Synthesis and evaluation of 18F-labeled benzylguanidine analogs for targeting the human norepinephrine transporter

Zhang, Hanwen; Huang, Ruimin; Pillarsetty, Nagavarakishore; Thorek, Daniel L.J.; Vaidyanathan, Ganesan; Serganova, Inna; Blasberg, Ronald G.; Lewis, Jason S.

doi:10.1007/s00259-013-2558-9

Cited by 53 publications

(61 citation statements)

References 23 publications

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“…On the other hand, the uptake of [ 18 F]MFBG and [ 18 F]PFBG, in SK-N-SH cells and NET-transduced C6 cells, although considerably lower than that seen for radioiodinated MIBG, was higher compared to that seen for [ 18 F]FPOIBG [16, 17]. [ 18 F]FIBG, the best 18 F-labeled analogue of MIBG, demonstrated an uptake in SK-N-SH cells which was about 15% higher than that of the co-incubated n.c.a.…”

Section: Resultsmentioning

confidence: 92%

“…MFBG was shown to be a better analogue of MIBG than PFBG; however, its radiochemical synthesis was more difficult. Both analogues were inferior to MIBG with respect to uptake in NET-expressing SK-N-SH human neuroblastoma cells in vitro and myocardial uptake in normal mice in vivo; however, interest in [ 18 F]MFBG for imaging has recently been revived [17, 18]. Hypothesizing that the lackluster performance of [ 18 F]MFBG and [ 18 F]PFBG might be due to the lack an iodine substituent on its benzene ring, which may be essential for bioactivity, we synthesized 4-[ 18 F]fluoro-3-iodobenzylguanidine ([ 18 F]FIBG) that is essentially MIBG with an added fluorine [19].…”

Section: Introductionmentioning

confidence: 99%

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Synthesis and evaluation of 4-[18F]fluoropropoxy-3-iodobenzylguanidine ([18F]FPOIBG): A novel 18F-labeled analogue of MIBG

Vaidyanathan

McDougald

Koumarianou

et al. 2015

Nuclear Medicine and Biology

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Introduction Radioiodinated meta-iodobenzylguanidine (MIBG), a norepinephrine transporter (NET) substrate, has been extensively used as an imaging agent to study the pathophysiology of the heart and for the diagnosis and treatment of neuroendocrine tumors. The goal of this study was to develop an 18F-labeled analogue of MIBG that like MIBG itself could be synthesized in a single radiochemical step. Towards this end, we designed 4-fluoropropoxy-3-iodobenzylguanidine (FPOIBG). Methods Standards of FPOIBG and 4-fluoropropoxy-3-bromobenzylguanidine (FPOBBG) as well as their tosylate precursors for labeling with 18F, and a tin precursor for the preparation of radioiodinated FPOIBG were synthesized. Radiolabeled derivatives were synthesized by nucleophilic substitution and electrophilic iododestannylation from the corresponding precursors. Labeled compounds were evaluated for NET transporter recognition in in vitro assays using three NET-expressing cell lines and in biodistribution experiments in normal mice, with all studies performed in a paired-label format. Competitive inhibition of [125I]MIBG uptake by unlabeled benzylguanidine compounds was performed in UVW-NAT cell line to determine IC50 values. Results [18F]FPOIBG was synthesized from the corresponding tosylate precursor in 5.2 ± 0.5% (n = 6) overall radiochemical yields starting with aqueous fluoride in about 105 min. In a paired-label in vitro assay, the uptake of [18F]FPOIBG at 2 h was 10.2 ± 1.5%, 39.6 ± 13.4%, and 13.3 ± 2.5%, in NET-expressing SK-N-SH, UVW-NAT, and SK-N-BE(2c) cells, respectively, while these values for [125I]MIBG were 57.3 ± 8.1%, 82.7 ± 8.9%, and 66.3 ± 3.6%. The specificity of uptake of both tracers was demonstrated by blocking with desipramine. The 125I-labeled congener of FPOIBG gave similar results. On the other hand, [18F]FPOBBG, a compound recently reported in the literature, demonstrated much higher uptake, albeit less than that of co-incubated [125I]MIBG. IC50 values for FPOIBG were higher than that obtained for MIBG and FPOBBG. Unlike the case with [18F]FPOBBG, the heart uptake [18F]FPOIBG in normal mice was significantly lower than that of MIBG. Conclusion Although [18F]FPOIBG does not appear to warrant further consideration as an 18F-labeled MIBG analogue, analogues wherein the iodine in it is replaced with a chlorine, fluorine or hydrogen might be worth pursuing. Advances in knowledge and implications for patient care An 18F-labeled analogue of the well-known radiopharmaceutical MIBG could have significant impact, potentially improving imaging of NET related disease in cardiology and in the imaging of neuroendocrine tumors. Although 18F-labeled analogues of MIBG have been reported including LMI1195, we undertook this work hypothesizing that based on its greater structural similarity to MIBG, FPOIBG might be a better analogue than LMI1195.

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Section: Resultsmentioning

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Synthesis and evaluation of 4-[18F]fluoropropoxy-3-iodobenzylguanidine ([18F]FPOIBG): A novel 18F-labeled analogue of MIBG

Vaidyanathan

McDougald

Koumarianou

et al. 2015

Nuclear Medicine and Biology

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“…18 F-MFBG (~19 GBq/mmol) ( 15 ), 18 F-FEAU (~22 GBq/μmol) ( 28 ), carrier-free 124 I-MIBG (>12 GBq/μmol), carrier-free 124 I-iodide, and carrier-free 124 I-FIAU were synthesized at Memorial Sloan Kettering Cancer Center ( 28 ). 123 I-MIBG (clinical formulation) was obtained from Nuclear Diagnostics Products.…”

Section: Methodsmentioning

confidence: 99%

“…These intrinsically non-immunogenic reporter systems include the human sodium iodide symporter ( hNIS )/ 124 I-iodide (13), the human norepinephrine transporter ( hNET )/ 123 I/ 124 I-metaiodobenzylguanidine (MIBG) ( 14 ) and 18 F-meta- 18 F-fluorobenzylguanidine ( 18 F-MFBG) ( 15 ), the human somatostatin receptor 2 ( SSTR2 / 68 Ga-DOTATOC) ( 16,17 ), the human ferritin/ 2+ Fe reporter ( 18 ), and the human transferrin receptor ( 19 ). More recently described reporter genes include the truncated and mutated human mitochondrial thymidine kinase type 2 (hΔTK2, hΔTK2DM) genes ( 20,21 ) and the mutated human deoxycytidine kinase (hdCKDM) gene ( 22–24 ).…”

mentioning

confidence: 99%

“…We compared the hNET / 18 F-MFBG and 123 I/ 124 I-MIBG reporter systems with the previously described hNIS, hdCKDM, and hsvTK reporter systems using radio-labeled 124 I-iodide, 18 F-FEAU, and 124 I-FIAU, respectively. We included 18 F-MFBG as an alternative to 123 I/ 124 I-MIBG, for imaging hNET reporter–transduced T cells, because of the superior tumor-to-background images that can be obtained at earlier times after administration of MFBG compared with MIBG ( 15,25 ). Using a murine preclinical model, we determined the minimum number of reporter-transduced T cells that could be imaged with the different reporter systems.…”

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Comparative Analysis of T Cell Imaging with Human Nuclear Reporter Genes

et al. 2015

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Monitoring genetically altered T cells is an important component of adoptive T cell therapy in patients, and the ability to visualize their trafficking/targeting, proliferation/expansion, and retention/death using highly sensitive reporter systems that do not induce an immunologic response would provide useful information. Therefore, we focused on human reporter gene systems that have the potential for translation to clinical studies. The objective of the in vivo imaging studies was to determine the minimum number of T cells that could be visualized with the different nuclear reporter systems. We determined the imaging sensitivity (lower limit of T cell detection) of each reporter using appropriate radiolabeled probes for PET or SPECT imaging. Methods Human T cells were transduced with retroviral vectors encoding for the human norepinephrine transporter (hNET), human sodiumiodide symporter (hNIS), a human deoxycytidine kinase double mutant (hdCKDM), and herpes simplex virus type 1 thymidine kinase (hsvTK) reporter genes. After viability and growth were assessed, 105 to 3 × 106 reporter T cells were injected subcutaneously on the shoulder area. The corresponding radiolabeled probe was injected intravenously 30 min later, followed by sequential PET or SPECT imaging. Radioactivity at the T cell injection sites and in the thigh (back-ground) was measured. Results The viability and growth of experimental cells were unaffected by transduction. The hNET/meta-18F-fluorobenzylguanidine (18F-MFBG) reporter system could detect less than 1 × 105 T cells because of its high uptake in the transduced T cells and low background activity. The hNIS/124I-iodide reporter system could detect approximately 1 × 106 T cells; 124I-iodide uptake at the T cell injection site was time-dependent and associated with high background. The hdCKDM/2′-18F-fluoro-5-ethyl-1-β-D-arabinofuranosyluracil (18F-FEAU) and hsvTK/18F-FEAU reporter systems detected approximately 3 × 105 T cells, respectively. 18F-FEAU was a more efficient probe (higher uptake, lower background) than 124I-1-(2-deoxy-2-fluoro-1-D-arabinofuranosyl)-5-iodouracil for both hdCKDM and hsvTK. Conclusion A comparison of different reporter gene–reporter probe systems for imaging of T cell number was performed, and the hNET/18F-MFBG PET reporter system was found to be the most sensitive and capable of detecting approximately 35–40 × 103 T cells at the site of T cell injection in the animal model.

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Hypervalent Iodine Compounds as Precursors for Biomedical Radiotracers

Telu

Siméon

et al. 2018

Patai's Chemistry of Functional Groups

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This chapter summarizes the increasing role that hypervalent aryliodine compounds, especially aryliodine(III) compounds, are serving as precursors for biomedical radiotracers due to their ease of synthesis, often adequate storage stabilities, and high reactivities in useful labeling reactions, especially those with short‐lived [ 18 F]fluoride ion ( t 1/2 = 109.8 min) for producing radiotracers for imaging with positron emission tomography.

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Synthesis and evaluation of 18F-labeled benzylguanidine analogs for targeting the human norepinephrine transporter

Cited by 53 publications

References 23 publications

Synthesis and evaluation of 4-[18F]fluoropropoxy-3-iodobenzylguanidine ([18F]FPOIBG): A novel 18F-labeled analogue of MIBG

Synthesis and evaluation of 4-[18F]fluoropropoxy-3-iodobenzylguanidine ([18F]FPOIBG): A novel 18F-labeled analogue of MIBG

Comparative Analysis of T Cell Imaging with Human Nuclear Reporter Genes

Hypervalent Iodine Compounds as Precursors for Biomedical Radiotracers

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