[Show abstract][Hide abstract] ABSTRACT: Previous reports have designated the labeled derivatives of [4-(phenylamino)-quinazoline-6-yl]-amide group as the most promising EGFR-PET imaging agent candidates. To further improve tracer qualifications and increase stability and solubility, additional derivatives of this group substituted at the 7-position with various lengths of fluoro-polyethyleneglycol (F-PEG) chains were synthesized. These novel derivatives inhibited EGFR autophosphorylation with IC(50) values of 5-40 nM. The compounds were successfully labeled with fluorine-18 at the PEG chain via a three-step radiosynthesis route. The labeled final products were obtained with a 13-32% decay corrected radiochemical yield, 99% radiochemical purity, and high specific activity.
Full-text · Article · Nov 2007 · Applied Radiation and Isotopes
[Show abstract][Hide abstract] ABSTRACT: Most prostate cancers are androgen dependent upon initial diagnosis. On the other hand, some very aggressive forms of prostate cancer were shown to have lost the expression of the androgen receptor (AR). Although the AR is routinely targeted in endocrine treatment, the clinical outcome remains suboptimal. Therefore, it is crucial to demonstrate the presence and activity of the AR in each case of prostate cancer, before and after treatment. While noninvasive positron emission tomography (PET) has the potential to determine AR expression of tumor cells in vivo, fully optimized PET imaging agents are not yet available. Based on molecular modeling, three novel derivatives of hydroxyflutamide (Compounds 1-3) were designed and synthesized. They contain an electron-rich group (dimethylamine) located on the methyl moiety, which may confer a better stability to the molecule in vivo. Compounds 1-3 have AR binding that is similar or higher than that of the currently used commercial drugs. An automated carbon-11 radiolabeling route was developed, and the compounds were successfully labeled with a 10-15% decay-corrected radiochemical yield, 99% radiochemical purity and a specific activity of 4Ci/mumol end of bombardment (n=15). These labeled biomarkers may facilitate the future quantitative molecular imaging of AR-positive prostate cancer using PET and may also allow for image-guided treatment of prostate cancer.
Full-text · Article · Sep 2006 · Nuclear Medicine and Biology
[Show abstract][Hide abstract] ABSTRACT: Overexpression of the EGFR has been linked to cell malignancy, metastasis and poor prognosis thus making it a target for several FDA approved drugs such as Gefitinib and Erlotinib. Unfortunately, these drugs have yielded suboptimal clinical results. In order to evaluate and monitor EGFR-targeted treatment response at the molecular level, several PET biomarkers have been developed. One of the lead irreversible inhibitors ð1Þ has been labeled with carbon-11, however the short half-life of this radioisotope limited the time window for in vivo studies. Compound 1 was successfully labeled with fluorine-18 via a multi-step radiosynthesis with 14% decay-corrected overall radiochemical yield, 98% radiochemical purity, specific activity of 1800 Ci/mmol ðn ¼ 10Þ at end of bombardment, and a total radiosynthesis time of 4 h including purification and formulation. ½ 18 F-1 will allow for prolonged in vivo studies including Micro-PET analysis of EGFR tumor-bearing animal models.
Preview · Article · May 2006 · Journal of Labelled Compounds
[Show abstract][Hide abstract] ABSTRACT: The in vivo results with our previously reported irreversible labeled inhibitor [(11)C]-ML03 suggested that more chemically stable inhibitors, labeled with a longer-lived radioisotope, could be better candidates for molecular imaging of epidermal growth factor receptor (EGFR) positive tumors. On the basis of this hypothesis we synthesized three new irreversible tyrosine kinase (TK) inhibitors with various chemical reactivities. The three new inhibitors were successfully labeled on the anilino moiety with [(124)I], starting with the 6-amino-4-[(3-tributylstannylphenyl)amino]-quinazoline (9) precursor. The cell-free results, obtained with these new irreversible inhibitors, indicated that compounds 5 (alpha-chloro-acetamide derivative) and 6 (4-dimethylamino-but-2-enoic amide derivative) possessed high potencies toward the EGFR with an irreversible inhibition effect. Compound 4 (alpha-methoxy-acetamide derivative) was found to be less potent, with only a partially irreversible effect. The high potency of compounds 5 and 6 toward the EGFR establishes their potential as PET agents for molecular imaging of EGFR positive tumors. Their prospect as PET biomarkers is further being investigated.
[Show abstract][Hide abstract] ABSTRACT: We have previously reported of labeled reversible and irreversible EGFR inhibitors, such as 4-(3,4-dichloro-6-fluoroanilino)-6,7-dimethoxyquinazoline (ML01) and 6-acrylamido-4-(3,4-dichloro-6-fluoroanilino)quinazoline (ML03), to be suboptimal as imaging agents. On the basis of these studies, a new generation of novel, more chemically stable irreversible inhibitors was labeled with carbon-11 as potential positron emission tomography (PET) biomarkers for molecular imaging of epidermal growth factor receptor (EGFR)-positive tumors. In these new labeled, irreversible inhibitors the acryl-amide group at the 6-position of the quinazoline ring was replaced with a 4-dimethylamino-but-2-enoic amide. The nonlabeled compounds were evaluated in vitro to determine their EGFR autophosphorylation IC(50) values. The IC(50) values indicated that these new irreversible compounds possess similar potencies towards the EGFR, as the parent compound, ML03. These compounds were labeled with carbon-11 at the dimethylamine moiety, using the well known labeling reagent C-11 MeI. The labeling procedure was automated using a commercial module. The final products were obtained with 10% decay corrected radiochemical yield, 99% radiochemical purity, 96% chemical purity, and a high specific activity of 2.7 Ci/micromol EOB. The high potency of these new labeled bioprobes towards the EGFR establishes their potential to serve as PET agents for molecular imaging of EGFR-positive tumors.
Full-text · Article · Jun 2004 · Nuclear Medicine and Biology