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The ability to accurately and easily locate sentinel lymph nodes (LNs) with noninvasive imaging methods would assist in tumor staging and patient management. For this purpose, we developed a lymphatic imaging agent by mixing fluorine-18 aluminum fluoridelabeled NOTA (1,4,7-triazacyclononane-N,N',N"-triacetic acid)-conjugated truncated Evans blue (18F-AlF-NEB) and Evans blue (EB) dye. After local injection, both 18F-AlF-NEB and EB form complexes with endogenous albumin in the interstitial fluid and allow for visualizing the lymphatic system. Positron emission tomography (PET) and/or optical imaging of LNs was performed in three different animal models including a hind limb inflammation model, an orthotropic breast cancer model, and a metastatic breast cancer model. In all three models, the LNs can be distinguished clearly by the apparent blue color and strong fluorescence signal fromEB aswell as a high-intensity PET signal from 18F-AlF-NEB. The lymphatic vessels between the LNs can also be optically visualized. The easy preparation, excellent PET and optical imaging quality, and biosafety suggest that this combination of 18F-AlF-NEB and EB has great potential for clinical application to map sentinel LNs and provide intraoperative guidance. [ABSTRACT FROM AUTHOR]

Abstract: The automated radiochemical synthesis of N-[2-(4-[18F]fluorobenzamido)ethyl]maleimide ([18F]FBEM, IUPAC name: N-maleoylethyl-4-[18F]fluorobenzamide), a prosthetic group for radiolabeling the free sulfhydryl groups of peptides and proteins, is herein described. 4-[18F]fluorobenzoic acid was first prepared by nucleophilic displacement of a trimethylammonium moiety on a pentamethylbenzyl benzoate ester with [18F]fluoride. In the second step the ester was cleaved under acidic conditions. Finally, 4-[18F]fluorobenzoic acid was coupled to N-(2-aminoethyl)maleimide using diethylcyanophosphate and diisopropylethyl amine. Following high-performance liquid chromatography (HPLC) purification, [18F]FBEM was obtained in 17.3±7.1% yield (not decay corrected) in approximately 95min. Isolation from the HPLC eluate and preparation for subsequent use, which was conducted manually, required an additional 10–15min. The measured specific activity for three batches was 181.3, 251.6, and 351.5GBq/μmol at the end of bombardment (EOB). [ABSTRACT FROM AUTHOR]

The expression of human epidermal growth factor receptor-2 (HER2) receptors in cancers is correlated with a poor prognosis. If assessed in vivo, it could be used for selection of appropriate therapy for individual patients and for monitoring of the tumor response to targeted therapies. We have radiolabeled a HER2-binding Affibody molecule with fluorine-18 for in vivo monitoring of the HER2 expression by positron emission tomography (PET). The HER2-binding ZHER2:342–Cys Affibody molecule was conjugated with N-2-(4-[18F]fluorobenzamido)ethyl]maleimide ([18F]FBEM). The in vitro binding of the resulting radioconjugate was characterized by receptor saturation and competition assays. For in vivo studies, the radioconjugate was injected into the tail vein of mice bearing subcutaneous HER2-positive or HER2-negative tumors. Some of the mice were pre-treated with non-labeled ZHER2:342−Cys. The animals were sacrificed at different times post-injection, and the radioactivity in selected tissues was measured. PET images were obtained using an animal PET scanner. In vitro experiments indicated specific, high-affinity binding to HER2. PET imaging revealed a high accumulation of the radioactivity in the tumor as early as 20 min after injection, with a plateau being reached after 60 min. These results were confirmed by biodistribution studies demonstrating that, as early as 1 h post-injection, the tumor to blood concentration ratio was 7.5 and increased to 27 at 4 h. Pre-saturation of the receptors with unlabeled ZHER2:342–Cys lowered the accumulation of radioactivity in HER2-positive tumors to the levels observed in HER2-negative ones. Our results suggest that the [18F]FBEM-ZHER2:342 radioconjugate can be used to assess HER2 expression in vivo. [ABSTRACT FROM AUTHOR]

The racemate 1, ((+/-)-(5-Chloro-2-methoxyphenyl)-1,3-dihydro-3-fluoro-6-(trifluoromethyl)- 2H-indol-2-one), is a potent, specific and novel opener of cloned large-conductance, calcium-activated (maxi-K) potassium channels. One of its enantiomers, BMS-204352 (MaxiPost™), is undergoing clinical evaluation for efficacy in patients with suspected acute stroke. In the current study, we have prepared [18F]-labeled 1 using a silver assisted nucleophilic substitution to examine its distribution and disposition in the rat, with particular emphasis on the brain. Biodistribution studies in rats confirm that brain uptake is rapid and occurs at high levels, and indicate that a major fraction of the compound in the brain does not accumulate by a specific, saturable mechanism. [Copyright &y& Elsevier]

In the process of developing [ 18 F]FBEM coupled target peptide, we have instituted a robust automated synthesis of [ 18 F]FBEM, a sulfhydryl (-SH) site specific agent for radiolabeling of peptides and proteins. The radiosynthesis generated 1.67–3.89 GBq (45.1–105.1 mCi, 7.5–18.8% non-decay corrected yield) of [ 18 F]FBEM from 22.2 GBq (600 mCi) of starting [ 18 F]fluoride with molar activity of 31.8 ± 5.3 GBq/µmol (0.86 ± 0.14 mCi/nmol) (n = 3) at the end of synthesis. Radiochemical purity was greater than 98%, and total synthesis time was ~90 min. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: To evaluate the usefulness of [18F]-6-fluorodopamine ([18F]-DA) and [18F]-L-6-fluoro-3,4-dihydroxyphenylalanine ([18F]-DOPA) positron emission tomography (PET) in the detection of subcutaneous (s.c.) and metastatic pheochromocytoma in mice; to assess the expression of the norepinephrine transporter (NET) and vesicular monoamine transporters 1 and 2 (VMAT1 and VMAT2), all important for [18F]-DA and [18F]-DOPA uptake. Furthermore, to compare tumor detection by micro-computed tomography (microCT) to magnetic resonance imaging (MRI) in individual mouse. Methods: SUVmax values were calculated from [18F]-DA and [18F]-DOPA PET, tumor-to-liver ratios (TLR) were obtained and expression of NET, VMAT1 and VMAT2 was evaluated. Results: [18F]-DA detected less metastatic lesions compared to [18F]-DOPA. TLR values for liver metastases were 2.26–2.71 for [18F]-DOPA and 1.83–2.83 for [18F]-DA. A limited uptake of [18F]-DA was found in s.c. tumors (TLR=0.22-0.27) compared to [18F]-DOPA (TLR=1.56-2.24). Overall, NET and VMAT2 were expressed in all organ and s.c. tumors. However, s.c. tumors lacked expression of VMAT1. We confirmed [18F]-DA''s high affinity for the NET for its uptake and VMAT1 and VMAT2 for its storage and retention in pheochromocytoma cell vesicles. In contrast, [18F]-DOPA was found to utilize only VMAT2. Conclusion: MRI was superior in the detection of all organ tumors compared to microCT and PET. [18F]-DOPA had overall better sensitivity than [18F]-DA for the detection of metastases. Subcutaneous tumors were localized only with [18F]-DOPA, a finding that may reflect differences in expression of VMAT1 and VMAT2, perhaps similar to some patients with pheochromocytoma where [18F]-DOPA provides better visualization of lesions than [18F]-DA. [Copyright &y& Elsevier]

Abstract: Tumors expressing the chemokine receptor CXCR4 have been reported to be more aggressive and to produce more metastatic seeding in specific organs, such as the bone marrow. However, evaluation of tumors for CXCR4 expression requires testing of ex vivo biopsy samples, and is not routinely done in cancer management. In prior work to address this issue, we and others have developed tracers for positron emission tomography (PET) that targeted CXCR4, but in addition to binding to CXCR4 these tracers also bound to red blood cells (and to other unrelated targets) in vivo. Here we report two new tracers based on the CXCR4 peptide antagonist 4F-benzoyl-TN14003 (T140) that bind to CXCR4, but not to undesired targets. These tracers, NOTA-NFB and DOTA-NFB, show slight reductions in both 1) binding affinities for CXCR4 and 2) inhibition of CXCL12 induced migration, compared to T140, in vitro. Both NOTA-NFB and DOTA-NFB specifically accumulate in CXCR4-positive, but not CXCR4-negative, tumor xenografts in mice and allow clear visualization of CXCR4 expression by PET. Evaluation of NOTA-NFB and DOTA-NFB for their potential to mobilize immune cells and progenitor cells from the bone marrow to the peripheral blood revealed slightly reduced, but still comparable, results to the parent molecule T140. The tracers reported here may allow the evaluation of CXCR4 expression in primary tumors and metastatic nodules, and enable better informed, more personalized treatment for patients with cancer. [Copyright &y& Elsevier]

Abstract: CXCR4 is a chemokine receptor which has been shown to be exploited by various tumors for increased survival, invasion, and homing to target organs. We developed a one step radiosynthesis for labeling the CXCR4-specific antagonist AMD3100 with Cu-64 to produce 64 Cu-AMD3100 with a specific activity of 11.28Ci/μmol (417GBq/μmol) at the end of radiosynthesis. Incorporation of Cu(II) ion into AMD3100 did not change its ability to inhibit cellular migration in response to the (only) CXCR4 ligand, SDF-1/CXCL12. 64 Cu-AMD3100 binding affinity to CXCR4 was found to be 62.7μM. Biodistribution of 64 Cu-AMD3100 showed accumulation in CXCR4-expressing organs and tissues, a renal clearance pathway, and an anomalous specific accumulation in the liver. We conclude that 64 Cu-AMD3100 exhibits promise as a potential PET imaging agent for visualization of CXCR4-positive tumors and metastases and might be used to guide and monitor anti-CXCR4 tumor therapy. [Copyright &y& Elsevier]

Abstract: A positron-emitting paclitaxel (PAC) derivative could allow in vivo measurement of multidrug resistance in tumors and, therefore, predict a potential chemotherapeutic benefit to patients. [18F]Paclitaxel was produced using a 2-reaction vessel automated synthesizer followed by HPLC purification. Optimized reaction conditions resulted in radiochemical yields of 21.2±9.6% at end of bombardment, radiochemical purity >99%, and specific activity of 159±43GBq/μmol. [18F]Paclitaxel activities of 1.33±0.729GBq () were obtained in sterile, pyrogen-free solution for IV administration. [Copyright &y& Elsevier]

Metal-organic framework (MOF) nanoparticles have shown great potential as carrier platforms in theranostic applications. However, their poor physiological stability in phosphate-based media has limited their biological applications. Here, we studied the dissociation of MOF nanoparticles under physiological conditions, both in vitro and in vivo , and developed an in situ polymerization strategy on MOF nanoparticles for enhanced stability under physiological conditions and stimulus-responsive intracellular drug release. With polymer wrapped on the surface serving as a shield, the nanoscale MOFs were protected from decomposition by phosphate ions or acid and prevented the loaded cargos from leaking. An in vivo positron emission tomography (PET) study of 64Cu-labelled porphyrinic MOF indicated prolonged circulation time of the in situ polymerized MOF nanoparticles and greater tumor accumulation than unmodified MOF nanoparticles. With enhanced stability, cargos loaded into MOF nanoparticles or prodrugs conjugated on the surface can be efficiently delivered and released upon stimulus-responsive cleavage. [ABSTRACT FROM AUTHOR]