1,2,4,5-tetrazine compound for bioorthogonal reaction as well as preparation method and application thereof
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A bioorthogonal, compound-based technique for rapid brain clearance in the fields of radiopharmaceutical chemistry and clinical nuclear medicine
Active Publication Date: 2017-12-29
BEIJING NORMAL UNIVERSITY
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In addition, from the perspective of targeted regions, the current related research mainly focuses on imaging outside the central nervous system such as tumo...
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Embodiment 1
[0032] Example 1 Synthesis of Intermediate 1
[0033] Weigh 665.8mg 4-(hydroxymethyl)benzonitrile, 1026.3mg acetonitrile, 259.2mg anhydrous nickel chloride in a 250mL round bottom flask, add 7821.9mg hydrazine hydrate (concentration 80%) dropwise, and heat at 60°C for 24 hours, cooled to normal temperature, weighed 5002.5 mg of sodium nitrite, dissolved in water and added dropwise. Then place it in an ice-water bath, add 2M hydrochloric acid dropwise until there are no more bubbles, extract with ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, concentrate by rotary evaporation, and separate on a silica gel column to obtain the product, namely intermediate 1, structure As follows, yield: 44%. 1 H NMR (400MHz, CDCl 3 )δ8.58(d, J=7.9Hz, 2H), 7.59(d, J=8.0Hz, 2H), 4.84(s, 2H), 3.10(s, 3H).
[0034]
Embodiment 2
[0035] Embodiment 2 synthetic intermediate 2
[0036] Intermediate 2 is prepared by reacting 3-(2-hydroxyethoxy)propionitrile with acetonitrile and hydrazine hydrate. The raw material ratio, solvent, and reaction conditions of the reaction are the same as those of Intermediate 1. The structure is as follows, and the yield : 17%. 1 H NMR (400MHz, CDCl 3 )δ4.11(t,J=6.2Hz,2H),3.69–3.67(m,2H),3.63–3.60(m,2H),3.58(t,J=6.2Hz,2H),3.05(s,3H ),2.56(s,1H).
[0037]
Embodiment 3
[0038] Embodiment 3 synthetic intermediate 3
[0039] Intermediate 3 is prepared by reacting 4-(2-hydroxyethoxy)benzonitrile with acetonitrile and hydrazine hydrate. The raw material ratio, solvent, and reaction conditions of the reaction are the same as those of Intermediate 1. The structure is as follows, and the yield : 44%. 1 H NMR (400MHz, CDCl 3 )δ8.55(d, J=8.9Hz, 2H), 7.10(d, J=8.9Hz, 2H), 4.20(t, J=4.6Hz, 2H), 4.03(t, J=4.6Hz, 2H) ,3.06(s,3H).
[0040]
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Abstract
The invention provides a 1,2,4,5-tetrazine compound for bioorthogonal reaction as well as a preparation method and application thereof, and also provides a new-structure 1,2,4,5-tetrazine compound labeled by <99m>Tc/Re, a preparation method thereof and application thereof in bioorthogonal reaction-based developing, and particularly in brain developing. The structure of the labeled compound is as shown in a formula (I) which is shown in the description. A reaction kinetics experiment shows that molecules and trans-cyclooctene derivatives have very high reaction activity, an in-vivo biodistribution experiment of normal mice shows that the molecules labeled by the <99m>Tc can effectively pass through blood brain barrier, and brain elimination is also faster, so that the 1,2,4,5-tetrazine compound can be a novel developing agent for intracerebral bioorthogonal reaction.
Description
technical field [0001] The invention relates to the technical fields of radiopharmaceutical chemistry and clinical nuclear medicine, in particular to a 1,2,4,5-tetrazine compound used in bioorthogonal reactions, a preparation method and application thereof. Background technique [0002] Bioorthogonal reaction (bioorthogonal reaction) is being widely used in the research of biology, chemistry and other fields. This kind of reaction can occur specifically under the physiological conditions in the organism without interfering with other biochemical reactions occurring simultaneously in the body. No damage to organisms and target biomolecules. An ideal bioorthogonal reaction needs to meet the following conditions: (1) selectivity with respect to other potentially active functional groups present on biomolecules; (2) carried out in an aqueous medium; (3) carried out under physiological pH conditions; (4) ) has a faster reaction rate at room temperature using low concentrations o...
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