TWI653052B - Preparation of [18f] t807 derivatives and uses thereof - Google Patents

Abstract

The present invention relates to an N-alkyl analog of [ ¹⁸ F]T807 and a process for the preparation thereof, and a composition comprising the N-alkyl analog of such [ ¹⁸ F]T807 and its use, for example, as a Tau protein developer .

Description

Preparation and use of [ 18 F]T807 derivatives

The present invention relates to N-alkyl analogs of [ ¹⁸ F]T807 and processes for their preparation, and to compositions comprising the N-alkyl analogs of [ ¹⁸ F]T807 and uses thereof.

Alzheimer' disease (AD) is one of the most common causes of death and disability worldwide, with significant clinical and socioeconomic impacts. It is characterized by degeneration of neurons in the hippocampus and cortex and the appearance of neuritic spots and neurofibrillary tangles (Goedert et al. , Science . 314, 777-781 (2006); Huang et al. , Cell . 148, 1204-1222) . (2012)>, and the main component of neurofibrillary tangles is the hyperphosphorylated Tau protein and its paired helical filaments (PHF). Alzheimer's disease is thought to be caused by the accumulation of abnormal beta-starch protein and Tau protein in the brain (Hashimoto M, Rockstein E, Crews L, Masliah E. Role of protein aggregation in mitochondrial dysfunction and neurodegeneration in Alzheimer's and Parkinson's Diseases. Neuromolecular Med. 2003, 4(1-2): 21-36). A positron emission tomography (PET) contrast agent for beta-amyloid protein and τ<Tau> protein will be used to non-invasively monitor the response to Alzheimer's drug therapy and promote the development of Alzheimer's disease drugs. . [ ¹⁸ F]T807 has proven to be a promising PHF-Tau protein tracer for the study of Alzheimer's disease in humans (Chien et al. , J Alzheimers Dis . 34, 457-468 (2013)). The inventors have previously developed an improved synthesis of such contrast agents (Huang et al. , J Labelled Cpd Radiopharm . 58, S170 (2015)) and used them in clinical studies. However, there is still a need for improved techniques for improving the ability to develop PHF-Tau in patients to expand clinical benefits.

In order to improve the brain uptake of [ ¹⁸ F]T807, the inventors synthesized three N-alkyl analogs of [ ¹⁸ F]T807 and evaluated their effects as a PHF-Tau protein contrast agent. It was found that the lipophilicity and whole brain uptake of these [ ¹⁸ F]T807 analogues in normal mice were significantly higher than that of [ ¹⁸ F]T807 itself, so PHF- was significantly improved compared to the [ ¹⁸ F]T807 system. Tau protein contrast agent.

Accordingly, the present invention provides a compound of the formula:

Wherein R is a C _1-3 alkyl group. In one embodiment, the R is methyl, ethyl, or n-propyl.

The invention also provides a diagnostic composition comprising a compound of the formula:

Wherein R is a C _1-3 alkyl group; and a pharmaceutically acceptable carrier or diluent (eg, physiological saline, etc.). In one embodiment, the R is methyl, ethyl, or n-propyl.

The invention further provides the use of a composition for the preparation of a Tau protein contrast agent, wherein the composition comprises a compound of the formula:

Wherein R is a C _1-3 alkyl group; and a pharmaceutically acceptable carrier or diluent (eg, physiological saline, etc.). In one embodiment, the R is methyl, ethyl, or n-propyl.

The present invention still further provides a method of producing a compound of the formula:

Wherein R is C _1-3 alkyl; the method comprises bringing a compound represented by the formula:

Reacts with K[ ¹⁸ F]/K _2.2.2 . In one embodiment, the R is methyl, ethyl, or n-propyl.

Figure 1 is a semi-preparative HPLC purification of [ ¹⁸ F]T807 and its N-alkyl analog.

Figure 2 is a section of a healthy control (70-year-old female) and a patient with Alzheimer's disease (85-year-old female) with a marginal slice of the human frontal lobe. The thickness of these sections is 10 μm and passes through [ ¹⁸ F]T807 and its N-alkane. The base analog was cultured (185 kBq/slice) (n = 1).

3 lines ^[18 F] T807-alkyl and N- whole brain microPET time like in normal mice (n = 3) - The activity profile.

The invention may be embodied in different forms and is not limited to the examples mentioned below. The following examples are merely representative of the various aspects and features of the present invention.

As previously reported, [ ¹⁸ F]T807 was synthesized by the TraceLab FX _FN module (Huang et al. , J Labelled Cpd Radiopharm . 58, S170 (2015)). Briefly, the corresponding nitro precursor was subjected to nucleophilic aromatic fluorination with K[ ¹⁸ F]/K _2.2.2 in DMSO at 130 ° C for 10 minutes, followed by hydrolysis with HCl and half Preparative HPLC (Phenomenex Luna (2) HILIC, 5 μm, 10×250 mm, 0.1% HCl, 3 ml/min, 254 nm) was purified to give the final product (1) . Three N-alkyl analogs of [ ¹⁸ F]T807 (3) (wherein R is a methyl group, an ethyl group, or a n-propyl group, and the corresponding compounds are respectively referred to as [ ¹⁸ F]NM-T807, [ ¹⁸ F] ^{NE-T807, [18 F]} NP-T807) is based on a method similar to the synthesis from the corresponding nitro precursors (2), but no subsequent hydrolysis reactions (scheme 1, Figure 1).

HPLC (Phenomenex Luna HILIC 200Å, 5 μm, 250 x 4.6 mm, 10% EtOH (pH = 2), 0.75 ml/min, 254 nm) and radioactive TLC (Silica plate, 10 cm, containing 80 μl of 40% NH4OH _{(aq) )} in _{MeOH / CH 2 Cl 2 (20ml} , 1/19)) radiochemical purity of these contrast agents. The log P of these contrast agents was measured by the reported method (Oya et al. , Nucl Med Biol . 27, 249-254 (2000)), and in healthy controls (70 year old females) and Alzheimer's disease patients (85 years old). In vitro autoradiography of these contrast agents was performed on post-mortem brain frontal lobe slices of females as previously reported (Chang et al. , Appl Radiat Isot, 67, 1397-1400 (2009)). For animal studies, fastened male ICR mice (n=3) were injected intravenously with approximately 200 μCi of each contrast agent and imaged with an Argus PET/CT scanner. A dynamic sinogram is generated with a picture of 12 x 10 seconds, 3 x 60 seconds, 3 x 300 seconds, 4 x 6000 seconds, and 2 x 900 seconds. An average microPET image of the entire scan (90 minutes) was obtained using eXplore Vista PET-CT MMWKS software.

The radiochemical yield (RCY) of [ ¹⁸ F]T807, [ ¹⁸ F]NM-T807, [ ¹⁸ F]NE-T807 and [ ¹⁸ F]NP-T807 synthesized by this method was 13 respectively. ±4 (n=15), 7±6 (n=5), 7±4 (n=5), and 5±1% (n=5), radiochemical purity >95%, and log P of 2.05, respectively ±0.10, 2.00±0.10, 2.11±0.17, and 2.42±0.13 (n=5). Autoradiography studies have shown that these [ ¹⁸ F]T807 analogs have specific binding in the frontal lobe of patients with Alzheimer's disease ( Figure 2 ). In normal mice, whole brain uptake of [ ¹⁸ F]T807, [ ¹⁸ F]NM-T807, [ ¹⁸ F]NE-T807 and [ ¹⁸ F]NP-T807 reached a maximum at 0.6 min after injection, and afterwards Was quickly washed out. The standard uptake values (SUV) of these contrast agents were 1.7, 3.2, 3.1, and 5.8, respectively ( Fig. 3 ).

From the experimental results, the lipophilicity and whole brain uptake of these analogs in normal mice were significantly higher than that of [ ¹⁸ F]T807 itself. In summary, the development ability of these [ ¹⁸ F]T807 analogs is significantly improved, so it can be used as a better PHF-Tau protein contrast agent than [ ¹⁸ F]T807.

A person skilled in the art will readily appreciate that the present invention can be easily accomplished with the results and advantages and those present in the present invention. The compounds, compositions, processes and methods of making the same, and uses thereof, are representative of the preferred embodiments, which are exemplary and not limited to the field of the invention. Those skilled in the art will be aware of the modifications and other uses therein. These modifications are intended to be within the spirit of the invention and are defined in the scope of the claims.

The present invention has been described in detail with reference to the embodiments of the present invention, and the invention may be Spirit and scope.

All of the patents and publications mentioned in the specification are subject to the ordinary skill in the art to which the invention pertains, and the entire contents of which are incorporated herein by reference. All patents and publications are hereby incorporated by reference to the same extent as if each individual publication is specifically and individually indicated.

The invention as exemplified herein may be practiced in the absence of any element, or a plurality of elements, limitations, or limitations. The nouns and expressions used are as a description and not a limitation of the description, and are not intended to be used to exclude any nouns and expressions that are equivalent to the features or parts thereof shown and described, but Various changes are possible within the scope of the patent application of the invention. Therefore, it is to be understood that the present invention has been disclosed and described herein in accordance with the preferred embodiments and the features of the present invention. Within the scope.

Claims (4)

a compound of the formula Wherein R is methyl, ethyl or n-propyl. A diagnostic composition comprising a compound of the formula Wherein R is methyl, ethyl or n-propyl; and a pharmaceutically acceptable carrier or diluent. A use of a composition for the preparation of a Tau protein contrast agent, wherein the composition comprises a compound of the formula: Wherein R is methyl, ethyl or n-propyl; and a pharmaceutically acceptable carrier or diluent. A method of making a compound of the formula: Wherein R is methyl, ethyl or n-propyl; which comprises a compound represented by the formula: Reacted with K[ ¹⁸ F]/K _{2.2.2 under} the reaction conditions of DMSO and at 130 ° C.