Rapid synthesis and in vitro and in vivo evaluation of folic acid derivatives labeled with fluorine-18 for PET imaging of folate receptor-positive tumors

Jammaz, I. Al; Al‐Otaibi, B.; Amer, Suad Bin; Okarvi, Subhani M.

doi:10.1016/j.nucmedbio.2011.03.004

Cited by 23 publications

(32 citation statements)

References 20 publications

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“…Therefore, it is expected that [ 68 Ga]NOTA-folate and [ 99m Tc]EC20 show similar renal uptake. Both tumor-to-kidney (0.31 ± 0.11) and tumor-to-liver ratios (12.43 ± 0.73) seem comparable to other, previously published data for other folate-targeted radiopharmaceuticals [3, 14, 28–34]. For a direct comparison, however, the individual compounds would have to be tested side-by-side.…”

Section: Discussionsupporting

confidence: 79%

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Development of a New Folate-Derived Ga-68-Based PET Imaging Agent

et al. 2017

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Purpose The folate receptor (FR) has emerged as an interesting diagnostic and therapeutic drug target with many potential applications in oncologic and inflammatory disorders. It was therefore the aim of this study to develop a folate-derived Ga-68-based positron emission tomography (PET) imaging tracer that is straightforward to radiolabel and could be broadly used in clinical studies. We validated its target binding affinity and specificity and compared it to [99mTc]EC20, the folate single-photon emission computed tomography (SPECT) imaging tracer that has been most extensively studied clinically so far. Procedures The new folic acid-derived PET imaging agent is linked via a polyethyleneglycol linker to the chelator 1,4,7-triazacyclononane-1,4,7-trisacetic acid (NOTA). This new compound, NOTA-folate, was labeled with gallium-68. We tested the probe’s stability in human plasma and its selectivity in vitro, using the FR-positive KB cell line as well as the FR-negative A549 cell line. The pharmacokinetic profile of [68Ga]NOTA-folate was evaluated in FR-positive KB mouse xenografts. Following intravenous injection of [68Ga]NOTA-folate (383 ± 53 µCi), PET/computed tomography (CT) imaging studies as well as biodistribution studies were performed using KB tumor-bearing mice (n = 3). In vitro as well as in vivo studies were performed in parallel with the SPECT imaging tracer [99mTc]EC20. Results In comparison to [99mTc]EC20 (radiochemical yield (RCY) = 82.0 ± 2.9 %, 91.8 ± 2.0 % purity), similar radiochemical yield (87.2 ± 6.9 %) and radiochemical purity (95.6 ± 1.8 %) could be achieved for [68Ga]NOTA-folate. For both tracers, we observed high affinity for FR-positive cells in vitro and high plasma stability. In PET/CT and biodistribution studies, [68Ga]NOTA-folate appeared to display slightly superior in vivo performance in comparison to [99mTc]EC20. In detail, 68Ga-NOTA-folate showed very good tumor uptake and retention (6.6 ± 1.1 %ID/g), relatively low kidney uptake (21.7 ± 1.1 %ID/g), and very low liver uptake (0.38 ± 0.08 %ID/g). In vivo blocking studies using a fivefold excess of EC20 reduced the tumor uptake to 2.5 ± 0.7 %ID/g, confirming receptor specific binding of [68Ga]NOTA-folate in vivo. Conclusion We validated a new Ga-68 folate-based PET imaging agent with excellent pharmacokinetics and tumor uptake. Based on a head-to-head comparison between both tracers, [68Ga]NOTA-folate is a suitable imaging probe for the delineation of FR-positive tumors and a promising candidate for clinical translation.

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Section: Discussionsupporting

confidence: 79%

“…As a matter of fact, numerous of folate-conjugated PET agents have already been proven to visualize FR-positive tumors in vivo [3, 28–31, 33–38]. In the past, different approaches were utilized for the synthesis of folate-based PET radiotracers.…”

Section: Discussionmentioning

confidence: 99%

Development of a New Folate-Derived Ga-68-Based PET Imaging Agent

et al. 2017

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“…In addition, PET probes using 18 F-folate derivatives have been developed for imaging FR-positive tumors (39). This imaging approach has also been used to identify inflamed joints in patients with rheumatoid arthritis (40). Together with our current study, available information suggests the feasibility of developing folate-based molecular imaging strategies based on these technologies that could be applied for monitoring and investigating pathologies of inflammatory lung diseases in humans.…”

Section: Nf-kb-dependent Inflammation Results In Increased Frb Expresmentioning

confidence: 65%

Molecular Imaging of Folate Receptor β–Positive Macrophages during Acute Lung Inflammation

Han

Zaynagetdinov

Yull³

et al. 2015

Am J Respir Cell Mol Biol

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Characterization of markers that identify activated macrophages could advance understanding of inflammatory lung diseases and facilitate development of novel methodologies for monitoring disease activity. We investigated whether folate receptor b (FRb) expression could be used to identify and quantify activated macrophages in the lungs during acute inflammation induced by Escherichia coli LPS. We found that FRb expression was markedly increased in lung macrophages at 48 hours after intratracheal LPS. In vivo molecular imaging with a fluorescent probe (cyanine 5 polyethylene glycol folate) showed that the fluorescence signal over the chest peaked at 48 hours after intratracheal LPS and was markedly attenuated after depletion of macrophages. Using flow cytometry, we identified the cells responsible for uptake of cyanine 5-conjugated folate as FRb 1 interstitial macrophages and pulmonary monocytes, which coexpressed markers associated with an M1 proinflammatory macrophage phenotype. These findings were confirmed using a second model of acute lung inflammation generated by inducible transgenic expression of an NF-kB activator in airway epithelium.Using CC chemokine receptor 2-deficient mice, we found that FRb 1 macrophage/monocyte recruitment was dependent on the monocyte chemotactic protein-1/CC chemokine receptor 2 pathway. Together, our results demonstrate that folate-based molecular imaging can be used as a noninvasive approach to detect classically activated monocytes/macrophages recruited to the lungs during acute inflammation.

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“…33–56 Our motivation for seeking yet another folate-targeted PET agent was prompted by the need to create an imaging agent that could meet the economic requirements for translation of a PET agent into the clinic. 18 F was selected ahead of 68 Ga not only because of the higher resolution images that it yields, 28, 57–59 but also because of the extensive production and distribution networks that already exists for 18 F. 58 Folate-NOTA-Al 18 F was preferred over earlier folate- 18 F conjugates for reasons that differ for each previous conjugate, including its higher specific activity, 39, 45, 47, 55 comparable or in some cases better radiochemical yield, 39, 40, 47, 49 and faster or simpler synthesis. 39, 40, 47, 49, 51 As a consequence, we propose that folate-NOTA-Al 18 F meets most of the requirements for eventual translation into human clinical trials.…”

Section: Discussionmentioning

confidence: 99%

Synthesis and Preclinical Evaluation of Folate-NOTA-Al¹⁸F for PET Imaging of Folate-Receptor-Positive Tumors

Chen

Meng²,

McQuade³

et al. 2016

Mol. Pharmaceutics

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Folate receptor-targeted PET radiotracers can potentially serve as versatile imaging agents for the diagnosis, staging, and prediction of response to therapy of patients with folate receptor (FR)-expressing cancers. Because current FR-targeted PET reagents can be compromised by complex labeling procedures, low specific activities, poor radiochemical yields or unwanted accumulation in FR negative tissues, we have undertaken to design an improved folate-PET agent that might be more amenable for clinical development. For this purpose, we have synthesized a folate-NOTAAl18F radiotracer and examined its properties both in vitro and in vivo. Methods Radiochemical synthesis of folate-NOTA-Al18F was achieved by incubating 18F− with AlCl3 for 2 min followed by heating in the presence of folate-NOTA for 15 min at 100 °C. Binding of folate-NOTA-Al18F to FR was quantitated in homogenates of KB and Cal51 tumor xenografts in the presence and absence of excess folic acid as a competitor. In vivo imaging was performed on nu/nu mice bearing either FR+ve (KB cell) or FR−ve (A549 cell) tumor xenografts, and specific accumulation of the radiotracer in tumor and other tissues was assessed by high-resolution micro-PET and ex vivo biodistribution in the presence and absence of excess folic acid. Image quality of folate-NOTA-Al18F was compared with that of 99mTc-EC20, a clinically established folate-targeted SPECT imaging agent. Results Total radiochemical synthesis and purification of folate-NOTA-Al18F was completed within 37 min, yielding a specific activity of 68.82±18.5 GBq/μmol, radiochemical yield of 18.6±4.5%, and radiochemical purity of 98.3±2.9%. Analysis of FR binding revealed a Kd of ~1.0 nM, and micro-PET imaging together with ex vivo biodistribution analyses demonstrated high FR-mediated uptake in an FR+ tumor and the kidneys. Conclusions Folate-NOTA-Al18F constitutes an easily prepared FR-targeted PET imaging agent with improved radiopharmaceutical properties and high specificity for folate receptor expressing tumors. Given its improved properties over 99mTc-EC20 (i.e. higher resolution, shorter image acquisition time, etc.), we conclude that folate-NOTA-Al18F constitutes a viable alternative to 99mTc-EC20 for use in identification, diagnosis, and staging of patients with FR-expressing cancers.

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Rapid synthesis and in vitro and in vivo evaluation of folic acid derivatives labeled with fluorine-18 for PET imaging of folate receptor-positive tumors

Cited by 23 publications

References 20 publications

Development of a New Folate-Derived Ga-68-Based PET Imaging Agent

Development of a New Folate-Derived Ga-68-Based PET Imaging Agent

Molecular Imaging of Folate Receptor β–Positive Macrophages during Acute Lung Inflammation

Synthesis and Preclinical Evaluation of Folate-NOTA-Al¹⁸F for PET Imaging of Folate-Receptor-Positive Tumors

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Rapid synthesis and in vitro and in vivo evaluation of folic acid derivatives labeled with fluorine-18 for PET imaging of folate receptor-positive tumors

Cited by 23 publications

References 20 publications

Development of a New Folate-Derived Ga-68-Based PET Imaging Agent

Development of a New Folate-Derived Ga-68-Based PET Imaging Agent

Molecular Imaging of Folate Receptor β–Positive Macrophages during Acute Lung Inflammation

Synthesis and Preclinical Evaluation of Folate-NOTA-Al18F for PET Imaging of Folate-Receptor-Positive Tumors

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Synthesis and Preclinical Evaluation of Folate-NOTA-Al¹⁸F for PET Imaging of Folate-Receptor-Positive Tumors