TY - JOUR
T1 - Evaluation of a bromine-76-labeled progestin 16α,17α-dioxolane for breast tumor imaging and radiotherapy
T2 - in vivo biodistribution and metabolic stability studies
AU - Zhou, Dong
AU - Sharp, Terry L.
AU - Fettig, Nicole M.
AU - Lee, Hsiaoju
AU - Lewis, Jason S.
AU - Katzenellenbogen, John A.
AU - Welch, Michael J.
N1 - Funding Information:
This work was supported by the DOE (DE FG02 86ER60401 to JAK and DE FG02-84ER-60218 to MJW) and the NIH (PHS 2R01 CA25836 to JAK).
PY - 2008/8
Y1 - 2008/8
N2 - 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 Po/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.
AB - 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 Po/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.
KW - Br-76 radiolabeling
KW - PET breast tumor imaging
KW - Progesterone receptor
KW - Radiotherapy
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U2 - 10.1016/j.nucmedbio.2008.05.001
DO - 10.1016/j.nucmedbio.2008.05.001
M3 - Article
C2 - 18678350
AN - SCOPUS:48349103001
SN - 0969-8051
VL - 35
SP - 655
EP - 663
JO - Nuclear Medicine and Biology
JF - Nuclear Medicine and Biology
IS - 6
ER -