Comparative breast tumor imaging and comparative in vitro metabolism of 16α-[18F]Fluoroestradiol-17β and 16β-[18f]fluoromoxestrol in isolated hepatocytes

Jonson, Stephanie D.; Bonasera, Thomas A.; Dehdashti, Farrokh; Cristel, Michael E; Katzenellenbogen, John A.; Welch, Michael J.

doi:10.1016/s0969-8051(98)00079-1

Cited by 49 publications

(49 citation statements)

References 30 publications

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“…A P value less than or equal to 0.05 was considered statistically significant. Figure 1 shows the typical biodistribution of 4FMFES over time, as assessed with 4 sequential rapid PET acquisitions over 2 h. Variable amounts of activity are deposited along the veins of the injected arm, proximal to the site of injection, as seen with other ER imaging agents (11). The liver showed a rapid and intense uptake, which decreased slowly over time as the massive biliary elimination occurred.…”

Section: Methodsmentioning

confidence: 99%

Assessment of Human Biodistribution and Dosimetry of 4-Fluoro-11β-Methoxy-16α-¹⁸F-Fluoroestradiol Using Serial Whole-Body PET/CT

Beauregard¹,

Croteau²,

Ahmed³

et al. 2008

J Nucl Med

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4-Fluoro-11b-methoxy-16a-18 F-fluoroestradiol (4FMFES) is a newly developed radiolabeled estradiol analog for PET imaging of estrogen receptors (ERs) that shows improved target-to-background ratios, compared with 16a-18 F-fluoroestradiol (FES), in small-animal models. The aim of this study was to assess the biodistribution, dosimetry, and safety of 4FMFES in healthy women. Methods: Ten healthy subjects (6 pre-and 4 postmenopausal women) who had fasted were injected with 66-201 MBq of 4FMFES at a high effective specific activity (median, 251 GBq/mmol). During a 2-h period, each subject underwent 4 serial rapid PET acquisitions and 2 low-dose CT acquisitions on a PET/CT camera. Volumes of interest were drawn over source organs for each PET acquisition, allowing the calculation of time-activity curves, residence times, and radiation dosimetry estimates. Serial blood samples were obtained to measure blood and plasma activity clearance. 4FMFES safety was assessed by blood and urine analyses and vital-sign monitoring. Results: A 4FMFES injection was well tolerated in all subjects. The liver showed high uptake, and the hepatobiliary excretion was massive. Little urinary excretion occurred. Uterus uptake was visualized in all subjects and remained relatively constant over time (maximum and mean standardized uptake values at 60 min were 5.34 6 3.32 and 2.68 6 1.89, respectively). Background activity was low and decreased over time, resulting in an increasing uterus-to-background ratio (12.1 6 2.2 at 60 min). The critical organ was the gallbladder (0.80 6 0.51 mGy/MBq), followed by the upper large intestine (0.13 6 0.04 mGy/MBq), small intestine (0.12 6 0.04 mGy/MBq), and liver (0095 6 0.019 mGy/MBq). For a typical 4FMFES dose of 185 MBq, the effective dose was calculated at 4.82 6 0.70 mSv. Conclusion: 4FMFES is considered safe for use in humans, and its effective dose remains well within acceptable limits. The absorbed dose to the gallbladder was relatively high and could potentially be reduced by injecting 4FMFES in patients who had not fasted. 4FMFES showed a significant, potentially estrogen receptor-mediated uterus uptake in both pre-and postmenopausal subjects.

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Section: Methodsmentioning

confidence: 99%

Assessment of Human Biodistribution and Dosimetry of 4-Fluoro-11β-Methoxy-16α-¹⁸F-Fluoroestradiol Using Serial Whole-Body PET/CT

Beauregard¹,

Croteau²,

Ahmed³

et al. 2008

J Nucl Med

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“…Diagnostic imaging can be achieved by the administration of a suitably radiolabeled ligand that accumulates in the receptor-positive tumor, where it can be detected and quantified by imaging. Such images can sometimes be used to predict whether hormone therapy will be effective [1][2][3][4]. In a related manner, a hormone receptor ligand labeled with a radionuclide (e.g., an Auger electron emitting isotope) that accumulates in a tumor through a receptormediated uptake process can deliver a cytotoxic dose of high linear energy transfer (LET) radiation selectively to the tumor cells, ablating the tumor while limiting widespread radiation toxicity.…”

Section: Introductionmentioning

confidence: 99%

“…Diagnostic imaging of breast and prostate tumors by positron emission tomography (PET) is well established and has been achieved using steroids labeled with fluorine-18, such as 16α-[ 18 F]fluoroestradiol (FES) [3,4] for breast tumor imaging and 16β-[ 18 F]fluoro-5α-dihydrotestosterone (FDHT) [5,6] for prostate cancer imaging. Although a number of steroids labeled with bromine and iodine radioisotopes have been prepared [7][8][9][10][11][12] and studied, especially in terms of their potential for selective radiotherapy, their use in imaging studies, particularly in humans, has been more limited [12].…”

Section: Introductionmentioning

confidence: 99%

“…In this report, we describe the 76 Br radiolabeling of 3, the in vivo biodistribution and metabolic stability studies of 3 in estrogen-primed immature female Sprague-Dawley rats as a potential agent for breath tumor imaging and radiotherapy. 4 Br was dried in a 5 mL Wheaton V vial at 130°C under very gentle N 2 flow. At ambient temperature, 20 µL acetic acid and 0.5 mg 4 in 50 µL methanol were added, and the solution was vortexed before addition of 100 µL 2 : 1 hydrogen peroxide/acetic acid (pre-mixed for at least 4 hours).…”

Section: Introductionmentioning

confidence: 99%

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

Sharp

Fettig

Lee

et al. 2008

Nuclear Medicine and Biology

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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. Results-[ 76 Br]3 was synthesized in 5% overall yield with specific activity being 200~1250 Ci/ mmol. [ 76 Br]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 non-specific 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]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]3 at 1 and 3 hours was compared with that of the 18 F analogs, [ 18 F]FFNP 1 and ketal 2. Method-16α,17α-[(R)-1'-α-(5-[ Conclusion-[76 Br]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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“…In the rat (no SHBG), 16b-fluoromoxestrol appeared well protected from metabolism by its 11b and 17a substituents (compared with 16a-fluoroestradiol), and it demonstrated high uptake in the uterus. In humans (with SHBG), however, PET trials with 16b-fluoromoxestrol failed to detect a single estrogen receptor-positive tumor in the 3 patients with known estrogen receptor-positive status (26), suggesting again that when SHBG is present, SHBG binding is a prerequisite for good target tissue uptake.…”

mentioning

confidence: 99%

7α-¹⁸F-Fluoromethyl-Dihydrotestosterone and 7α-¹⁸F-Fluoromethyl-Nortestosterone: Ligands to Determine the Role of Sex Hormone–Binding Globulin for Steroidal Radiopharmaceuticals

Parent¹,

Dence²,

Sharp³

et al. 2008

J Nucl Med

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Sex hormone-binding globulin (SHBG) is believed to play a key role in steroidal radiopharmaceutical delivery to target tissues in humans. To better understand the action of SHBG, we have synthesized and tested in vivo 2 novel 18 F-labeled androgens: 7a-18 F-fluoromethyl-dihydrotestosterone (7a-18 F-FM-DHT) and 7a-18 F-fluoromethyl-nortestosterone (7a-18 F-FM-norT). Both 7a-18 F-FM-DHT and 7a-18 F-FM-norT have high affinity for the androgen receptor (AR); however, 7a-18 F-FM-DHT has a high affinity for SHBG, whereas 7a-18 F-FM-norT has a relatively low affinity. Methods: We developed an efficient radiochemical synthesis for both 7a-18 F-FM-DHT and 7a-18 F-FM-norT, producing them in good radiochemical yield and high specific activity. Biodistribution studies of both compounds were done on diethylstilbestrol-pretreated and DHT-blocked Sprague-Dawley male rats. Metabolism studies were done to determine the amount of intact ligand in the prostate. Results: We obtained 7a-18 F-FM-DHT and 7a-18 F-FM-norT in radiochemical yields of about 30% and radiochemical purities of greater than 99%. Rat biodistribution studies showed selective AR-mediated uptake in the prostate for both compounds. Both compounds showed relatively little defluorination, but the norT analog was more metabolically stable than the DHT analog. Conclusion: These studies show that 7a-18 F-FM-DHT and 7a-18 F-FM-norT have potential for use in human clinical imaging trials to evaluate more definitively the role of SHBG in radiotracer delivery of steroidal systems to target tissues.

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Comparative breast tumor imaging and comparative in vitro metabolism of 16α-[18F]Fluoroestradiol-17β and 16β-[18f]fluoromoxestrol in isolated hepatocytes

Cited by 49 publications

References 30 publications

Assessment of Human Biodistribution and Dosimetry of 4-Fluoro-11β-Methoxy-16α-¹⁸F-Fluoroestradiol Using Serial Whole-Body PET/CT

Assessment of Human Biodistribution and Dosimetry of 4-Fluoro-11β-Methoxy-16α-¹⁸F-Fluoroestradiol Using Serial Whole-Body PET/CT

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

7α-¹⁸F-Fluoromethyl-Dihydrotestosterone and 7α-¹⁸F-Fluoromethyl-Nortestosterone: Ligands to Determine the Role of Sex Hormone–Binding Globulin for Steroidal Radiopharmaceuticals

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Comparative breast tumor imaging and comparative in vitro metabolism of 16α-[18F]Fluoroestradiol-17β and 16β-[18f]fluoromoxestrol in isolated hepatocytes

Cited by 49 publications

References 30 publications

Assessment of Human Biodistribution and Dosimetry of 4-Fluoro-11β-Methoxy-16α-18F-Fluoroestradiol Using Serial Whole-Body PET/CT

Assessment of Human Biodistribution and Dosimetry of 4-Fluoro-11β-Methoxy-16α-18F-Fluoroestradiol Using Serial Whole-Body PET/CT

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

7α-18F-Fluoromethyl-Dihydrotestosterone and 7α-18F-Fluoromethyl-Nortestosterone: Ligands to Determine the Role of Sex Hormone–Binding Globulin for Steroidal Radiopharmaceuticals

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Resources

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Assessment of Human Biodistribution and Dosimetry of 4-Fluoro-11β-Methoxy-16α-¹⁸F-Fluoroestradiol Using Serial Whole-Body PET/CT

Assessment of Human Biodistribution and Dosimetry of 4-Fluoro-11β-Methoxy-16α-¹⁸F-Fluoroestradiol Using Serial Whole-Body PET/CT

7α-¹⁸F-Fluoromethyl-Dihydrotestosterone and 7α-¹⁸F-Fluoromethyl-Nortestosterone: Ligands to Determine the Role of Sex Hormone–Binding Globulin for Steroidal Radiopharmaceuticals