CN1225451C - Aliphatic acid metabolic imaging agent beta-methyl-15-parafluoro [18F] phenyl-pentadecanoic acid and synthesizing method thereof - Google Patents
Aliphatic acid metabolic imaging agent beta-methyl-15-parafluoro [18F] phenyl-pentadecanoic acid and synthesizing method thereof Download PDFInfo
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Abstract
The present invention relates to an aliphatic acid metabolic imaging agent beta-methyl-15-parafluoro((18)<F> phenyl-pentadecanoic acid and a synthesizing method thereof, particularly to a fluorine-labeled aliphatic acid myocardial metabolism imaging agent. Beta-methyl-phenyl-pentadecanoic acid in the *I-BMIPP structure is used as a precursor and reformed to form the substance (18)<F>-BMFPP of the present invention, and (18)<F>-BMFPP is compound which is independently designed and synthesized by the present invention. Omega bromine undecanoic acid is used as initial raw materials to synthesize BMPPA through polystep reaction. In the present invention, labelled precursor NO2-BMPPA and nonradioactive BMFPP are obtained through the nitration, esterification, reduction, diazotization and diazonium decomposition of BMPPA, and the nucleophilic displacement reaction of the labelled precursor NO2-BMPPA is carried out to synthesize (8)<F>-BMFPP. The present invention improves the iodination method for synthesizing intermediate bodies such as benzene dodecyl iodine and alpha-methyl-benzene tetradecyl iodine. The present invention enhances yield and reduces cost because of the improvement.
Description
Technical field
A kind of fatty acid metabolism developer Beta-methyl-15-to fluorine [
18F] phenyl-pentadecylic acid and synthetic method thereof, relate to a kind of fluorine mark lipid acid myocardial metabolic agent.
Background technology
Over past ten years, positron emission fault (PET) video picture has been widely used in the clinical and fundamental research of tumour, neuropsychiatric disease and cardiovascular disorder etc. clinically, and progressively becomes the new scientific research method of gene function and new drug development research.The application of PET and development be unable to do without the PET positron emitting tracer, and clinical positron emitting tracer commonly used because the transformation period is short, can not rely on from external import, lean on development voluntarily.In medical short-half-life nucleic,
18F has the relatively long transformation period (110min), can closely use in addition at the PET center, and is in recent years, right abroad
18The research Showed Very Brisk of the various positron emitting tracers of F mark.
The problem of myocardial viability estimation is the focus of nuclear cardiology in recent years always, though
201Tl and
99mTc-MIBI single photon computerized tomography (SPECT) myocardial perfusion imaging has been done highly effective work, but the PET aspect, glucose (
18F-FDG) myocardial metabolic imaging and
13NH
3Myocardial perfusion imaging is acknowledged as " gold " standard of judging myocardial viability.Abroad, the work of lipid acid cardiac muscle SPECT metabolism video picture is very deep, domestic owing to not can manufacture
123I, this work can't be goed deep into.
Lipid acid is the main energy derive of cardiac muscle, and myocardium fatty acid metabolism and myocardium residing state are closely related, and when myocardial ischaemia, the picked-up of myocardium lipid acid and removing also change thereupon, so fluorine mark lipid acid can be used for the estimation of myocardial cell's survival.Relatively more successful in recent years has
18F-FTHA and
18F-FTP respectively at 6 and 4 assorted unisulfur stoms of longer chain fatty acid, has reduced the beta-oxidation speed of lipid acid, obviously prolongs its residence time in cardiac muscle, studies show that
18F mark lipid acid is by plastosome oxidation picked-up, and the myocardium radioactivity speed of concentrating can reflect the rate of oxidation of longer chain fatty acid, has been used for clinical atraumatic ground at present and has measured myocardium substrate utilization state, instructs clinical drug therapy.
Summary of the invention
The purpose of this invention is to provide a kind of fatty acid metabolism developer Beta-methyl-15-to fluorine [
18F] phenyl-pentadecylic acid and synthetic method thereof.
Technical scheme of the present invention
On-radiation compound Beta-methyl-15-is to fluorophenyl-pentadecylic acid (β-methyl-fluorophenylpentadecanoic acid is abbreviated as BMFPP), structural formula:
Target precursors NO
2-BMPPA is through nucleophilic displacement reaction, obtain target compound Beta-methyl-15-to fluorine [
18F] phenyl-pentadecylic acid, be called for short
18F-BMFPP is a positron emitting tracer.
BMFPP is used for the radioactivity target compound
18The standard substance that the F-BMFPP ultraviolet is identified.
Its synthetic method is
BMFPP is to be that parent is transformed with Beta-methyl-phenyl-pentadecylic acid in the BMIPP structure, and this is that we design the synthetic compound voluntarily.With the acid of ω bromo-n-11 is starting raw material, through 14 and ten six-step processes, obtains labelled precursor NO respectively
2-BMPPA and on-radiation compd B MFPP.The synthetic method reference literature of BMPPA [GoodmanMM, et al, J.Med.Chem.1984 wherein; 27:390-397] in method, and some improvement have been done, promptly when synthetic (5) and (8), the iodate method that needing in the document to replace expensive raw material with better simply iodate method, the productive rate of committed step is significantly improved, and to BMPPA, total recovery is about 44% (document is 21%) from the benzene lauryl alcohol, reduced synthetic cost, the infrared spectra of resulting BMPPA, mass spectrum and hydrogen spectrum data are all consistent with document.Set out with BMPPA, decompose, obtain labelled precursor NO through nitrated, esterification, reduction, diazotization and diazonium salt
2-BMPPA and on-radiation compd B MFPP are again by labelled precursor NO
2It is synthetic that-BMPPA carries out nucleophilic displacement reaction
18F-BMFPP.
Beneficial effect of the present invention
As mentioned above, when synthetic (5) and (8), needing in the document to replace the iodate method of expensive raw material with better simply iodate method, the productive rate of committed step is significantly improved, to BMPPA, total recovery is about 44% (document is 21%), has reduced synthetic cost from the benzene lauryl alcohol.
Detect with TLC and HPLC
18F-BMFPP prepares the radiochemical purity of liquid all greater than 95%, and is free
18F and
18The resolution of F-BMFPP is better, on-radiation BMFPP and radioactivity
18The retention time unanimity of F-BMFPP shows that marker is desired obtaining
18F-BMFPP.
18F-BMFPP solution was at room temperature placed 3 hours, and RCP does not have obvious change; External protein binding is high and stablize fat-soluble height.Above result shows
18The external performance of F-BMFPP is good, possesses the condition as myocardial developer.
The radioactive uptake of experimental period in-seam not in time prolongation and increase, show
18Metabolism is without this link of direct defluorinate in vivo for F-BMFPP, and this is consistent with the expection imagination, and the prompting fluorine atom is substituted on the fragrant phenyl ring, is difficult for defluorinate, and the body internal stability is better.
Description of drawings
Fig. 1 BMFPP and
18The F-BMFPP color atlas
Embodiment
1, be starting raw material with ω-bromo-n-11 acid, through synthesizing of the synthetic BMPPA ω of polystep reaction-bromine undecanoyl benzene (1)
In the there-necked flask of 500ml, add 54g exsiccant ω-bromo-n-11 acid, 20ml sulfur oxychloride, 0.5mlDMF.Stirring heating backflow 1h is cooled to about 10 ℃, adds the benzene of the dry no thiophene of 250ml, 32 gram Aluminum chloride anhydrouss.Continue reflux 2h, cooling is poured in the 300ml water, tells the benzene layer, and water layer extracts once with benzene, the combined benzene layer, and evaporate to dryness, the resistates underpressure distillation gets colourless product (1), productive rate about 60%.Its bp:220 ℃/2kPa, mp:49～51 ℃.Ultimate analysis: theoretical value (measured value) is C%:62.77 (62.69), H%:7.69 (7.87).IR(cm
-1)：3030(-CH
2)，1680(-CO-)，1500，770，690(-ph)。
Synthesizing in the 500ml there-necked flask of 12-oxo benzene lauronitrile (2), add 0.2mol compound (1), 200ml DMSO, 0.22mol NaCN
Behind 90 ℃ of stirring reaction 4h, cooling is poured in the 400ml water, filters, and solid sherwood oil recrystallization gets white plates crystal (2), productive rate 90%.Its mp:56～57 ℃.Ultimate analysis: theoretical value (measured value) is C%:79.70 (79.52), H%:9.23 (9.64), N%:5.16 (5.07).IR(cm
-1)：1680(-CO-)，2245(-CN)。
Synthesizing of benzene methyl dodecanoate (3)
In the 500ml four-hole boiling flask, add 0.20mol compound (2), the hydrazine hydrate of 0.3mol 85%, 1.0mol potassium hydroxide, 250ml glycol ether.Behind the reflux 2h, slowly be warming up to 210 ℃, keep the about 4h of reaction, emit until no gas.Reactant is poured in the 300ml water, and the benzene laurostearic acid is separated out in acidifying.Must purifying, the benzene laurostearic acid of gained is added in the 500ml there-necked flask, add 250mL methyl alcohol again, the 10ml vitriol oil.Back flow reaction 4h pours reaction solution in the 300ml water into, uses extracted with diethyl ether three times, the combined ether layer, and the evaporate to dryness ether, the resistates underpressure distillation gets colourless liquid (3), and productive rate is 90%.Its bp:196 ℃/2Kpa, ultimate analysis: theoretical value (measured value) is C%:78.62 (78.45), H%:10.34 (9.97).IR(cm
-1)：1730(-COOCH3)。
Synthesizing of benzene lauryl alcohol (4)
Add the 0.1mol Lithium Aluminium Hydride in the 500mL there-necked flask, the 200ml anhydrous diethyl ether stirs the 50ml anhydrous ether solution that drips 0.1mol compound (3) down.The control rate of addition slowly refluxes reaction solution, after dropwising, and backflow 4h.Cooling is slowly poured in the water, is acidified to clarification, uses extracted with diethyl ether three times, the combined ether layer, and evaporate to dryness ether, resistates sherwood oil recrystallization gets white crystal (4), productive rate 90%.mp：40～41℃。Ultimate analysis: theoretical value (measured value) is C%:82.44 (83.32), H%:11.45 (11.76).IR(cm
-1)：3500(-OH)。
Synthesizing of benzene dodecyl iodine (5)
In 150ml single port flask, add 0.1mol compound (4), 0.06mol iodine, 0.1mol red phosphorus.Stirring heating is reacted 40h in 150～160 ℃ of oil baths.Reactant is poured in the water, filtered, use extracted with diethyl ether three times, combined ether layer, evaporate to dryness ether.The resistates cooling is made leacheate with sherwood oil, crosses silicagel column.Merge whole leacheates, behind anhydrous sodium sulfate drying, the evaporate to dryness sherwood oil, crude product (5), must purifying, carry out next step reaction.
Synthesizing of Alpha-Methyl-benzene ethyl myristate (6)
In the 500ml there-necked flask, add 100ml 1.2mol/L n-butyllithium solution, be cooled to-60 ℃, drip 4 of 0.14mol, 4-dimethyl-2-Yi Ji oxazole (being dissolved in 50ml THF) solution.After low temperature (78 ℃) reacts 1h down, be warming up to-35 ℃, drip the 50ml THF solution of 0.1mol benzene dodecyl iodine crude product (5), dropwise, continue to stir 1h.Rise to room temperature, continue to stir 1h.Reaction solution is poured in the water, be acidified to neutrality, use extracted with diethyl ether three times, combined ether layer, evaporate to dryness ether.Resistates and 200ml 95% ethanol and 15ml vitriol oil backflow 24h.Cooling is poured in the 200ml water, uses extracted with diethyl ether three times, the combined ether layer, and behind anhydrous sodium sulfate drying, the evaporate to dryness ether, underpressure distillation gets weak yellow liquid (6), and two step overall yields are 85%.Bp:224 ℃/2KPa, ultimate analysis: theoretical value (measured value) is C%:79.77 (79.38), H%:10.98 (10.87).IR(KBr，cm
-1))：1730(-COOC
2H
5)。
Synthesizing of Alpha-Methyl-benzene tetradecyl alcohol (7)
In the 500ml there-necked flask, add 0.1mol LiAlH
4, the 200ml anhydrous diethyl ether stirs, and drips the 50mL anhydrous ether solution of 0.1mol compound (6).Dropwise, continue stirring and refluxing 4h.After the cooling, reaction solution is poured in the water, used extracted with diethyl ether three times, combined ether layer, evaporate to dryness ether.The resistates underpressure distillation gets colourless liquid (7), and productive rate is 90%.Bp:210 ℃/2Kpa, ultimate analysis: theoretical value (measured value) is C%:82.89 (82.69), H%:11.84 (10.58).IR(KBr，cm
-1))：3500(-OH)。
Synthesizing of Alpha-Methyl-benzene tetradecyl iodine (8)
In 150ml single port flask, add 0.1mol compound (7), 0.06mol iodine, 0.1mol red phosphorus.Stirring heating is reacted 40h in 150～160 ℃ of oil baths.Reactant is poured in the water, filtered, use extracted with diethyl ether three times, combined ether layer, evaporate to dryness ether.The resistates cooling is made leacheate with sherwood oil, crosses silicagel column.Merge whole leacheates, behind anhydrous sodium sulfate drying, the evaporate to dryness sherwood oil, crude product (8), must purifying, carry out next step reaction.
Synthesizing of Alpha-Methyl-benzene 15 nitriles (9)
In the 500ml there-necked flask, add 0.1mol crude product (8), 200ml DMSO, 0.12mol NaCN, in 90 ℃ of stirring reaction 4h, pour in the water, use extracted with diethyl ether three times, the combined ether layer, the evaporate to dryness ether, the resistates underpressure distillation gets colourless liquid (9), and two step overall yields are 70%.Bp:206 ℃/2Kpa, ultimate analysis: theoretical value (measured value) is C%:84.34 (84.19), H%:11.18 (10.97), N%:4.47 (4.86).IR(KBr，cm
-1))：2245(-CN)。
Synthesizing of Beta-methyl-benzene pentadecanoic acid (BMPPA)
In the 500mL there-necked flask, add 0.1mol compound (9), 200mL ethylene glycol, 0.5mol KOH, back flow reaction is to there not being NH
3Emit.Reaction solution is poured in the water, cooling, solid is separated out in acidifying, uses acetone recrystallization, gets white granular solid BMPPA, and productive rate is 90%.mp：38～39℃。Ultimate analysis: theoretical value (measured value) is C%:79.52 (79.09), H%:10.84 (9.74).IR(KBr，cm
-1))：3030(-CH)，2919，2853(-CH2)，1704(-C＝O)。
1HNMR(CDCl
3，δ(10
-6))：0.96(d，3H，CHCH
3)，1.27(s，22H，CH
2)，1.95(s，1H，CH)，2.25(d，2H，CHCH
2CO
2)，2.58(t，2H，phCH
2)，7.27(s，5H，Ar-H)。MS，m/e：332(M
+，8)，314(M
+-H
2O，11)，104(M
+-H
3C(CH
2)
9CH(CH
3)CH
2COOH，18)，92(M
+-HC(CH
2)
10CH(CH
3)CH
2COOH，34)，91(M
+-(CH
2)
11CH(CH
3)CH
2COOH，100)。
2, with the BMPPA complex sign precursor NO that sets out
2-BMPPA and on-radiation BMFPP
Synthesizing of Beta-methyl-15-p-nitrophenyl-pentadecylic acid (10)
To fill 30ml nitration mixture (HNO
3/ H
2SO
4, 100ml beaker V/V=1.3/1) places ice-water bath, under agitation adds 10g BMPPA, finishes, and continues to stir after 1 hour, and reaction solution is poured in the frozen water, filters.
Get white solid (10) 9.5g, productive rate 83.8% with acetone recrystallization.mp＝64～65℃。IR(KBr，cm
-1)：2917，2850(-CH)，1706(-C＝0)，1517，1351(-NO
2)。Ultimate analysis: theoretical value (measured value) is C%:70.03 (70.18), H%:9.28 (9.46), N%:3.71 (3.28).MS，m/z：378(M+1，20)，360(M
+-OH，100)。
1HNMR(CDCl
3，δ(10
-6))：0.95(d，3H，-CH
3)，1.30(m，20H，-CH
2-)，1.58(t，2H，-CH
2COO)，1.90(S，1H，CH(CH
3)CH
2COO)，2.15(m，2H，ph-NH
2)，2.50(t，2H，phCH
2)，3.80(s，1H，COOH)，6.92(d，2H，Ar-H)，7.57(S，2H，Ar-H)。
Beta-methyl-15-p-nitrophenyl-pentadecylic acid methyl esters (NO
2-BMPPA) synthetic
In 100mL single port flask, add 9g (10), 50mL methyl alcohol, the 2mL vitriol oil behind the stirring and refluxing 2h, is poured in the water, uses extracted with diethyl ether, the evaporate to dryness ether.The resistates acetone recrystallization gets the about 8.7g of white solid (being liquid under the room temperature), productive rate: 93.5%.mp：24-26℃。IR(KBr，cm
-1)：3027(-CH)，2924，2853(-CH
2)，1742(-C＝0)，1517，1353(-NO
2)。Ultimate analysis: theoretical value (measured value) is C%:70.59 (70.48), H%:9.46 (9.87), N%:3.58 (3.90).MS，m/z：391(M
+，30)，290(M
+-CH
2CH(CH
3)CH
2COOCH
3，35)，98(M
+-NO
2-ph(CH
2)
10，-OCH
3，100)，
1HNMR(CDCl
3，δ(10
-6))：0.95(d，3H，-CH
3)，1.30(m，20H，-CH
2-)，1.60(t，2H，-CH
2COO)，1.95(S，1H，CH(CH
3)CH
2COO)，2.25(m，2H，-CH
2CH(CH
3))，2.65(t，2H，phCH
2)，3.70(S，3H，-OCH
3)，7.20(d，2H，Ar-H)，7.57(d，2H，Ar-H)。
Synthesizing of Beta-methyl-15-p-amino phenyl-pentadecylic acid (11)
Add (10) 2g, distilled water 30ml and concentrated hydrochloric acid 1ml in two mouthfuls of flasks of 100ml, stirring and refluxing 6 hours in this process, adds the 1g reduced iron powder in batches.Question response finishes, and is cold slightly, topples over and anhydrates, and adds 30ml acetone backflow 20min, filtered while hot, and yellow solid (11) 1.6g is separated out in the mother liquor cooling, productive rate 86.9%, mp:90～92 ℃; IR (KBr, cm
-1): 3347,3284 (N-H), 2919,2852 (C-H), 1672cm
-1(-C=0); Ultimate analysis: theoretical value (measured value) is C%:76.08 (76.65), H%:10.66 (10.49), N%:4.03 (4.58): MS, m/e:347 (M
+, 40), 106 (M
+-(CH
2)
11CH (CH
3) CH
2COOH, 100);
1HNMR (CDCl
3), δ (10
-6)): 0.93 (d, 3H ,-CH
3), 1.35 (m, 22H ,-CH
2-), 1.58 (t, 2H ,-CH
2COO), 1.90 (S, 1H, CH (CH
3) CH
2COO), 2.15 (m, 1H, ph-NH
2), 2.35 (m, 1H, ph-NH
2), 2.50 (t, 2H, phCH
2), 3.90 (S, 1H, COOH), 6.65 (d, 2H, Ar-H), 7.00 (d, 2H, Ar-H).
Beta-methyl-15-is synthetic to fluorophenyl-pentadecylic acid (BMFPP)
In the 100ml flask, add (11) 1g, 50%H
2SO
420ml, heated and stirred to solution are homogeneous phase (about 90 ℃), are chilled to below 5 ℃, and this moment, solution was suspension liquid, slowly dripped 0.3g NaNO
2Solution continues stirring reaction 30min, adds NaBF
4Saturated sulphuric acid soln 5ml, behind the room temperature reaction 24h, centrifugal treating obtains the tawny solid, infrared analysis is in 2275cm
-1Strong absorption is arranged, show that it is a diazonium salt, after drying, in 130 ℃ of heating 15 minutes, the product extracted with diethyl ether, acetone recrystallization obtains yellow needle-like crystal 0.87g, productive rate 87%.mp：20～22℃，IR(KBr，cm-1)：2919，2851(-C-H)，1715(-C＝0)，1692(-ph)。Ultimate analysis: theoretical value (measured value) is C%:75.43 (75.70), H%:10.00 (9.79).MS(m/e)：350(M
-，40)，332(M
+-OH，35)，109(M
+-(CH
2)
11CH(CH
3)CH
2COOH，100)。
1HNMR(CDCl
3)，δ(10
-6))：0.95(d，3H，-CHCH
3)，1.25(S，22H，CH2)，2.05(s，1H，CH)，2.45(d，2H，CHCH
2COO)，2.60(t，2H，ph-CH2)，6.90(d，2H，Ar-H)，7.57(d，2H，Ar-H)。
3,
18The preparation of F-BMFPP
By labelled precursor NO
2-BMPPA carries out the nucleophilic displacement reaction preparation, and the nucleophilic reaction equation is as follows:
1. fluoridize poly-ammonium (kryptofix/K
+ 18F
-) preparation
By
18O (p, n)
18The carrier free that the F reaction generates
18F
-, be enriched on the anion-exchange column QMA.Use 1mlK
2CO
3-K
2.22(2mmol/L contains K to acetonitrile solution
2.2.210mg) solution will
18F
-Dash to reaction tubes, under nitrogen gas stream, behind 105 ℃ of heating evaporates to dryness, add anhydrous acetonitrile again, 2 * 0.5ml, azeotropic vaporization is to doing, and is standby.
2. the nucleophilic method is carried out
18The F mark
Oil bath heating method: in above-mentioned standby pipes, add fluorine labelled precursor NO
2-BMPPA (6mg is dissolved among the 1ml methyl-sulphoxide DMSO), oil bath be warming up to 140 ℃ the reaction 20min after, put cold, with 10ml HCl (0.1mol/L) dilution, the solution that obtains is crossed Sep-Pak
TMC-18 post (in advance with 5ml ethanol and the activation of 10ml water) is used 10ml HCl (0.5mol/L) flushing again, discards leacheate, will be adsorbed on Sep-Pak with anhydrous diethyl ether 2ml
TMIn the penicillin bottle of radioactivity drip washing to one cleaning on the C-18 post, after nitrogen dried up, (0.2mol/L 0.5ml), in 90 ~ 95 ℃ of oil baths behind the heating 5min, was put coldly, adds acetate (30 μ l) to neutral, crosses Sep-Pak to add sodium hydroxide solution
TMThe C-18 post with the flushing of 10ml water for injection, discards leacheate, will be adsorbed on Sep-Pak with anhydrous diethyl ether 2ml
TMIn the penicillin bottle of radioactivity drip washing to one cleaning on the C-18 post, after nitrogen dried up, RCP was surveyed in the small amount of ethanol dissolving, and calculated radiochemical yield (EOB), total preparation time 90-110min.
Microwave heating method: above-mentioned standby pipes put cold after, add fluorine labelled precursor (6mg is dissolved among the 1ml DMSO), put in the microwave oven, behind 462W reaction 3min, take out, put coldly, aftertreatment is all the same, total preparation time 50-60min.
3.
18The preparation of F-BMFPP injection liquid
Before the injection, above-mentioned sample is added in the HSA solution of 4-6%, in 37 ℃ hatch 30min after, cross the aseptic filter membrane of 0.22 μ m promptly.
4, RCP measures
1. TLC: with product
18The F-BMFPP point sample is in silica gel paper or WhatmanIII chromatographic paper one end, the ether ascending development, and after drying, segmentation detects, and calculates RCP.
2. HPLC: adopt analysis mode C-18 reversed-phase column (ODS, 5 μ m, 3.9 * 150mm), moving phase is 85% acetonitrile, flow velocity 1.0ml/min.Get product
18F-BMFPP 10 μ l (counting about 10K) sample introduction is measured with radioactive detector and UV-detector respectively
18F-BMFPP and BMFPP, the retention time and the radioactivity of observing on-radiation BMFPP
18Whether the radioactivity peak of F-BMFPP is consistent.
5,
18The F-BMFPP study on the stability
The gained injection liquid is placed down in room temperature (25 ℃),, measured the RCP of marker respectively at 1h, 2h and 3h.
6, PC measures
Get marker (RCP＞95%, 5 * 10
4Cpm) add respectively in n-Octanol monophosphate damping fluid (0.1mo/LpH7.00 and the 7.40) two-phase system (V/V=3/3), mixing, behind vortex vibration 3 * 1min, 4000rpm centrifugation 5min, in two pipes, get the 1ml n-Octanol and the 1ml aqueous solution respectively and survey counting, get the 1ml n-Octanol again and inject 3.0ml phosphate buffered saline buffer/2.0ml n-Octanol two-phase system, so repeat 4 times, calculate cpm
Organic phase/ cpm
WaterRatio, constant until ratio, PC=1g[cpm
Organic phase/ cpm
Water]
7,
18Distribute in the F-BMFPP rat body
The SD rat, body weight 200～250g is divided into 5 groups at random, 3 every group.Tail vein injection
18F-BMFPP injection liquid 0.2ml (3.7MBq), after injection 2,10,30,60 and 120min respectively with each group rat sacrificed by decapitation, get tissues such as blood, the heart, liver, spleen, lung, kidney intestines, after claiming weight in wet base, survey tissue radiation, simultaneously by injected dose preparation standard pipe with gamma counter, tracking measurement calculates the percent value (%ID/g wet tissue) that every gram tissue radiation accounts for injected dose.
8, external protein binding experiment
Will
18F-BMFPP (does not add HSA, RCP＞95%, radiocounting 5 * 10
4Cpm), add to the 1ml human serum albumin (HSA, 10g/L, pH7.40PBS) in, hatch 2,5,15,30,60 and 120min respectively at 37 ℃, calculate with the Tricholroacetic Acid precipitator method
18The external protein binding rate of F-BMFPP.
Claims (2)
1, a kind of compound, its name be called Beta-methyl-15-to fluorine [
18F] phenyl-pentadecylic acid, structural formula is
Be called for short
18F-BMFPP.
2, according to claim 1 Beta-methyl-15-to fluorine [
18F] synthetic method of phenyl-pentadecylic acid, comprise that with the acid of ω bromo-n-11 be raw material, through the synthetic BMPPA of polystep reaction, it is characterized in that setting out and decompose through nitrated, esterification, reduction, diazotization and diazonium salt with BMPPA, obtain labelled precursor NO
2-BMPPA and on-radiation compd B MFPP are again by labelled precursor NO
2-BMPPA carries out nucleophilic displacement reaction and makes
18F-BMFPP;
Synthesize Beta-methyl-15-p-nitrophenyl-pentadecylic acid by the BMPPA nitration reaction: will fill the 30ml nitration mixture, HNO
3/ H
2SO
4, V/V=1.3/1, the 100ml beaker place ice-water bath, under agitation add 10g BMPPA, finish, continue to stir after 1 hour, reaction solution is poured in the frozen water, filter, get white solid 9.5g with acetone recrystallization, productive rate 83.8%;
Esterification is synthesized Beta-methyl-15-p-nitrophenyl-pentadecylic acid methyl esters: in 100mL single port flask, add 9g Beta-methyl-15-p-nitrophenyl-pentadecylic acid, 50mL methyl alcohol, the 2mL vitriol oil, behind the stirring and refluxing 2h, pour in the water, use extracted with diethyl ether, the evaporate to dryness ether, the resistates acetone recrystallization, white solid or liquid 8.7g, mp:24～26 ℃, productive rate: 93.5%;
Reduction reaction is synthesized Beta-methyl-15-p-amino phenyl-pentadecylic acid: add 2g Beta-methyl-15-p-nitrophenyl-pentadecylic acid, distilled water 30ml and concentrated hydrochloric acid 1ml, stirring and refluxing 6 hours in two mouthfuls of flasks of 100ml, in this process, add the 1g reduced iron powder, reaction finishes in batches, cold slightly, topple over and anhydrate, add 30ml acetone backflow 20min, filtered while hot, the mother liquor cooling, separate out yellow solid 1.6g, mp:90～92 ℃, productive rate 86.9%;
Synthetic Beta-methyl-the 15-of diazotization and diazonium salt decomposition reaction is to fluorophenyl-pentadecylic acid: add Beta-methyl-15-p-amino phenyl-pentadecylic acid 1g in the 100ml flask, 50%H
2SO
420ml, heated and stirred to solution is homogeneous phase, is chilled to below 5 ℃, and this moment, solution was suspension liquid, slowly dripped 0.3gNaNO
2Solution continues stirring reaction 30min, adds NaBF
4Saturated sulphuric acid soln 5ml, behind the room temperature reaction 24h, centrifugal treating obtains the tawny solid, after drying, in 130 ℃ of heating 15 minutes, the product extracted with diethyl ether, acetone recrystallization obtains yellow needle-like crystal 0.87g, mp:20～22 ℃, productive rate 87%;
Nucleophilic displacement reaction:
(1) fluoridize the preparation that gathers ammonium, by
18O (p, n)
18The carrier free that the F reaction generates
18F
-, be enriched on the anion-exchange column QMA, be 2mmol/L with 1ml concentration, contain K
2.2.2The K of 10mg
2CO
3-K
2.2.2Acetonitrile solution will
18F
-Dash to reaction tubes, under nitrogen gas stream, behind 105 ℃ of heating evaporates to dryness, add anhydrous acetonitrile again, 2 * 0.5ml, azeotropic vaporization is to doing, and is standby;
(2) the nucleophilic method is carried out
18The F mark adds labelled precursor NO in the standby pipes of (1) described preparation
2-BMPPA, 6mg are dissolved in the 1ml methyl-sulphoxide, and oil bath is warming up to 140 ℃ of reactions 20min or 462W microwave reaction 3min, takes out, and put coldly, make through aftertreatment
18F-BMFPP;
Wherein, BMPPA is Beta-methyl-15-phenyl-pentadecylic acid, NO
2-BMPPA is Beta-methyl-15-p-nitrophenyl-pentadecylic acid methyl esters, BMFPP be Beta-methyl-15-to fluorophenyl-pentadecylic acid,
18F-BMFPP be Beta-methyl-15-to fluorine [
18F] phenyl-pentadecylic acid.
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