The International Journal of Applied Radiation and Isotopes

1985

DOI: 10.1016/0020-708x(85)90207-8

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Cyclotron isotopes and radiopharmaceuticals—XXXV astatine-211

Richard M. Lambrecht

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Cited by 95 publications

(77 citation statements)

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“…211At was isolated from the target by a modification of a published procedure (15,16). The distillation temperature was increased to 715-750'C and the distillation time decreased to 15-30 min.…”

mentioning

confidence: 99%

“…Similar tumor localization was observed in the second experiment when the mAb labels were reversed. In both studies, differences in tumor uptake were statistically significant (Student's t test; P < 0.01, 3 hr; P < 0.001, [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24] hr). With Mel-14 F(ab')2, no significant differences were observed in tumor localization of 2"At and 131I until 24 hr, at which time the "3'1-labeled mAb exhibited higher uptake (12.8 Tumor/normal tissue ratios of 211At after injection of 211At-labeled Mel-14 F(ab')2 and control RPC 5 F(ab')2 are compared in Fig.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Labeling monoclonal antibodies and F(ab')2 fragments with the alpha-particle-emitting nuclide astatine-211: preservation of immunoreactivity and in vivo localizing capacity.

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et al. 1989

Proc. Natl. Acad. Sci. U.S.A.

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a-Particles such as those emitted by 21'At may be advantageous for radioimmnunotherapy since they are radiation of high linear energy transfer, depositing high energy over a short distance. Here we describe a strategy for labeling monoclonal antibodies and F(ab')2 fragments with 211At by means of the bifunctional reagent N-succinimidyl 3-(trimethylstannyl)benzoate. An intact antibody, 81C6, and the F(ab')2 fragment of Mel-14 (both reactive with human gliomas) were labeled with 211At in high yield and with a specific activity of up to 4 mCi/mg in a time frame compatible with the 7.2-hr half-life of 211At. Quantitative in vivo binding assays demonstrated that radioastatination was accomplhed with maintenance of high specific binding and affinity. Comparison of the biodistribution of 211At-labeled Mel-14 F(ab')2 to that of a nonspecific antibody fragment labeled with 21'At and 131I in athymic mice bearing D-54 MG human glioma xenografts demonstrated selective and specific targeting of 211At-labeled antibody in this human tumor model. and in vivo (7,8). In order to ensure the formation of an aryl astatide bond, a method was developed for astatinating proteins via acylation withp-astatobenzoic acid (9). Although this approach has markedly increased the in vivo stability of 2"1At-labeled proteins, even after subsequent optimization (10) the radiochemical yield and specific activity (maximum of 1 astatine atom per 20,000 protein molecules) are inadequate to permit meaningful biological evaluation of the radiotherapeutic potential of 211At-labeled mAbs.This paper describes a method that utilizes N-succinimidyl 3-(trimethylstannyl)benzoate (m-MeATE; ATE, "alkyltin ester") for labeling mAbs with 2lAt. An IgG2b immunoglobulin and an IgG2a F(ab')2 fragment were labeled with 211At in high yield and maintained immunoreactivity and affinity after astatination. Moreover, biodistribution studies in athymic mice bearing subcutaneous tumors indicated that selective tumor uptake of 211At can be achieved following administration of 211At-labeled mAbs.From a radiobiological perspective, nuclides that emit aparticles could offer advantages for certain radiotherapeutic applications. For example, 6-to 8-MeV a-particles (1 eV = 1.602 x 10-19 J) have a range in tissue of55-80 ,m, providing the potential for matching the cellular specificity of a monoclonal antibody (mAb) and radiation with cytotoxic effects limited to only a few cell diameters. These a-particles have a linear energy transfer (LET) of maximum relative biological effectiveness about 8 times that of 13-or y-radiation (1). The cytotoxic effects of high-LET radiations are thought to be irreparable (2), presumably due to the relatively high proportion of non-rejoining DNA strand breaks that they have been observed to induce in vitro (3). Since the cytotoxic effects of a-particles are nearly oxygen-independent (1), eradication of hypoxic tumor-cell populations also might be possible. IgG2a that does not bind to any known antigen. Methods for the production of F(ab')2 f...

“…211At was isolated from the target by a modification of a published procedure (15,16). The distillation temperature was increased to 715-750'C and the distillation time decreased to 15-30 min.…”

mentioning

confidence: 99%

“…Similar tumor localization was observed in the second experiment when the mAb labels were reversed. In both studies, differences in tumor uptake were statistically significant (Student's t test; P < 0.01, 3 hr; P < 0.001, [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24] hr). With Mel-14 F(ab')2, no significant differences were observed in tumor localization of 2"At and 131I until 24 hr, at which time the "3'1-labeled mAb exhibited higher uptake (12.8 Tumor/normal tissue ratios of 211At after injection of 211At-labeled Mel-14 F(ab')2 and control RPC 5 F(ab')2 are compared in Fig.…”

mentioning

confidence: 99%

Labeling monoclonal antibodies and F(ab')2 fragments with the alpha-particle-emitting nuclide astatine-211: preservation of immunoreactivity and in vivo localizing capacity.

¹

,

²

,

³

et al. 1989

Proc. Natl. Acad. Sci. U.S.A.

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a-Particles such as those emitted by 21'At may be advantageous for radioimmnunotherapy since they are radiation of high linear energy transfer, depositing high energy over a short distance. Here we describe a strategy for labeling monoclonal antibodies and F(ab')2 fragments with 211At by means of the bifunctional reagent N-succinimidyl 3-(trimethylstannyl)benzoate. An intact antibody, 81C6, and the F(ab')2 fragment of Mel-14 (both reactive with human gliomas) were labeled with 211At in high yield and with a specific activity of up to 4 mCi/mg in a time frame compatible with the 7.2-hr half-life of 211At. Quantitative in vivo binding assays demonstrated that radioastatination was accomplhed with maintenance of high specific binding and affinity. Comparison of the biodistribution of 211At-labeled Mel-14 F(ab')2 to that of a nonspecific antibody fragment labeled with 21'At and 131I in athymic mice bearing D-54 MG human glioma xenografts demonstrated selective and specific targeting of 211At-labeled antibody in this human tumor model. and in vivo (7,8). In order to ensure the formation of an aryl astatide bond, a method was developed for astatinating proteins via acylation withp-astatobenzoic acid (9). Although this approach has markedly increased the in vivo stability of 2"1At-labeled proteins, even after subsequent optimization (10) the radiochemical yield and specific activity (maximum of 1 astatine atom per 20,000 protein molecules) are inadequate to permit meaningful biological evaluation of the radiotherapeutic potential of 211At-labeled mAbs.This paper describes a method that utilizes N-succinimidyl 3-(trimethylstannyl)benzoate (m-MeATE; ATE, "alkyltin ester") for labeling mAbs with 2lAt. An IgG2b immunoglobulin and an IgG2a F(ab')2 fragment were labeled with 211At in high yield and maintained immunoreactivity and affinity after astatination. Moreover, biodistribution studies in athymic mice bearing subcutaneous tumors indicated that selective tumor uptake of 211At can be achieved following administration of 211At-labeled mAbs.From a radiobiological perspective, nuclides that emit aparticles could offer advantages for certain radiotherapeutic applications. For example, 6-to 8-MeV a-particles (1 eV = 1.602 x 10-19 J) have a range in tissue of55-80 ,m, providing the potential for matching the cellular specificity of a monoclonal antibody (mAb) and radiation with cytotoxic effects limited to only a few cell diameters. These a-particles have a linear energy transfer (LET) of maximum relative biological effectiveness about 8 times that of 13-or y-radiation (1). The cytotoxic effects of high-LET radiations are thought to be irreparable (2), presumably due to the relatively high proportion of non-rejoining DNA strand breaks that they have been observed to induce in vitro (3). Since the cytotoxic effects of a-particles are nearly oxygen-independent (1), eradication of hypoxic tumor-cell populations also might be possible. IgG2a that does not bind to any known antigen. Methods for the production of F(ab')2 f...

“…The macrocyclic crown thioether 1,5,9,13-tetrathiacyclohexadecane-3,11-diol (16aneS 4 211 At was produced on the CS-30 cyclotron at the Duke University Medical Center. The targets were prepared from pure metallic bismuth and were irradiated with 28 MeV α particles using the 209 Bi(α,2n) 211 At reaction.…”

Section: Reagents and Radioactivitymentioning

confidence: 99%

“…Rh[16aneS 4 The optimization of reaction conditions was focused on increasing the yield of synthesis, ideally, in a reaction time suitable for use with 7.2 h half-life 211 At. The influences of time and temperature of heating, concentrations of metal cations, sulfur ligand 16aneS 4 -diol, and pH of the solutions on the reaction yields were determined.…”

Section: Preparation Of Rh[16anes 4 -Diol]*i/ 211 At and Ir[16anes 4 mentioning

confidence: 99%

Preparation of Rh[16aneS₄-diol]²¹¹At and Ir[16aneS₄-diol]²¹¹At Complexes as Potential Precursors for Astatine Radiopharmaceuticals. Part I: Synthesis

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2008

Bioconjugate Chem.

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The goal of this study was to evaluate a new approach that can be applied for labeling biomolecules with 211 At. Many astatine compounds that have been synthesized are unstable in vivo, providing motivation for seeking different 211 At labeling strategies. The approach evaluated in this study was to attach astatide anions to soft metal cations, which are also complexed by a bifunctional ligand. Ultimately, this complex could in principle be subsequently conjugated to a biomolecule with the proper selection of ligand functionality. We report here the attachment of 211 At − and *I − (*I = 131 I or 125 I) anions to the soft metal cations Rh(III) and Ir(III), which are complexed by the 1,5,9,13-tetrathiacyclohexadecane-3,11-diol (16aneS 4 -diol) ligand. Radioactive *I − anions were used for preliminary studies directed at the optimization of reaction conditions and to provide a baseline for comparison of results with 211 At. Four complexes Rh[16aneS 4 -diol]*I/ 211 At and Ir[16aneS 4 -diol] *I/ 211 At were synthesized in high yield in a one-step procedure, and the products were characterized mainly by paper electrophoresis and reversed-phase HPLC. The influences of time and temperature of heating and concentrations of metal cations and sulfur ligand 16aneS 4 -diol, as well as pH on the reaction yields were determined. Yields of about 80% were obtained when the quantities of Rh(III) or Ir(III) cations and 16aneS 4 -diol ligand in the solutions were 62.5 nmol and 250 nmol, respectively, and the pH ranged 3.0-4.0. Syntheses required heating for 1-1.5 h at 75-80 °C. The influence of microwave heating on the time and completeness of the complexation reaction was evaluated and compared with the conventional method of heating in an oil bath. Microwave synthesis accelerates reactions significantly. With microwave heating, yields of about 75% for Rh[16aneS 4 -diol] 131 I and Ir[16aneS 4 -diol] 131 I complexes were obtained after only 20 min exposure of the reaction mixtures to microwave radiation. In conclusion, this study has shown that it is possible to attach an astatide anion to soft metal cations in a simple and fast one-step procedure, with high yields. These complexes will be evaluated as reagents for labeling biomolecules.

“…There are a number of procedures reported for extracting 21'At from an irradiated Bi target, and a recent review of the subject is available (Ruth et al, 1988). The dry distillation method is the most convenient approach and it has been described in detail elsewhere (Lambrecht and Mirzadeh, 1985).224Raf3.7 d) -* 212Pbf10.6 h) .--* 2'2Bi(60.6 minl. Bismuth-212 is available from the 224Ra/212Bi…”

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confidence: 99%

Generator-produced alpha-emitters

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1998

Applied Radiation and Isotopes

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This review briefly describes the nuclear characteristics and production parameters for 7.2-h 211At, 60.6-min 212Bil 45.6-min 213Bi, 1 1 d 233Ra, and 20-h 255Fm. These a-emitting radioisotopes are the subject of current interest for a-partide-mediated radioimmunotherapy. IntroductionAlpha particles are of considerable interest for radioimmunotherapy applications. Due to their short range in tissue (a few cell diameters), and high linear-energy-transfer (LET), a-particles are especially suited for targeting micrometatases and single tumor cells such as leukemia and other blood-borne diseases (Bloomer et a/., 1984, Ruegg, et a/., 1990, Huneke, et a/., 1992, Junghans, et a/., 1993, Hartmann, et a/., 1994, Kennel and Mirzadeh, 1997, Scheinberg, 1997. The list of potential radionuclides for these applications includes only five a-emitting radioisotopes, namely 211At (tIQ = 7.2 h), 212Bi (t1,2 = 60.6 m), 213Bi (tlQ = 45.6 m), 233Ra ( t l M = 11 d), and 255Fm (tln = 20 h). A list of the generator-produced a-emitters and the corresponding references are given in 1 DISCLAIMERPortions of this document may be illegible in electronic imRge products. Images are produced from the best available original document. 21'Rn(14.6 h) + *"At(7.2 h). Astatine-211 can be produced through the decay of 14.6 h 211Rn. The 21'Rn, in turn, is produced through a number of nuclear reactions which are summarized in Table 3. The corresponding references are also given in this table. These reactions include spallation of Th with high energy protons having a cross-section of 0.7 mb at 28 GeV protons or by photo-spallation of Th with a cross-section of 0.13 mb at a photon energy of 300 MeV. The production of 2'1Rn by the 209BitLi14n]211Rn reaction, with a amax = 0.7 b at E , = 54 MeV and yield of -2 pCi/nA at '/z saturation, has also been reported. By far, the predominant nuclear reaction for the production of 211Atl however, is not through a generator system but by direct activation of 209Bi with 28 MeV u particles, The maximum of the excitation function for this reaction is -1 b at E , = 29MeV. In order to minimize the production of radiocontaminant 210Po, the a-particle should exit the Bi target at E , = 20 MeV, limiting the Bi thickness to only 100 pg.cm-*. The typical yield is -1.5 mCi/pA at half saturation (-3.5 hours of irradiation). Since there are only a few cyclotrons in the U.S. capable of accelerating a-particles to -28 MeV, the required energy for the production of 211At via the 209Bi[a,2n] reaction, the availability of 211At is also very limited. There are a number of procedures reported for extracting 21'At from an irradiated Bi target, and a recent review of the subject is available (Ruth et al, 1988). The dry distillation method is the most convenient approach and it has been described in detail elsewhere (Lambrecht and Mirzadeh, 1985).224Raf3.7 d) -* 212Pbf10.6 h) .--* 2'2Bi(60.6 minl. Bismuth-212 is available from the 224Ra/212Bigenerator system, where 224Ra is the daughter of 1.9-y =%I . Th-228 is the second member of the 232Th ...

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