Reagents for Astatination of Biomolecules: Comparison of the in Vivo Distribution and Stability of Some Radioiodinated/Astatinated Benzamidyl and nido-Carboranyl Compounds

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• 作者：D. Scott Wilbur ; Ming-Kuan Chyan ; Donald K. Hamlin ; Brian B. Kegley ; Reudi Risler ; Pradip M. Pathare ; Janna Quinn ; Robert L. Vessella ; Catherine Foulon ; Michael Zalutsky ; Timothy J. Wedge ; and M. Fred
• 刊名：Bioconjugate Chemistry
• 出版年：2004
• 出版时间：January 2004
• 年：2004
• 卷：15
• 期：1
• 页码：203 - 223
• 全文大小：424K
• 年卷期：v.15,no.1(January 2004)
• ISSN：1520-4812

文摘

An investigation has been conducted to assess the in vivo stability of a series of astatinated benzamidesand astatinated nido-carborane compounds in mice. It was hypothesized that the higher bond strengthof boron-astatine bonds in the nido-carboranes might provide increased stability toward in vivodeastatination. Four tri-n-butylstannylbenzamides were prepared for radiohalogenation and evaluationin vivo. Those compounds were N-propyl-4-(tri-n-butylstannyl)benzamide 1a, N-propyl-3-(tri-n-butylstannyl)benzamide 2a, ethyl 4-tri-n-butylstannylhippurate 3a, and 4-tri-n-butylstannyl-hippuricacid 4a. Seven mono-nido-carboranyl derivatives were prepared for radiohalogenation and in vivoevaluation. Four of the seven mono-carboranyl derivatives (5a, 6a, 7a, 13a) contained a 3-(nido-carboranyl)propionamide functionality, and the remaining compounds (8a, 8g, 10a) contained a 4-(nido-carboranyl)aniline functionality. Two additional derivatives (11a, 12a) were prepared that containedbis-(nido-carboranylmethyl)benzene moieties (also referred to as Venus flytrap complexes (VFCs). Allbenzamide and nido-carborane compounds underwent facile iodination and radiohalogenation, excepta 4-(nido-carboranyl)aniline derivative, 8a. Iodination of 8a resulted in a mixture, of which the desirediodinated product was a minor component. Therefore, radiohalogenation was not attempted. It isbelieved that the mixture of products is due to the presence of a thiourea bond. Previous studies haveshown that thiourea bonds can interfere with halogenation reactions. In vivo comparisons of thecompounds were conducted by co-injection of dual labeled (^125/131I and ²¹¹At) compounds. Tissuedistribution data were obtained at 1 and 4 h postinjection of the radiolabeled compounds, as that wassufficient to determine if astatine was being released. Stability of the astatinated compound wasassessed by the difference in concentration of radioiodine and astatine in lung and spleen. All of thebenzamides were found to undergo rapid deastatination in vivo. The nido-carborane derivativesappeared to be slightly more stable to in vivo deastatination; however, they had long blood residencetimes. The surprising finding was that the VFC derivatives did not release ²¹¹At in vivo, even thoughthey rapidly localized to liver. This finding provides encouragement that stable conjugates of ²¹¹Atmay be attained if appropriate modifications of the VFC can be made to redirect their excretion throughthe renal system.