3-[211At]astato-4-fluorobenzylguanidine: a potential therapeutic agent with prolonged retention by neuroblastoma cells

Vaidyanathan, Ganesan; Zhao, Xiaoguang; Larsen, Roy H.; Zalutsky, Michael R.

doi:10.1038/bjc.1997.366

Cited by 16 publications

(20 citation statements)

References 15 publications

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“…[47][48][49][50]. Among these analogues, the alpha-emitting characteristics and prolonged tissue retention of [ 211 At]MABG, may make this a particularly promising agent for treatment of such neuroendocrine tumors [51,52].…”

Section: Future Challenges For Effective Treatmentmentioning

confidence: 99%

Current Progress and Future Challenges in the Biochemical Diagnosis and Treatment of Pheochromocytomas and Paragangliomas

Eisenhofer¹,

Siegert²,

Kotzerke³

et al. 2008

Horm Metab Res

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Findings from five independent studies -with close to 350 patients with pheochromocytoma and more than 2 500 in whom the tumor was excluded -indicate that measurements of plasma free metanephrines provide an overall diagnostic sensitivity of 98 % and specificity of 92 %. The recommendation that initial testing for the tumor should always include measurements of either plasma or urinary fractionated metanephrines results from recognition of the high diagnostic sensitivity of measurements of plasma metanephrines. The few patients with pheochromocytoma in whom the test may not yield a positive result include those with very small tumors or microscopic disease and others with tumors that do not produce norepinephrine and epinephrine. Such patients are typically normotensive and do not exhibit symptoms of catecholamine excess. Additional measurements of methoxytyramine can be useful for detecting those tumors that produce only dopamine. Suboptimal diagnostic specificity and difficulties in distinguishing truefrom false-positive elevations of plasma metanephrines remain challenges for diagnosis. Improvements in analytical technology (e.g., liquid chromatography with tandem mass spectrometry) and new strategies for follow-up testing provide possible solutions to these problems. The single most important remaining clinical care challenge is the development of effective cures for patients with malignant disease. Current treatments, none of which are truly satisfactory, include chemotherapy and radiopharmaceutical therapy with 131 I-labelled miodobenzylguanidine or radioactive somatostatin analogues. Improvements in treatment may in the future come from several fronts, but proof of efficacy ideally will require well-coordinated multicenter prospective trials in larger numbers of patients than in previous studies.

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Section: Future Challenges For Effective Treatmentmentioning

confidence: 99%

Current Progress and Future Challenges in the Biochemical Diagnosis and Treatment of Pheochromocytomas and Paragangliomas

Eisenhofer¹,

Siegert²,

Kotzerke³

et al. 2008

Horm Metab Res

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“…Because the range of 211 At α-particles is equivalent to only a few cell diameters, we hypothesized that substitution of 211 At for 125 I in the halodeoxyuridine framework would yield an agent that could exert high-LET effects on adjacent cells not in S-phase [56]. Furthermore, the recoil nuclei created during α-particle decay have a range of only 0.09 µm, and would have intracellular localized high LET effectiveness similar to that of 125 I.…”

Section: Astatine-211-labeled Compounds Undergoing Dna Incorporationmentioning

confidence: 96%

“…The uptake of this compound by pigmented B16 murine melanoma cells was shown to be about 5 times higher than amelanotic cells, documenting the involvement of melanin in this process [51]. The therapeutic effectiveness of 4-[ 211 At]astato-MTB for human melanoma xenografts grown as pulmonary micrometastases [52] as well as subcutaneous tumors and lymph node metastases [53] [56]. This has led to the recent investigation of other compounds that can be labeled with 211 At and incorporated into cellular DNA.…”

Section: Astatine-211-labeled Compounds Undergoing Dna Incorporationmentioning

confidence: 99%

“…As shown in Fig. 7, this was accomplished via the astatodestannylation of 5-(trimethylstannyl)-2'-deoxyuridine in a 3:1 mixture of acetic acid:30% hydrogen peroxide [56]. Using a 1-min reaction time, [ 211 At]AUdR was synthesized in 85-90% yield in a specific activity of in excess of 75 GBq/mmol.…”

Section: Astatine-211-labeled Compounds Undergoing Dna Incorporationmentioning

confidence: 99%

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Astatine-211-Labeled Radiotherapeutics An Emerging Approach to Targeted Alpha-Particle Radiotherapy

Zalutsky

Vaidyanathan²

2000

CPD

170

102

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Targeted radiotherapy or endoradiotherapy is an appealing approach to cancer treatment because of the potential for delivering curative doses of radiation to tumor while sparing normal tissues. Radionuclides that decay by the emission of alpha-particles such as the heavy halogen astatine-211 (211At) offer the exciting prospect of combining cell-specific molecular targets with radiation having a range in tissue of only a few cell diameters. Herein, the radiobiological advantages of alpha-particle targeted radiotherapy will be reviewed, and the rationale for using 211At for this purpose will be described. The chemistry of astatine is similar to that of iodine; however, there are important differences which make the synthesis and evaluation of 211At-labeled compounds more challenging. Perhaps the most successful approach that has been developed involves the astatodemetallation of tin, silicon or mercury precursors. Astatine-211 labeled agents that have been investigated for targeted radiotherapy include [211At]astatide, 211At- labeled particulates, 211At-labeled naphthoquinone derivatives, 211At-labeled methylene blue, 211At-labeled DNA precursors, meta-[211At]astatobenzylguanidine, 211At-labeled biotin conjugates, 211At-labeled bisphosphonates, and 211At-labeled antibodies and antibody fragments. The status of these 211At-labeled compounds will be discussed in terms of their labeling chemistry, cytotoxicity in cell culture, as well as their tissue distribution and therapeutic efficacy in animal models of human cancers. Finally, an update on the status of the first clinical trial with an 211At-labeled targeted therapeutic, 211At-labeled chimeric anti-tenascin antibody 81C6, will be provided.

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“…13,[17][18][19][20][21][22][23][24][25][26] One of the major impediments to the clinical evaluation of [ 211 At]MABG is that the labeling method developed for this compound is not ideal for large scale production, in part, because it involves an HPLC purification step. Although the method provided [ 211 At]MABG in high yield, only <1 mCi had been synthesized at a time.…”

Section: Introductionmentioning

confidence: 99%

A kit method for the high level synthesis of [211At]MABG

Vaidyanathan

Affleck

Alston

et al. 2007

Bioorganic & Medicinal Chemistry

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Meta-[ 211 At]astatobenzylguanidine ([ 211 At]MABG), an analogue of meta-iodobenzylguanidine (MIBG) labeled with the α-emitter 211 At, targets the norepinephrine transporter. Because MABG has been shown to have excellent characteristics in preclinical studies, it has been considered to be a promising targeted radiotherapeutic for the treatment of tumors such as micrometastatic neuroblastoma that over express the norepinephrine transporter. To facilitate clinical evaluation of this agent, a convenient method for the high level synthesis of [ 211 At]MABG that is adaptable for kit formulation has been developed. A tin precursor anchored to a solid-support was treated with a methanolic solution of 211 At in the presence of a mixture of H 2 O 2 /HOAc as the oxidant; [ 211 At] MABG was isolated by simple solid-phase extraction. By using C-18 solid-phase extraction, the radiochemical yield from twenty-five batches was 63 ± 13%; however, loss of radioactivity during evaporation of the methanolic solution was a problem. This difficulty was avoided by use of a cation exchange resin cartridge for isolation of [ 211 At]MABG, which resulted in radiochemical yields of 63 ± 9% in a shorter duration of synthesis. The radiochemical purity was more than 90% and no chemical impurity has been detected. The final doses were sterile and apyrogenic. These results demonstrate that [ 211 At]MABG can be prepared via a kit method at radioactivity levels anticipated for initiation of clinical studies.

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3-[211At]astato-4-fluorobenzylguanidine: a potential therapeutic agent with prolonged retention by neuroblastoma cells

Cited by 16 publications

References 15 publications

Current Progress and Future Challenges in the Biochemical Diagnosis and Treatment of Pheochromocytomas and Paragangliomas

Current Progress and Future Challenges in the Biochemical Diagnosis and Treatment of Pheochromocytomas and Paragangliomas

Astatine-211-Labeled Radiotherapeutics An Emerging Approach to Targeted Alpha-Particle Radiotherapy

A kit method for the high level synthesis of [211At]MABG

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