/w)=5.09 plus or minus 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. [ super(76)Br]16 alpha , 17 alpha -[(R)-1'- alpha -(5-bromofuryhnethylidene)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. [ super(76)Br]16 alpha , 17 alpha -[(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 plus or minus 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 plus or minus 0.14 and 0.89 plus or minus 0.16 %ID/g at 1 h, respectively) was relatively high. [ super(76)Br]16 alpha , 17 alpha -[(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 [ super(76)Br]bromide. The level of free [ super(76)Br]bromide in blood remained high during the experiment (2.11 plus or minus 0.14 %ID/g at 1 h and 1.52 plus or minus 0.24 %ID/g at 24 h). The tissue distribution of [ super(76)Br]16 alpha , 17 alpha -[(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 super(18)F analogs, [ super(I8)F]FFNP fluoro furanyl norprogesterone (FFNP) 1 and ketal 2. [ super(76)Br]16 alpha , 17 alpha -[(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.