Synthesis of MMP inhibitor radiotracers [<sup>11</sup>C]methyl‐CGS 27023A and its analogs, new potential PET breast cancer imaging agents

Fei, Xiangshu; Zheng, Qi; Hutchins, Gary D.; Li, Xuan; Stone, K. Lee; Carlson, Kathy; Mock, Bruce H.; Winkle, Wendy L.; Glick-Wilson, Barbara E.; Miller, Kathy D.; Fife, Rose S.; Sledge, George W.; Sun, Hui; Carr, Raymond E.

doi:10.1002/jlcr.570

Cited by 35 publications

(20 citation statements)

References 32 publications

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“…102,103 Then, research groups focused on the development of several PET-compatible, mainly 11 C-and 18 F-labeled, CGS 25966 and CGS 27023A derivatives. [104][105][106][107] Preclinical evaluation of these tracers was either not successful 108 or not published. 104,105 Recently, novel fluorinated MMPIs, based on the lead structures, CGS 25966 and CGS 27023A, were synthesized and the inhibition potencies of the compounds were evaluated in in vitro MMP inhibition assays for MMP2, 8, 9, and 13.…”

Section: Nuclear Imaging Of Tumor Angiogenesismentioning

confidence: 99%

“…[104][105][106][107] Preclinical evaluation of these tracers was either not successful 108 or not published. 104,105 Recently, novel fluorinated MMPIs, based on the lead structures, CGS 25966 and CGS 27023A, were synthesized and the inhibition potencies of the compounds were evaluated in in vitro MMP inhibition assays for MMP2, 8, 9, and 13. With the exception of one compound, all fluorinated hydroxamates are still potent, broad-spectrum MMPIs (IC 50 ¼ 0.5-527 nM).…”

Section: Nuclear Imaging Of Tumor Angiogenesismentioning

confidence: 99%

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Radionuclide Imaging of Tumor Angiogenesis

Dijkgraaf

Boerman

2009

Cancer Biotherapy and Radiopharmaceuticals

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Angiogenesis is a multistep process regulated by pro- and antiangiogenic factors. In order to grow and metastasize, tumors need a constant supply of oxygen and nutrients. For growth beyond 1-2 mm in size, tumors are dependent on angiogenesis. Inhibition of angiogenesis is a new cancer treatment strategy that is now widely investigated clinically. Researchers have begun to search for objective measures that indicate pharmacologic responses to antiangiogenic drugs. Therefore, there is a great interest in techniques to visualize angiogenesis in growing tumors noninvasively. Several markers have been described that are preferentially expressed on newly formed blood vessels in tumors (alpha(v)beta(3) integrin, vascular endothelial growth factor, and its receptor, prostate-specific membrane antigen) and in the extracellular matrix surrounding newly formed blood vessels (extra domain B of fibronectin, Tenascin-C, matrix metalloproteinases, and Robo-4). Several ligands targeting these markers have been tested as a radiotracer for imaging angiogenesis in tumors. The potential of some of these tracers, such as radiolabeled cyclic RGD peptides and radiolabeled anti-PSMA antibodies, has already been tested in cancer patients, while for markers such as Robo-4, the ligand has not yet been identified. In this review, an overview on the currently used nuclear imaging probes for noninvasive visualization of tumor angiogenesis is given.

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Section: Nuclear Imaging Of Tumor Angiogenesismentioning

confidence: 99%

Section: Nuclear Imaging Of Tumor Angiogenesismentioning

confidence: 99%

Radionuclide Imaging of Tumor Angiogenesis

Dijkgraaf

Boerman

2009

Cancer Biotherapy and Radiopharmaceuticals

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“…Nevertheless, the authors described that the preparations of hydroxamic acids 12a and 12b were characterised by low radiochemical yields, long reaction times and complicated purification procedures that prevented a reliable routine production and further in vitro and in vivo evaluations [118,119]. These drawbacks could be circumvented by aiming at the alternative lead structure of a hydroxamic acid methylester.…”

Section: Radiolabelled Mmpis: Synthesis In Vitro and In Vivo Evaluationmentioning

confidence: 99%

“…Although the labelled MMPIs 12c-r were synthesised as potential PETtracers for breast cancer, in vivo evaluations were not published [119][120][121]. In contrast, MMPI 12s was applied to two animal models of breast cancer, MCF-7 xenograft transfected with IL-1 and MDA-MB-435 xenograft in athymic mice.…”

Section: Radiolabelled Mmpis: Synthesis In Vitro and In Vivo Evaluationmentioning

confidence: 99%

Molecular Imaging of Matrix Metalloproteinases In Vivo Using Small Molecule Inhibitors for SPECT and PET

Wagner

Breyholz²,

Faust³

et al. 2006

CMC

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Matrix metalloproteinases (MMPs) are a family of zinc- and calcium-dependent secreted or membrane anchored endopeptidases. MMPs are involved in many physiological processes but also take part in the pathophysiological mechanisms responsible for a wide range of diseases. Pathological expression and activation of MMPs are associated with cancer, atherosclerosis, stroke, arthritis, periodontal disease, multiple sclerosis and liver fibrosis. Thus, noninvasive visualisation and quantification of MMP activity in vivo are of great interest in basic research and clinical application. This can be achieved by scintigraphic molecular imaging techniques such as single photon emission computed tomography (SPECT) and positron emission tomography (PET) provided suitable radiolabelled tracers exist, e.g. radioactive inhibitors of matrix metalloproteinases (MMPIs). The approach to monitor MMP activity in vivo using radiolabelled small molecule inhibitors suitable for SPECT and PET is summarised in this review. Briefly, latest advances in scintigraphic imaging are introduced and followed by a report about the enzyme class of MMPs. The involvement of MMPs in cancer and atherosclerosis is exemplified and small molecule MMPIs are classified. Subsequently, the development of radiolabelled small molecule MMPIs, their synthesis and in vitro and in vivo evaluation is reviewed. Finally, an outlook on the clinical potential of labelled MMPIs in diagnostic algorithms is given.

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“…[47–50] However, [ 18 F]-FESAHA is — to the best of the authors’ knowledge given extensive literature searches — the first radiotracer (1) to employ this particular synthetic route to a hydroxamic acid and (2) incorporate the hydroxamic acid after the 18 F radionuclide in a simple one-pot synthesis.…”

Section: Introductionmentioning

confidence: 99%

The synthesis and evaluation of N1-(4-(2-[18F]-fluoroethyl)phenyl)-N8-hydroxyoctanediamide ([18F]-FESAHA), A PET radiotracer designed for the delineation of histone deacetylase expression in cancer

Zeglis

Pillarsetty

Divilov

et al. 2011

Nuclear Medicine and Biology

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Introduction-Given the significant utility of suberoylanilide hydroxamic acid (SAHA) in chemotherapeutic protocols, a PET tracer that mimics the histone deacetylase (HDAC) inhibition of SAHA could be a valuable tool in the diagnosis, treatment planning, and treatment monitoring of cancer. Here, we describe the synthesis, characterization, and evaluation of N 1 -(4-(2-[ 18 F]-fluoroethyl)phenyl)-N 8 -hydroxyoctanediamide ([ 18 F]-FESAHA), a PET tracer designed for the delineation of HDAC expression in cancer. Methods-FESAHA was synthesized and biologically characterized in vivo and in vitro.[ 18 F]-FESAHA was then synthesized in high radiochemical purity, and the logP and serum stability of the radiotracer were determined. In vitro cellular uptake experiments and acute biodistribution and small animal PET studies were performed with [ 18 F]-FESAHA in mice bearing LNCaP xenografts. Results-[18 F]-FESAHA was synthesized in high radiochemical purity via an innovative onepot procedure. Enzymatic inhibition assays illustrated that FESAHA is a potent HDAC inhibitor, with IC 50 values from 3 nM to 1.7 μM against the eleven HDAC subtypes. Cell proliferation experiments revealed that the cytostatic properties of FESAHA very closely resemble those of SAHA in both LNCaP cells and PC-3 cells. Acute biodistribution and PET imaging experiments revealed tumor uptake of [ 18 F]-FESAHA and substantially higher values in the small intestine, kidneys, liver, and bone.Conclusion-The significant non-tumor background uptake of [ 18 F]-FESAHA presents a substantial obstacle to the use of the radiotracer as an HDAC expression imaging agent. The study at hand, however, does present a number of lessons critical to both the synthesis of hydroxamic acid containing PET radiotracers and imaging agents aimed at delineating HDAC expression.

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Synthesis of MMP inhibitor radiotracers [¹¹C]methyl‐CGS 27023A and its analogs, new potential PET breast cancer imaging agents

Cited by 35 publications

References 32 publications

Radionuclide Imaging of Tumor Angiogenesis

Radionuclide Imaging of Tumor Angiogenesis

Molecular Imaging of Matrix Metalloproteinases In Vivo Using Small Molecule Inhibitors for SPECT and PET

The synthesis and evaluation of N1-(4-(2-[18F]-fluoroethyl)phenyl)-N8-hydroxyoctanediamide ([18F]-FESAHA), A PET radiotracer designed for the delineation of histone deacetylase expression in cancer

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Synthesis of MMP inhibitor radiotracers [11C]methyl‐CGS 27023A and its analogs, new potential PET breast cancer imaging agents

Cited by 35 publications

References 32 publications

Radionuclide Imaging of Tumor Angiogenesis

Radionuclide Imaging of Tumor Angiogenesis

Molecular Imaging of Matrix Metalloproteinases In Vivo Using Small Molecule Inhibitors for SPECT and PET

The synthesis and evaluation of N1-(4-(2-[18F]-fluoroethyl)phenyl)-N8-hydroxyoctanediamide ([18F]-FESAHA), A PET radiotracer designed for the delineation of histone deacetylase expression in cancer

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Synthesis of MMP inhibitor radiotracers [¹¹C]methyl‐CGS 27023A and its analogs, new potential PET breast cancer imaging agents