TW201201846A - Iodo precursor for a PET imaging agent of amyloid plaques - Google Patents

Abstract

The invention relates to a precursor for a [18F]-labeled PET tracer for imaging of Alzheimer's Disease, its synthesis and the process for preparing the respective [18F]-labeled PET tracer.

Description

201201846 VI. Description of the Invention: [Technical Field] The present invention relates to a novel precursor for a positron emission tomography (PET) contrast agent for combining and contrasting amyloid deposits, and a method for preparing the same . [Prior Art] Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by loss of memory, loss of cognition, and loss of behavioral stability. The pathology of AD is defined as extracellular senile plaques composed of fibrous deposits of beta amyloid peptide, and neurofibrillary tangles composed of pairs of helical fibers of hyperphosphorylated butyl. A Αβ peptide containing 39 to 43 amino acids is derived from a larger amyloid precursor protein (App). In the amyloidogenic pathway, APP is cleaved by continuous proteolysis of β- and γ-secretase to give the Αβ peptide. The Αβ peptide is released as a soluble protein and can be measured in small amounts in the cerebrospinal fluid (CSF) of the normal aged brain. During the development of AD, Αβ peptide aggregates and forms powder-killing sediments in the brain parenchyma and vasculature. Diffuse senile plaques can be measured after death, and amyloid can be measured in blood vessels during histological examination. Protein (recently referenced by Blenn〇w et al. Lancet. July 29, 2006; 368 (9533): 387-403) » Alzheimer's disease is becoming a huge health and socio-economics worldwide problem. A great deal of research is devoted to the development of techniques and methods for early detection and effective treatment of the disease. Currently, the clinical diagnostic accuracy of AD for academic devices using memory diseases is about 85 to 90% (Petrella JR et al, Radiology. 2003 226: 315-36). It is based on the exclusion of many diseases that lead to similar symptoms, neurological and psychiatric cautious examinations, and neuropsychological tests. However, histological examination of the brain after death remains the only method of confirming the disease. Therefore, it is considered that detecting a pathological feature of the disease in vivo (deposition of amyloid aggregates in the brain) has a great influence on early detection of AD and differentiation from other dementias. In addition, the goal of most disease-modifying therapies in development is to reduce amyloid loading in the brain. Therefore, angiographic amyloid loading in the brain can provide the necessary means to classify patients and perform therapeutic monitoring. Furthermore, it is also known that amyloid deposits play a role in amyloidoses in which amyloid abnormalities are deposited in different organs and/or tissues, causing diseases. A recent reference is Chiti et al., Annu Rev Biochem. 2006; 75: 333-66 The potential ligand for the amyloid agglutination in the brain must exhibit high binding affinity for amyloid, and Must cross the blood-brain barrier. Regarding the PET tracer binding in the brain of AD patients, the PET tracer that has been studied in humans is: [F-18] FDDNP (Shoghi-Jadid et al., Am J Geriatr Psychiatry 2002; 10: 24-35) [C-ll] PIB (Klunk et al., Ann Neurol. 2004 55: 306-319), [C-ll] SB-13 (Verhoeff et al., Am J Geriatr Psychiatry 2004; 12: 584-595) ' [ F-18]

Bay 94-9172 (Rowe et al., Lancet Neurol 2008, 7: 129-135), [C-ll] BF227 (Kudo et al, J Nucl. Med 2007; 49: 554-561), and [F-18] PIB (Farrar et al., Turku PET Symposium 2007, Abstract 49). Recent references are: Lockhardt, Drug Discov Today, 2006 11: 1093-1099; Henriksen et al., Eur. J. Nucl. 153900.doc s 201201846

Med. Mol. Imaging 2007; Cohen, Mol. Imaging Biol. 2007 9: 204-216; Nordberg, Curr. Opin Biol. 2007, 20: 398-402; Small et al., Neurology 2008 7: 161-172; Nordberg, Eur. J. Nucl. Med. Mol. Imaging 2008, 35, S46-S50. § The most advanced development of the PET agent, in addition to specific binding to amyloid deposits in the brain, still shows the disadvantage, that is, non-specific accumulation, especially in the brain of AD patients and healthy controls White matter area. Non-specific background binding typically interferes with image quality and can, for example, affect the quantification of amyloid proteins and the diagnosis of the initial stages of the disease. It has recently been discovered that a compound of the general formula is a pET tracer (pcT/) for detecting amyloid deposits in patients with a disease specific for amyloid-related diseases at an early stage of the disease. Ep 2009/006406):

Therefore, a tracer is required and one is required for one use; the gas is commercially applicable to the t method for high yield (4) to produce a precursor that is suitable for use in such a method. It has been applied to the precursors of this method by extracting them. This problem has been solved by providing the heart as a precursor to the leaving group. [Summary of the Invention]

丞 ammonium storm. Among these, it is generally believed that the nitro and trimethylammonium groups are most reactive with 153900.doc 201201846 F-18, followed by bromine and chlorine. The iodine leaving group is considered to be the least reactive. In one example only, 'Zhang and Horti stated that iodine is superior to the bromine leaving group [2]. It is stated that if the [18F] fluoride/kryptophene (KryptoHx) 222/potassium carbonate (K2C03) 1 bromopyridine precursor contained in dimercaptosulfoxide (DMSO) is used, the yield is poor (2 to 7°/.). When a corresponding iodine precursor is used, the yield of the radiochemical is from 6 to 8% or more, and the absolute value of the yield can be from 8 to 15%. We have surprisingly found that the erb precursor 1 d is more reactive than the desert precursor 2 a and is therefore more suitable for the radiofluorination reaction, i.e., the synthesis of [18F] tracer 3. Unlike Zhang, which uses [l8]F]fluoride/kreviphene 222/K2C〇3 contained in DMS0, we use a different fluorination method' and we have found that its fluorination yield is higher than current technology. a lot of.

Precursor Id

Precursor 2a 153900.doc

S 201201846

[18F] Illustrator 3 Bromine Precursor 2a Using [Up] Fluoride/Tetrabutylammonium Hydroxide (TBAOH) in DMS0, the attenuation-corrected radiochemical yield obtained by ours is ~15 %. When I use iodine precursor 1 (1, the radioactive chemical yield is 40% or more, and the absolute value of the radiochemical yield after attenuation correction is 56%. Therefore, an embodiment of the present invention A compound of the formula: or a salt thereof is preferably a pharmaceutically acceptable salt thereof:

In the present invention, a preferred salt is a pharmaceutically acceptable salt of the compound of the present invention. The invention also encompasses salts which are not themselves suitable for pharmaceutical use, but which can be used, for example, to isolate or purify the compounds of the invention. The pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts with inorganic acids, diacids and sulfonic acids, for example, salts with the following acids: hydrochloric acid, hydrogen acid, sulfuric acid, phosphoric acid, sulfonic acid, ethanesulfonic acid , terephthalic acid, sulfonic acid, naphthalene dibasic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid and benzoic acid. 153900.doc 201201846 and another embodiment of the invention is a method of preparing a compound of the formula

Compound of the formula

Ny^ Ο

I reacts with a radioactive fluorinating agent. A preferred embodiment of the invention is a method of preparing a compound of the formula

Compound of the formula

React with the radioactive fluorinating agent at a high level, under a dish, in an organic solvent or organic solvent mixture 153900.doc 201201846. The temperature may range from 14 〇 to 22 (TC, preferably from 160 to 20 〇t, and more preferably from 170 to 190. (:, more preferably from 175 to i85 ° C. A microwave reactor may be used as needed. If so, The reaction can then be carried out in the same or at a higher temperature with a shorter reaction time. In a preferred embodiment, [isF]fluoride/TBA〇H and a solvent are used as the fluorinating agent. In a preferred embodiment, the fluorinating reagent is 4,7,13,16,21,24-hexaoxa-U oxadiazabicyclo[8.8.8]-hexane hexahexane (crown ether salt Krebife (Krypt〇fix) Kl8F), K18F, H18F, KHI8F2 or 18p of the four-base salt. The preferred fluorinating agent is KUF, HUF, or !^%. The solvent used can be N, N-dimethyl The amine (_), dimethyl sulfoxide (surface 0), acetonitrile (MeCN), N, N. dimercaptoamine (dma), etc. are preferably DMS oxime, MeCN MF. The solvent may also be the above solvent. Mixture. Another aspect of the invention is a method of preparing a compound of the formula

Compound of the formula

H2n

153900.doc 0 201201846 Compared with 2-Block. Determine the 4-acid retardation reaction. The preferred aspect of the present invention is a method for preparing a compound of the following formula: ν(〇^〇) a salt of a compound of the following formula

0 is reacted with 2-iodopyridine-4-carboxylic acid. The salt is preferably a hydrochloride salt. Another aspect of the invention is a method of preparing a compound of the formula

Wherein 'first remove the protecting group of the compound of the formula

And then reacted with 2-mothidine-4-carboxylic acid. F-18 radiolabeling process 153900.doc jq β - Β 201201846 Those skilled in the art are familiar with the [F_18] radiolabeling process. For example, radiolabeling can be carried out as described below. [F-1 8] Fluoride can be prepared by using a silver target (1 mL) containing [0-18] water in a cyclotron to perform u〇(p,n)18F anti-" by proton bombardment. should. The [F_18] fluoride aqueous solution can be passed through a tube (for example, QMA-resin tube Waters, Sep Pak Light QMA, model: WAT023525). Subsequent addition can be achieved by adding, for example, a clopidogrel 2.2.2/Κπ〇3 solution (Credefifa is 4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[888] ]_Heptane hexane, so that the captured [F-18] fluoride is dissolved from the tube. The nucleophilic substitution reaction of the precursor is preferably carried out in a base such as tetrabutylammonium hydroxide (NBu4〇H), tetrabutylcarbonate ((NBu4)2C〇3), tetrabutylammonium carbonate (NBU4HC〇) 3), K2C〇34) in the presence and temperature. The addition of a crown ether such as Krebfi (K2 2 can have a positive effect on the reaction, especially in the presence of K2C〇3 as a base. The preferred drying method for potassium fluoride Krefelder complex is: continuous addition The solvent can be used as a reaction solvent under acetonitrile. Solvents such as acetonitrile, DMF, DMSO can be used as the reaction solvent. The labeled product can be purified by solid phase extraction using a tube tube. The preferred tube is Sep_Pak pius C18. (Waters, WAT020515). The tube can be rinsed with water and the compound can be removed using the acetonitrile. The dissolved compound can be diluted with water and subsequently subjected to preparative HPLC purification. Preferably, the HPLC column is Reverse phase column, such as Gemini 5 μ C 18 11〇A, 25〇*1〇mm (phen〇menex, 〇〇g_ 4435-N0). It can be used with buffer solution, acid, water, etc., such as acetonitrile, methanol, A mixture of organic solvents such as ethanol is used as the mobile phase. 153900.doc 201201846 The solution can then be diluted, for example, with water, and concentrated by a tube and solvent exchanged.

Radiotracers to the labeling of macromolecules such as proteins and oligonucleotides. Ernst Schering Research Foundation workshop(62): 1 13-57, 2007, ISBN 978-3-540-32623-6.

[2] Zhang Y. ; Synthesis of 6-chloro-3-((2-(S)-azetidinyl) methoxy)-5-(2-['8F] Fluoropyridin-4-yl)pyridine ([18F]NIDA522131) A novel potential radioligand for studying extrathalamic nicotinic acetylcholine receptors by PET. J Label Compd Radiopharm 2004; 47: 947-952. [Embodiment] Examples The methods of synthesis and labeling are listed in the following examples. The examples illustrate certain aspects and advantageous results of the above methods and are presented by way of illustration and not limitation. Example 1 N-(2-{4-[5-(Benzyloxy) ° ratio _2_yl] σ bottom 嘻-1 _ group}_2_side oxyethyl)-2-break ratio.定-4-甲含胺 a) 5-benzyloxy-2-bromopyridinium

153900.doc

S -12- 201201846 Add 14.75 g (86.21 mmol) of benzyl bromide and 23 82 g (m4 mm 〇1) of potassium carbonate to 1〇.og (57.47 „1„1〇1)2_bromo-5_hydroxyl Pyridine in 4 mL of N,N-monodecylcarbamide (DMF) solution. The mixture was stirred at 6 ° C for 6 h and stirred at room temperature overnight. The suspension was filtered, and after evaporation of the solvent, the residue was subjected to silica gel chromatography using a dichloromethane-methanol gradient. Yield: 14.82 g (96.7 ° / 〇). MS (ESIpos): m/z = 264, 266 [M+H] + h-NMROOO MHz, chloroform _d): s [ppm] = 5 1 〇(s, 2H), 7 i6 (dd, 1H), 7.32-7.47 (m, 6H), 8.14 (d, 1H). b) 1-(5-decyloxy-π ratio _2-yl)-moxazin h〇-〇-〇/~^ All glass containers were dried at 10 (TC). 561 mg (0 61 mm〇 l) bis(monophenylarhenylidene)dipalladium (0) and 52 〇mg (〇83 mm〇1) BINAP (2,2'-bis(diphenylphosphino, dinaphthyl)) 5 2722 mmol) piperazine in 180 mL of toluene solution, followed by the addition of 147 to 55 66. mmol) of 5_nooxyl-pyridine (Example U) in tetrahydrofuran (THF) solution, followed by the addition of 8· 〇 2 g (83.48 mmol) of a suspension of sodium citrate in THF. The reaction mixture was refluxed for 6 h and stirred at rt overnight. After evaporation of the solvent, the residue was chromatographed using a dichloromethane/methanol gradient. 153900.doc 13- 201201846 Yield: 7.12 g (47.0%). MS (ESIpos): m/z = 270 [M+H] + W-NMRPOO MHz 's.s.ssssssssssssssssssssssssssssssssssssssssss 5.04 (s, 2H), 6.63 (d, 1H), 7.21 (dd, 1H), 7.29-7.48 (m, 5H), 8.00 (d, 1H) 〇c) (2-{4-[5-(benzyl) Oxy))pyridin-2-yl]piperazine-byl}_2-side oxyethyl) tert-butyl amide

3. Add 3.43 mL (26.43 mmol) of isobutyl phthalate at -15 ° C dropwise to 500 mL of 4.63 g (26,43 mmol) of third butoxycarbonyl-glycine (Aldrich) THF and 5 mL of triethylamine (35.87 mmol) were allowed to stand and allowed to stand at this temperature for 15 min. Subsequently, a solution of 7.12 g of 1·(5·benzyloxy-pyridin-2-yl)-piperazinium b) and 18 mL of triethylamine (129 mmol) in 200 mL of THF/dichloromethane (1: 1) The solution was slowly added to the cold/cold solution to keep the temperature below -1 Torr for another 15 min and then allowed to reach the dish. After stirring overnight, the solvent was evaporated and the residue was dissolved in ethyl acetate. The solution was washed successively with an aqueous solution of sodium carbonate, water, aqueous hydrochloric acid (HCl), saturated aqueous sodium chloride, and finally dried over sulfuric acid, and then evaporated. The residue was subjected to gel chromatography using a calcined / acetic acid (10) gradient. Yield: 8.04 g (70.6%). MS (ESIpos): m/z = 427 [M+H] + 153900.doc -14. 201201846 h-NMRpOO MHz 'gas imitation-d) : δ [ppmpue (s,9H) 3 36 3.45 (m, 2H) , 3.51 (br. s·, 4H), 3.70-3.81 (m, 2H), 4.02 (d 2H), 5.05 丨 (s, 2H), 5.53 (br. s., 1H), 6.65 (d, lH) , 7.23 (dd 1H), 7.30-7.48 (m, 5H), 8.00 (d, 1H). d) N-(2-{4-[5-(Benzyloxy)acridin-2-yl]piperazin-1-yl}-2-yloxyethyl)-2-iodopyridin-4-indole Guanamine

8.0 g (18.76 mmol) of (2-{4-[5-(benzyloxy)pyridin-2-yl]piperoneyl}-2-oxoethyl)aminocarbamic acid tert-butyl ester ( Ic) was suspended in 160 mL of diethyl ether solution containing 2 n HCl and stirred at room temperature overnight. The precipitate was transferred and washed with ether and at 4 Torr. (:, under vacuum, yield. 7 g. 4 g (quant.). The product was used in the next step without further purification. MS (ESIpos): m/z = 327 [M+H] + 624 mg (1. 2 mmol) hexafluorophosphoric acid (stupid triazole·yloxy)tripyridinium basal scale (PyBOP) and 0-70 mL (4 mmol) N-ethyl·ν, Ν-diisopropylamine added In a solution of 274 mg (1.10 mmol) of 2-iodopyridine-4-carboxylic acid (Alfa Aesar) and 363 mg (1.0 mmol) of the hydrochloride salt obtained in 15 mL of DMF, and the reaction mixture was After stirring at room temperature overnight, the residue was dissolved in ethyl acetate. The bath was washed with water and a saturated aqueous solution of sodium chloride, dried over sodium sulfate, and then evaporated. 153900.doc 15 201201846 A suitable fraction of the residue was concentrated and concentrated using a dioxin/曱3? gradient. Yield: 320 mg (53.8%) MS (ESIpos): m/z = 558 [M+H] + 丨H-NMR (600 MHz, DMSO-d6): δ [p ], layered, and combined: 2,52 2.60 (m, 2H), 2.74-2.76 (m, 4H), 3 36 1' · -3· 37 (m, (s, 2H), 6.02 (d, 1H), 6.46-6.62 (m ^ called), 6.96 (d (d, 1H), 7.38 (d, 1H), 7.69 (d, 1H), 8·17_8 22 (m Example 2 (m,in) a) N_(2-{4_[5_(f-oxy) mouth ratio bite I base] Niang嗓·^基卜^ base)-2-bromopyridine-4-carboxamide gas base B

8.0 g (18.76 mmol) of (2-{4-[5-(benzyloxy)pyridin-2-yl]pyridinyl}-2-yloxyethyl)carbamic acid tert-butyl ester (丨c) The suspension was suspended in 160 mL of diethyl ether solution of HCl 1 and stirred at room temperature overnight to evaporate the precipitate and washed with ether and dried at 40 ° C under vacuum to yield 7.4 g (quant.). The product was used in the next step without further purification. MS(ESIpos) : m/z=327 [M+H] + will be 3.13 (6.〇111111〇1)?丫80? and 2.75 1111>]^-ethyl-1^,>^-two different Propylamine was added to contain 1.01 g (5.01 mmol) of 2-bromopyridine-4-carboxylic acid (Aldrich) -16-153900.doc

S 201201846 and 2.0 g (5.51 mmol) of the above-prepared hydrochloride salt in 16 mL of DMF solution, and the mixture was stirred at room temperature overnight. After evaporating the solvent, the residue was subjected to a layer chromatography using ethyl acetate/ethanol gradient, and the appropriate fractions were combined and concentrated. Yield: 739 mg (27.7%). MS (ESIpos): m/z = 510, 512 [M+H] + 1H-NMR (400 MHz, DMSO-d6): δ [ppm]=2.72 (s, 1H), 2.88 (s, 1H), 3.40 -3.48 (m, 2H), 3.51-3.64 (m, 4H), 4.21 (d, 2H) 5.07 (s, 2H), 6.86 (d, 1H), 7.25-7.48 (m, 6H), 7.81 (dd 1H ), 7.95 (d, 1H), 8.02 (s, 1H), 8.56 (d, 1H), 9.06 (s, 1H). b) N-(2-{4-[5-(Benzyloxy)pyridin-2-yl]piperazine-i-yl-2-ytoxyethyl)-2-fluoropyridine-4-carboxamide (cold standard)

F 8.0 g (18.76 mmol) (2-{4-[5-(benzyloxy)pyridine-2-yl] piperazinyl}-2-oxoethyl)carbamic acid tert-butyl ester (lc It was suspended in 160 mL of diethyl ether solution containing 2 n of HCl and stirred at room temperature overnight. The precipitate was removed and washed with ether and dried under vacuum at 40 °C. Yield: 7.4 g (quantitative). The product was used in one, r - step without further purification. MS (ESIpos): m/z = 327 [M+H] + 784 mg (1.5 mmol) of PyBOP and 0.80 mL of N-ethyl_Nn _ ' ' 153900.doc 17 201201846 propylamine added to 177 Mg(l·25 mm〇l)2_flurazepole_4_decanoic acid (Aldrich) and 501 mg (1.38 mmol) of the above prepared hydrochloride salt in 4 mL of DMF solution and the reaction mixture Stir at room temperature overnight. After evaporating the solvent, the residue was subjected to silica gel chromatography using a gradient of ethyl acetate/ethanol. Yield: 315 mg (50%). MS (ESIpos): m/z = 449 [M+H] + 1H-NMR (400 MHz, DMSO-d6): δ [ppm] = 3.37 (br. Ss 2H) 3.44 (br. s., 2H), 3.52-3.66 (m,4H), 4.22 (d,2H), 5.07 (s, 2H), 6.83 (d, 1H), 7.27-7.47 (m, 6H), 7.53 (s, 1H), 7.7〇. 7.81 (m, 1H), 7.95 (d, 1H), 8.39 (d, 1H), 9.01 (t, 1H). Example 3

Oxyethyl)-2-fluoro. By biting _4_甲甲胺' by labeling n_(2_丨4_[5_(benzyloxy) ° pyridine-2-yl]piperazin-1-yl}_2-sideoxyethyl)_2_ Bromo 0-pyridin-4-decylamine (Example 2a) obtained

[8F]fluoride aqueous solution (38.7 GBq) was contained in QMA tube (Waters) (activated with 5 mL of 0.5 M K2C03 solution, 1 mL of water and 1 mL of air)

The solution was dissolved in 2 mL TBAOH solution (1.5 mL MeCN, 0.5 mL Η2〇+8 TBAOH solution (40%)), and the solution was passed to the reactor 153900.doc •18·201201846. The solvent was removed by heating at 80 ° C for 3 min (N 2 gas flow and vacuum) and at 120 ° C for an additional 3 min (vacuum). Anhydrous MeCN (1 mL) was added and evaporated as described above. A 500 μM anhydrous dimercaptoarylene (DMSO) solution containing the precursor 2a (5 mg) was added. After heating at 180 ° C for 20 min, the crude reaction mixture was diluted with 4 mL water / MeCN (50:50) and purified by preparative HPLC: ACE 5-C18-HL 250 mm x 10 mm; equal concentration, 25% 0.1% aqueous solution of trifluoroacetic acid in acetonitrile, flow rate: 4 mL/min; tR~22 min. The collected HPLC fractions were diluted with 40 mL of water and fixed on a Sep-Pak plus short tC 18 tube (Waters), and the tube was washed with 5 mL of water and dissolved in 1 mL of ethanol to yield 1000 μΐ. 3.5 GBq of the F-18-labeled product in ethanol (yield corrected by radiochemical yield of 15.5%; > 96% HPLC), total synthesis time was ~80 min. The desired F-18-labeled product 3 (tR = 3.2 min) was analyzed by analytical HPLC: ACE3-C18 50 mm>< 4,6 mm; solvent gradient: within 7 minutes, starting from 5% 0.1% trifluoroacetic acid solution of acetonitrile to 0.1 ° / with 95% acetonitrile. The tri-I acetic acid solution, flow rate · 2 mL/min, was confirmed by the corresponding radioactive F-19 fluoride standard 2b co-injected on analytical HPLC (tR = 3.1 min). An alternative method of the above method may also be: dissolving the QMA card tube by using 2 mL of tetrabutylammonium hydroxide (TBAOH) solution (1.5 mL of acetonitrile (MeCN), 0.3 mL of H20+8 pL TBAOH solution (40%)) (Waters) ) and dissolved in the reactor. The open vial was then heated in an aluminum heater at 120 ° C for 10 min under a stream of nitrogen to remove the solvent. Anhydrous MeCN (1 mL) was added and evaporated as described above. 153900.doc 19 201201846 • [18F]-N-(2-{4-[5-(Anoxia)0 is more than 2 bases]#1 base}2 side oxyethyl)-2-fluoropyridine _4_ guanamine, by labeling N_(2_{4_[5_(oxy group) ° ratio. 1,4-yl] oxazine small group}_2 side oxyethyl)_2_ mothium pyridine 4-carbamide (example id) obtained

Add [F] aqueous fluoride solution (11 GBq) to QMA tube (Waters) (activated with 5 mL of 0.5 M K2C03 solution, 1 mL of water and 1 〇 claw^ air)

The solution was dissolved in 2 mL TBAOH solution (1.5 mL MeCN, 0.5 mL Η20+8 μί TBAOH solution (40%)) and dissolved in the reactor. The solvent was removed by heating at 80 ° C for 3 min (N 2 gas flow and vacuum) and heating at 120 ° C for a further 3 min (vacuum). Anhydrous MeCN (1 mL) was added and the evaporation was carried out as described below. A 500 μΐ anhydrous DMSO solution containing the precursor ld (5 mg) was added. After heating at i80 ° C for 2 〇 min, the crude reaction mixture was diluted with 4 mL water / MeCN (50:50) and purified by preparative HPLC. ACE 5-C18-HL 250 mm x 10 mm; A solution containing 23% acetonitrile in water (containing 〇.1% trifluoroacetic acid) at a flow rate of 4 mL/min; tR~33 min 稀释 Diluted the collected HPLC fractions with 40 mL of water and fixed in Sep-

On the Pak plus short tC18 card (Waters), the tube was washed with 10 mL of water and dissolved in 1 mL of ethanol, and dissolved in the product vial to obtain the F-18-labeled product 3 (3.4 GBqp total synthesis time was ~95 min, 153900.doc -20· 201201846 and the attenuation-corrected radiochemical yield was 56% (radiochemical purity > 99% (HPLC)). Analytical HPLC required F- 18-labeled product 3 (tR = 3.2 min): ACE3-C18 50 mm>< 4,6 mm; solvent gradient: starting from 5% acetonitrile in 0.1% trifluoroacetic acid solution over 7 minutes to 95 % acetonitrile in 0. 1% tri-acetic acid solution, flow rate: 2 mL/min, and confirmed by co-injection of the corresponding non-radioactive F-19 fluorine standard 2b (tR = 3.0 min) on analytical HPLC. An alternative method of the above method may also be: dissolving the QMA cartridge by using 2 mL of tetrabutylammonium hydroxide (TBAOH) solution (1.5 mL of acetonitrile (MeCN), 0.3 mL of Η20+8 μί ΤΒΑΟΗ solution (40%)) (Waters) And dissolving into the reactor. The exposure is then heated at 120 ° C in an aluminum heater by nitrogen flow. The solvent was removed for 10 min. Anhydrous MeCN (1 mL) was added and evaporated as described above. [Simplified Schematic] Figure 1: Preparative HPLC for purification of product 3 of the precursor Id as the starting material Chromatogram. Figure 2: Analytical HPLC chromatogram (gamma detection) of product 3 with precursor Id as the starting material. Figure 3: Analytical HPLC chromatogram (UV detection) of 2b corresponding to Figure 2 • Figure 4: Preparative HPLC chromatogram of product 3 used to purify precursor 2a as the starting material. Figure 5: Analytical HPLC chromatogram of product 3 of precursor 2a as starting material (γ Detection) Figure 6: Analytical HPLC chromatogram (UV detection) of 2b corresponding to Figure 5. 153900.doc -21 -

Claims (1)

201201846 VII. Patent application scope: 1 · A compound of the following formula, or a suitable salt thereof 2. A method of preparing a compound of the formula Compound of the formula Reacts with radioactive fluorinating agents. 3. A method of preparing a compound of the formula Which makes the compound of the following formula 153900.doc 201201846 The radioactive fluorinating agent is reacted in an organic solvent at a high temperature. a Organic solvent mixture 4. The method of claim 2 or 3, wherein [18F]fluoride/tba〇h is used as a destructurizer. 5. A method of preparing a compound of the formula: 6. A method for preparing a compound of the formula Wherein compound 0 of the following formula is reacted with 2-iodopyridine-4-carboxylic acid. 7. A method for preparing a compound of the formula I53900.doc Ο 201201846 a salt of a compound of the formula 0 is reacted with 2-iodopyridine-4-carboxylic acid. 8. The method of claim 7, wherein the salt is a hydrochloride salt. 9. A method of preparing a compound of the formula Wherein the protecting group of the compound of the following formula is removed And then reacted with 2-iodopyridine-4-carboxylic acid. 153900.doc