A multimodal molecular imaging probe p-ffgd-tco and its preparation method and application
A molecular imaging and multi-modal imaging technology, applied in chemical instruments and methods, pharmaceutical formulations, in vivo radioactive preparations, etc., can solve the problems of unfavorable tumor imaging detection, limiting tumor sensitivity and resolution, etc., and achieve high sensitivity and spatial resolution The effect of high rate and high spatial resolution
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Embodiment 1
[0105] Example 1: Design, synthesis and characterization of probes
[0106] Route S1 shows the structural design of probes P-FFGd-TCO and FFGd-TCO.
[0107]
[0108] Route S1
[0109] Reaction conditions: (a) HBTU, DIPEA, THF, r.t., 2h, 84%; (b) (i) diethyl chlorophosphate, DIPEA, r.t., 2h; (ii) TMS-Br, r.t., 24h, 49% ; (c) (E)-Cyclooct-4-enyl 2,5,2-dioxa-1-pyrrolidinyl carbonate (TCO-NHS), DIPEA, DMF, r.t., 4h, 94%; ( d) GdCl 3 ,NaHCO 3 , pH 6-7, r.t., 12h, 74%; (e) DMF, NaHCO 3 , pH 9-10, r.t., 12h, 86%.
[0110] Synthesis of Compound 1: Compound 1 was synthesized by a standard solid-phase peptide synthesis (SPPS) procedure (Nat. Protocol., 2007, 2, 3247), using 2-chlorotrityl chloride resin, Fmoc-protected amino acid and 1, 4,7,10-Tetraazacyclododecane-1,4,7-tri-tert-butyl acetate-10-acetic acid. After the solid phase synthesis reaction step, the product was cleaved from the resin using 1% TFA in DCM. After the solvent was removed by rotary evaporation in vacuo, ...
Embodiment 2
[0126] Example 2: Design, Synthesis and Characterization of Tetrazine Probes
[0127] Routes S3, S4 and S5 show multiple tetrazine-linked imaging probes for imaging detection of tumor ALP in cells and in vivo in combination with the probe P-FFGd-TCO.
[0128] (1) Synthesis of probe Tz-FITC:
[0129]
[0130] Route S3
[0131] Reaction conditions: (a) DIPEA, DMF, r.t., 2h, 92%.
[0132] 5-fluorescein isothiocyanate (23 mg, 0.06 mmol), 3-(4-benzylamino)-1,2,4,5-tetrazine (11.5 mg, 0.06 mmol) and DIPEA (28 μL, 15 mmol) Mix in 2 mL of DMF, and stir the mixture at room temperature for 2 hours in the dark. After completion of the reaction the reaction mixture was purified by semi-preparative HPLC. Tz-FITC was obtained as an orange solid after lyophilization. Yield: 31.8 mg (92%). 1 H NMR (400MHz, DMSO-d 6 )δ10.59(s,1H),10.22(s,1H),8.70(s,1H),8.51(d,J=8.4Hz,2H),8.28(s,1H),7.81(dd,J=8.4 ,1.9Hz,1H),7.66(d,J=8.4Hz,2H),7.23(d,J=8.3Hz,1H),6.69(d,J=2.3Hz,2H),6.67–6.55(m,4H ), 4.9...
Embodiment 3
[0143] Embodiment 3: Probe performance test
[0144] 1. Detection of enzyme cleavage response and self-assembly of probes to ALP
[0145] (1) Firstly, the response performance of the probe P-FFGd-TCO (100 μM) to ALP was studied in the ALP digestion buffer solution (containing 1% DMSO, 10 mM Tris, pH 8.0). like figure 2 As shown in a, the probe P-FFGd-TCO (100μM) and ALP (500U / L) were incubated in Tris buffer (pH=8.0) at 37°C for 0-30min, and the reaction was detected by high performance liquid chromatography (HPLC). The liquid was analyzed, and the results showed that P-FFGd-TCO(t R =15.0min) can be converted into the dephosphorylated product FFGd-TCO (t R = 17.5 min).
[0146] (2) Next, the reaction changes of the probe before and after adding ALP were studied. With the rapid dephosphorylation, the original ultraviolet absorption peaks of P-FFGd-TCO at 605nm and 652nm gradually shifted to 690nm, and due to self-assembly The π-π stacking effect of the process has a shoul...
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