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Phosphoramidate derivatives of hydroxysteroids as inhibitors of prostate-specific membrane antigen.

ABSTRACT: Prostate-specific membrane antigen (PSMA) is a membrane-bound cell surface peptidase which is over-expressed in prostate cancer cells. The enzymatic activities of PSMA are understood but the role of the enzyme in prostate cancer remains conjectural. We previously confirmed the existence of a hydrophobic binding site remote from the enzyme's catalytic center. To explore the specificity and accommodation of this binding site, we prepared a series of six glutamate-containing phosphoramidate derivatives of various hydroxysteroids (1a-1f). The inhibitory potencies of the individual compounds of the series were comparable to a simple phenylalkyl analog (8), and in all cases IC50 values were sub-micromolar. Molecular docking was used to develop a binding model for these inhibitors and to understand their relative inhibitory potencies against PSMA.

SUBMITTER: Wu LY

PROVIDER: S-EPMC2254654 | biostudies-literature | 2008 Jan

REPOSITORIES: biostudies-literature

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Phosphoramidate derivatives of hydroxysteroids as inhibitors of prostate-specific membrane antigen.

Wu Lisa Y LY Do Jacinda C JC Kazak Marat M Page Helen H Toriyabe Yoko Y Anderson Marc O MO Berkman Clifford E CE

Bioorganic & medicinal chemistry letters 20071030 1

Prostate-specific membrane antigen (PSMA) is a membrane-bound cell surface peptidase which is over-expressed in prostate cancer cells. The enzymatic activities of PSMA are understood but the role of the enzyme in prostate cancer remains conjectural. We previously confirmed the existence of a hydrophobic binding site remote from the enzyme's catalytic center. To explore the specificity and accommodation of this binding site, we prepared a series of six glutamate-containing phosphoramidate derivat ...[more]

PMID: 18023582

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Project description:Agents targeting prostate-specific membrane antigen (PSMA) comprise a rapidly emerging class of radiopharmaceuticals for diagnostic imaging of prostate cancer. Unlike most other PSMA agents with a urea backbone, CTT1057 is based on a phosphoramidate scaffold that irreversibly binds to PSMA. We conducted a first-in-humans phase I study of CTT1057 in patients with localized and metastatic prostate cancer. Methods: Two patient cohorts were recruited. Cohort A patients had biopsy-proven localized prostate cancer preceding radical prostatectomy, and cohort B patients had metastatic castration-resistant prostate cancer. Cohort A patients were imaged at multiple time points after intravenous injection with 362 ± 8 MBq of CTT1057 to evaluate the kinetics of CTT1057 and estimate radiation dose profiles. Mean organ-absorbed doses and effective doses were calculated. CTT1057 uptake in the prostate gland and regional lymph nodes was correlated with pathology, PSMA staining, and the results of conventional imaging. In cohort B, patients were imaged 60-120 min after injection of CTT1057. PET images were assessed for overall image quality, and areas of abnormal uptake were contrasted with conventional imaging. Results: In cohort A (n = 5), the average total effective dose was 0.023 mSv/MBq. The kidneys exhibited the highest absorbed dose, 0.067 mGy/MBq. The absorbed dose of the salivary glands was 0.015 mGy/MBq. For cohort B (n = 15), CTT1057 PET detected 97 metastatic lesions, and 44 of 56 bone metastases detected on CTT1057 PET (78.5%) were also detectable on bone scanning. Eight of 32 lymph nodes positive on CTT1057 PET (25%) were enlarged by size criteria on CT. Conclusion: CTT1057 is a promising novel phosphoramidate PSMA-targeting 18F-labeled PET radiopharmaceutical that demonstrates similar biodistribution to urea-based PSMA-targeted agents, with lower exposure to the kidneys and salivary glands. Metastatic lesions are detected with higher sensitivity on CTT1057 imaging than on conventional imaging. Further prospective studies with CTT1057 are warranted to elucidate its role in cancer imaging.

Project description:(86)Y (half-life = 14.74 h, 33% ?(+)) is within an emerging class of positron-emitting isotopes with relatively long physical half-lives that enables extended imaging of biologic processes. We report the synthesis and evaluation of 3 low-molecular-weight compounds labeled with (86)Y for imaging the prostate-specific membrane antigen (PSMA) using PET. Impetus for the study derives from the need to perform dosimetry estimates for the corresponding (90)Y-labeled radiotherapeutics.Multistep syntheses were used in preparing (86)Y- 4: - 6: PSMA inhibition constants were evaluated by competitive binding assay. In vivo characterization using tumor-bearing male mice was performed by PET/CT for (86)Y- 4: - 6: and by biodistribution studies of (86)Y- 4: and (86)Y- 6: out to 24 h after injection. Quantitative whole-body PET scans were recorded to measure the kinetics for 14 organs in a male baboon using (86)Y- 6 RESULTS: Compounds (86)Y- 4: - 6: were obtained in high radiochemical yield and purity, with specific radioactivities of more than 83.92 GBq/?mol. PET imaging and biodistribution studies using PSMA-positive PC-3 PIP and PSMA-negative PC-3 flu tumor-bearing mice revealed that (86)Y- 4-6: had high site-specific uptake in PSMA-positive PC-3 PIP tumor starting at 20 min after injection and remained high at 24 h. Compound (86)Y- 6: demonstrated the highest tumor uptake and retention, with 32.17 ± 7.99 and 15.79 ± 6.44 percentage injected dose per gram (%ID/g) at 5 and 24 h, respectively. Low activity concentrations were associated with blood and normal organs, except for the kidneys, a PSMA-expressing tissue. PET imaging in baboons reveals that all organs have a 2-phase (rapid and slow) clearance, with the highest uptake (8 %ID/g) in the kidneys at 25 min. The individual absolute uptake kinetics were used to calculate radiation doses using the OLINDA/EXM software. The highest mean absorbed dose was received by the renal cortex, with 1.9 mGy per MBq of (86)Y- 6:Compound (86)Y- 6: is a promising candidate for quantitative PET imaging of PSMA-expressing tumors. Dosimetry calculations indicate promise for future (90)Y or other radiometals that could use a similar chelator/scaffold combination for radiopharmaceutical therapy based on the structure of 6.

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Phosphoramidate derivatives of hydroxysteroids as inhibitors of prostate-specific membrane antigen.

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Phosphoramidate derivatives of hydroxysteroids as inhibitors of prostate-specific membrane antigen.

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