Abstract: Acidic amino acid peptides have a high affinity for bone. Previously, we demonstrated that radiogallium complex-conjugated oligo-acidic amino acids possess promising properties as bone-seeking radiopharmaceuticals. Here, to elucidate the effect of stereoisomers of Glu in Glu-containing peptides [(Glu)14] on their accumulation in the kidney, the biodistributions of [67Ga]Ga-N,N′ -bis-[2-hydroxy- 5-(carboxyethyl)benzyl]ethylenediamine-N,N′ -diacetic acid-conjugated (L-Glu)14 ([67Ga]Ga-HBED-CC- (L-Glu)14), [67Ga]Ga-HBED-CC-(D-Glu)14, [67Ga]Ga-HBED-CC-(DL-Glu)14, and [67Ga]Ga-HBED-CC- (D-Glu-L-Glu)7 were compared. Although the accumulation of these compounds in the bone was comparable, their kidney accumulation and retention were strikingly different, with [67Ga]Ga-HBED-CC- (D-Glu-L-Glu)7 exhibiting the lowest level of kidney accumulation among these compounds. Repeated D- and L-peptides may be a useful method for reducing renal accumulation in some cases.
Keywords:
kidney accumulation ; bone imaging ; glutamic acid ; bone metastases ; gallium
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With benzotriazol-1-ol; O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; for 1h;
Commercially available Nalpha-(9-Fluorenylmethoxycarbonyl)-D-glutamic acid 7-t-butyl ester (1.14 g), TBTU (0.87 g), HOBt (0.37 g) and DIPEA (940 muL) as a solution in NMP (20 mL) was added to compound 5. The reaction mixture was shaken for one hour. The reaction mixture was filtered through a glass sinter funnel then the solid was washed with N-methylpyrrolidine (3×15 mL), methanol (3×15 mL), and again with N-methylpyrrolidine (3×15 mL). The reaction was judged to be complete using the Kaiser Test (vide supra), yielding the resin bound compound 79.
With benzotriazol-1-ol; O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; for 17h;
Commercially available Nalpha-(9-Fluorenylmethoxycarbonyl)-D-glutamic acid gamma-t-butyl ester (0.98 g), TBTU (0.74 g), HOBt (0.31 g) and DIPEA (810 muL) as a solution in NMP (20 mL) was added to compound 71 (1.8 g). The reaction mixture was shaken for seventeen hours. The reaction mixture was filtered through a glass sinter funnel then the solid was washed with N-methylpyrrolidine (3×15 mL), methanol (3×15 mL), and again with N-methylpyrrolidine (3×15 mL) to give compound 85.
With benzotriazol-1-ol; O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; for 3h;
Commercially available Nalpha-(9-Fluorenylmethoxycarbonyl)-D-glutamic acid gamma-t-butyl ester (2.29 g), TBTU (1.73 g), HOBt (0.73 g) and DIPEA (1.9 mL) as a solution in NMP (25 mL) were added to compound 114 (3.3 g). The mixture was shaken for three hours. The reaction mixture was filtered through a glass sinter funnel then the solid was washed with N-methylpyrrolidine (3×25 mL), methanol (3×25 mL), and again with N-methylpyrrolidine (3×25 mL) to give compound 120.
(R)-4-((S)-2-Acetylamino-3-carboxy-propionylamino)-4-((S)-1-{(1S,2S)-1-[(S)-2-cyclohexyl-1-((E)-(S)-1-ethyl-2-hydroxy-pent-3-enylcarbamoyl)-ethylcarbamoyl]-2-methyl-butylcarbamoyl}-3-methyl-butylcarbamoyl)-butyric acid[ No CAS ]
(R)-4-((S)-2-Acetylamino-3-carboxy-propionylamino)-4-((S)-1-{(1S,2S)-1-[(S)-2-cyclohexyl-1-((E)-(S)-1-ethyl-2-oxo-pent-3-enylcarbamoyl)-ethylcarbamoyl]-2-methyl-butylcarbamoyl}-3-methyl-butylcarbamoyl)-butyric acid[ No CAS ]
(R)-4-((S)-2-Acetylamino-3-carboxy-propionylamino)-4-((S)-1-{(1S,2S)-1-[(S)-2-cyclohexyl-1-((S)-1-ethyl-2-oxo-pentylcarbamoyl)-ethylcarbamoyl]-2-methyl-butylcarbamoyl}-3-methyl-butylcarbamoyl)-butyric acid[ No CAS ]
(R)-4-((S)-2-Acetylamino-3-carboxy-propionylamino)-4-((S)-1-{(1S,2S)-1-[(S)-2-cyclohexyl-1-((E)-(S)-1-ethyl-2-oxo-4-thiazol-2-yl-but-3-enylcarbamoyl)-ethylcarbamoyl]-2-methyl-butylcarbamoyl}-3-methyl-butylcarbamoyl)-butyric acid[ No CAS ]
(R)-4-((S)-2-Acetylamino-3-carboxy-propionylamino)-4-((S)-1-{(1S,2S)-1-[(S)-2-cyclohexyl-1-((E)-(S)-1-ethyl-2-hydroxy-4-thiazol-2-yl-but-3-enylcarbamoyl)-ethylcarbamoyl]-2-methyl-butylcarbamoyl}-3-methyl-butylcarbamoyl)-butyric acid[ No CAS ]
(R)-4-((S)-2-Acetylamino-3-carboxy-propionylamino)-4-((S)-1-{(1S,2S)-1-[(S)-2-cyclohexyl-1-((S)-1-ethyl-2-oxo-4-thiazol-2-yl-butylcarbamoyl)-ethylcarbamoyl]-2-methyl-butylcarbamoyl}-3-methyl-butylcarbamoyl)-butyric acid[ No CAS ]
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 14 Peptides Containing Different Optical Isomers of Glutamic Acid.png)
