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Fluoride-18 marked dopamine D4 receptor developing agent and preparation method thereof

A technology of dopamine and imaging agent, which is applied in the fields of chemistry and medicine, can solve the problem of small specificity, and achieve the effect of high product yield, high purity and simple process

Active Publication Date: 2013-05-22
HUNAN INSTITUTE OF ENGINEERING
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Atypical antipsychotics, such as clozapine (Clozapine) for D 4 Receptors exhibit a higher 2 The receptor has relatively high affinity and relatively strong specificity, while typical antipsychotic drugs, such as raclopride (Raclopride), haloperidol (Haloperidol) 4 The receptor has high affinity but low specificity, even with D 2 Receptors are more likely to bind

Method used

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  • Fluoride-18 marked dopamine D4 receptor developing agent and preparation method thereof
  • Fluoride-18 marked dopamine D4 receptor developing agent and preparation method thereof
  • Fluoride-18 marked dopamine D4 receptor developing agent and preparation method thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0019] Example 1: 2-[4-(4-[ 18 Synthesis of F]fluorobenzyl)piperazin-1-ylmethyl]pyrazolo[1,5-α]pyridine

[0020] (1) Synthesis of 2-[4-piperazinecarbaldehyde-1-ylmethyl]pyrazolo[1,5-α]pyridine

[0021] Dissolve 0.1465g (1.000mmol) of pyrazolo[1,5-α]pyridine-2-carbaldehyde and 0.1712g (1.499mmol) of N-formylpiperazine in 10mL of dichloromethane, and add sodium triacetoxyborohydride 0.6782g (3.242mmol), stirred at room temperature for 24 hours, added ice water, mixed well, extracted with dichloromethane, dried the organic layer with anhydrous sodium sulfate, separated and purified by column chromatography to obtain yellow solid 2-[4-piper Azinecarbaldehyde-1-ylmethyl]pyrazolo[1,5-α]pyridine 0.1048g, yield 42.9%. Mp116.9°C. 1 H NMR (CDCl 3 ,500MHz)δ:2.69(br s,4H,-(CH 2 ) 2 N piperazinyl);3.18(br s,4H,-(CH 2 ) 2 Npiperazinyl); 3.85(br s,2H,-CH 2 );6.49(s,1H,3-H);6.72(dd,J=7.3Hz,1H,6-H);7.05(dd,J=7.2Hz,1H,5-H);7.50(br d, J=8.5Hz,1H,4-H);7.82(s,1H,-CHO);8.41(dd,J=7.0Hz,J=1...

Embodiment 2

[0032] Example 2: 2-[4-(4-[ 18 Synthesis of F]fluorobenzyl)piperazin-1-ylmethyl]pyrazolo[1,5-α]pyridine

[0033] (1) Synthesis of 2-[4-piperazinecarbaldehyde-1-ylmethyl]pyrazolo[1,5-α]pyridine

[0034] Dissolve 0.1465g (1.000mmol) of pyrazolo[1,5-α]pyridine-2-carbaldehyde and 0.3420g (2.996mmol) of N-formylpiperazine in 10mL of acetonitrile, and add 0.6750g of sodium triacetoxyborohydride (3.185mmol), after stirring at room temperature for 20 hours, add ice water, mix well and extract with acetonitrile, the organic layer is dried with anhydrous sodium sulfate, separated and purified by column chromatography to obtain yellow solid 2-[4-piperazine formaldehyde-1 -ylmethyl]pyrazolo[1,5-α]pyridine 0.1312g.

[0035] (2) Synthesis of 2-[4-piperazin-1-ylmethyl]pyrazolo[1,5-α]pyridine

[0036] 2-[4-piperazine formaldehyde-1-ylmethyl]pyrazolo[1,5-α]pyridine (0.1000g, 0.4093mmol) and 6mol / L H 2 SO 4 (10mL) reacted at 60°C for 10 hours, cooled to room temperature, added concentrated...

Embodiment 3

[0041] Example 3: In vitro receptor binding analysis of 2-[4-(4-fluorobenzyl)piperazin-1-ylmethyl]pyrazolo[1,5-α]pyridine

[0042] Take 33 test tubes (12×60mm) and divide them into 3 groups: total binding tube (TB tube, 1×3), non-specific binding tube (NSB tube, 1×3), sample tube (SB tube, 9×3 branch). Add [ 3 H]Spiperone (spiperone) (the final concentration is 0.7nmol / L), add 100 μL of buffer solution to the total binding tube, add (+)-Butaclamol hydrochloride (butaclamol hydrochloride) 20 μL to the non-specific binding tube ( The final concentration is 1 μM), and a series of concentrations of 2-[4-(4-fluorobenzyl)piperazin-1-ylmethyl]pyrazolo[1,5-α]pyridine dissolved in DMF and water were added to the sample tube (Ligand) (The final concentration of each tube is 1×10 -11 mol / L, 1×10 -10 mol / L, 1×10 -9 mol / L, 1×10 -8 mol / L, 1×10 -7 mol / L, 1×10 -6 mol / L, 1×10 -5 mol / L, 1×10 -4 mol / L, 1×10 -3 mol / L), various reagents and dopamine receptors were added according to Tab...

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Abstract

The invention discloses a fluoride-18 marked dopamine D4 receptor developing agent and a preparation method thereof. The fluoride-18 marked dopamine D4 receptor developing agent is 2-[4-(4-[<18>F] fluorobenzyl) piperazine-1-yl methyl] pyrazolo [1, 5-alpha] pyridine, and the structural formula of the developing agent is shown in a formula (I). The preparation method comprises three steps of: step one, reacting pyrazolo [1, 5-alpha] pyridine-2-formaldehyde with N-formoxyl piperazine to generate 2-[4-piperazine formaldehyde-1-yl methyl) pyrazolo [1, 5-alpha] pyridine; step two, hydrolyzing 2-[4-piperazine formaldehyde-1-base methyl) pyrazolo [1, 5-alpha] pyridine under a strong acidic condition to generate 2-[4-piperazine-1-yl methyl) pyrazolo [1, 5-alpha] pyridine; and step three, reacting 2-[4-piperazine-1-yl methyl) pyrazolo [1, 5-alpha] pyridine with 4-[<18>F] fluorobenzaldehyde to generate a target molecule. 2-[4-(4-[<18>F] fluorobenzyl) piperazine-1-yl methyl] pyrazolo [1, 5-alpha] pyridine prepared by the method can be used for dopamine D4 receptor development and is a specific dopamine D4 receptor developing agent.

Description

technical field [0001] The invention belongs to the technical field of chemistry and medicine, in particular to a fluorine-18 labeled dopamine D 4 Receptor imaging agent and preparation method, the imaging agent is 2-[4-(4-[ 18 F]fluorobenzyl)piperazin-1-ylmethyl]pyrazolo[1,5-α]pyridine. Background technique [0002] The dopamine system is related to motor control, learning, cognition, etc., and is necessary for normal brain function; dopamine receptors are closely related to mental disorders, schizophrenia, attention deficit hyperactivity disorder, and Parkinson's disease. dopamine D 4 The receptor belongs to the G-protein coupled receptor, which consists of 387 amino acids, and its gene is related to D 2 The receptor gene belongs to chromosome 11 at position 11p15. dopamine D 4 Receptor plays an important role in the etiological development of schizophrenia, encoding the D 4 There may be an important link between the gene of the receptor and schizophrenia and addicti...

Claims

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Application Information

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IPC IPC(8): A61K51/04C07D471/04A61K101/02
Inventor 李谷才袁立华
Owner HUNAN INSTITUTE OF ENGINEERING
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