Improved pharmacokinetics and cholecystokinin-2 receptor (CCK2R) targeting for diagnosis and therapy
A technology of x1-x2-asp-x3, x4-x5-x6-x7-x1-x2-asp-x3 for improved pharmacokinetics and cholecystokinin-2 receptor for diagnosis and therapy (CCK2R) targeting field, which can solve the problems of unsuccessful improvement of in vivo biological half-life and targeting characteristics, and failure to improve biological half-life
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Embodiment 1
[0152] Example 1: Synthesis of Peptide Mimetics of the Invention
[0153] Synthesis of the peptidomimetics of the invention was performed using standard 9-fluorenylmethoxycarbonyl (Fmoc) chemistry.
[0154] In basic medium, use excess Fmoc-protected amino acids, 1-hydroxy-7-azabenzotriazole (HOAt) and (2-(7-aza-1H-benzotriazol-1-yl) - 1,1,3,3-Tetramethyluronium hexafluorophosphate (HATU), peptide mimetic assembled on Rink Amide MBHA resin (Novabiochem, Hohenbrunn, Germany) in N-methyl-2-pyrrolidone (NMP) Reactive side chains of amino acids are masked with appropriate protecting groups. After assembly of the desired amino acid sequence, coupling of Boc-protected DOTA or HYNIC is performed followed by cleavage of the peptidomimetic from the resin with simultaneous removal of the acid Stable protecting group. After HPLC purification and lyophilization, the peptidomimetic was obtained in >20% yield and ≥95% chemical purity as confirmed by RP-HPLC and MALDI-TOF MS. Using standar...
Embodiment 2
[0158] Example 2: Peptide mimetics of the invention have increased stability in human serum in vitro
[0159] To characterize the radiolabeled peptidomimetics in vitro, stability in human serum was investigated. At 37°C, use 111 In-labeled peptidomimetics were incubated in fresh human serum at a concentration of 500–2000 pmol / mL for up to 24 h, and degradation was assessed by radioactive HPLC. For this purpose, human serum samples were precipitated with ACN, centrifuged at 2000 g for 2 min, diluted with water (1:1 / v:v), and then placed on a column equipped with a Phenomenex Jupiter Proteo C12 ( 4μm, 250x4.6mm) column or Bischoff Chromatography Nucleosil C18 column ( 5 μm, 250 x 4.6mm) on a Dionex chromatographic system including radiodetection and UV detection, using different water / acetonitrile / 0.1%TFA gradient systems for HPLC analysis. Such as figure 1 As shown in , when compared to 111 In labeled DOTA-MG11 and 111Radiolabeled peptidomimetics in human serum when I...
Embodiment 3
[0160] Example 3: Binding of peptidomimetics of the invention to serum proteins
[0161] In addition, the binding of the protein to serum proteins was studied. For this purpose, the 111 In-labeled peptidomimetics were incubated in fresh human serum (500 pmol / mL) at 37°C in duplicate and passed through Sephadex G-50 size exclusion chromatography (GE Healthcare lllustra, Little Chalfont) after 4 and 24 h. , UK) for analysis. The percentage of protein binding was determined by measuring the column and eluate in a 2480 Wizard2 automatic gamma-counter (Perkin Elmer Life Sciences and Analytical Sciences, Turku, F). The results are summarized in Table 5.
[0162] Table 5: Determined after 4 and 24h of incubation in human serum 111 In-labeled peptidomimetics compared to 111 In-DOTA-MG11, 111 In-DOTA-MGS1 and 111 Protein binding of In-DOTA-MGS4 (expressed as percentage of radioligand bound to serum protein)
[0163]
[0164] When compared to those showing 111 In-DOTA-MG11,...
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