Methods and materials for making pet radiotracers

Abstract

To provide methods and materials for making PET radiotracers.SOLUTION: Embodiments of the present disclosure provide compositions comprising compounds useful to make radiotracers for positron emission tomography imaging, as well as methods for making and using these compositions. The present disclosure also provides packaged compositions comprising precursor compounds and / or intermediates for labeled compounds (e.g., precursor 1 or precursor 3), as well as instructions for making the labeled compounds and methods for using the compounds (e.g., written instructions for their use).SELECTED DRAWING: None

Description

Technical Field

[0001] Cross - Reference to Related Applications This application claims the benefit of U.S. Patent Application No. 17 / 314,366, filed May 7, 2021, entitled "METHODS AND MATERIALS FOR MAKING PET RADIOTRACERS", which is commonly owned and was filed concurrently, under 35 U.S.C. § 120, and which is incorporated herein by reference in its entirety.

Background Art

[0002] Background The present disclosure generally relates to compositions and methods for performing positron emission tomography (PET), and more particularly, to compositions and methods useful for the development and use of 18 F - based PET tracers for PET imaging techniques. 18 The long physical half - life (109 minutes) of F - based tracers is highly desirable as it enables clinical studies without the need for an on - site cyclotron. Further, when using modern PET camera technology, quantitative measurements of radioactivity concentration can be made with high - level time sampling and good statistical accuracy.

[0003] useful for PET imaging techniques 18 Additional compositions and methods designed for making F - based PET tracers useful in positron emission tomography are needed in the art. The development of new and efficient methods and materials for making 18 F - labeled tracers useful in positron emission tomography provides those skilled in the art with a greater opportunity to examine a range of clinical phenomena.

Summary of the Invention

Means for Solving the Problems

[0004] Summary The invention disclosed herein has several embodiments. Embodiments of the invention include, for example, the general formula: [Chemistry] A composition comprising a substance containing a compound having (wherein PG contains a protecting group and LG contains a leaving group). Usually, in such an embodiment of the present invention, the nitrogen atom bonded to the protecting group is bonded to two protecting groups as represented by "N(PG)2". Alternatively, this nitrogen atom is bonded to one protecting group and a hydrogen atom and as represented by "NHPG". In an exemplary embodiment of the present invention, the composition is precursor 1 or precursor 3: [Chemistry] (wherein t Bu contains a tert-butyloxycarbonyl alcohol protecting group, Boc contains a tert-butyloxycarbonylamine protecting group, THP contains a tetrahydropyranyl alcohol protecting group, EOE contains an ethoxyethyl alcohol protecting group, and Tf contains a triflate leaving group) contains at least one of them.

[0005] The composition of the present invention may contain several formulations. For example, in some embodiments of the present invention, the compound having the above general formula (e.g., precursor 1 and / or precursor 3) is not placed in a solvent. In other embodiments of the present invention, the compound is placed in a solvent, for example, at least one of acetonitrile, dimethyl sulfoxide, dimethylformamide, tert-amyl alcohol, tetrahydrofuran, dioxane, and sulfone is placed in one containing it. In a particular embodiment of the present invention, the composition consists essentially of the compound. In some embodiments of the present invention, the composition consists essentially of the compound placed in a solvent.

[0006] In a particular embodiment of the present invention, the composition further 18 F, 131 I, 125 I, 124 I, 123 I, 121 I, 77 Br, and 75It contains isotopes selected from the group consisting of Br. In some embodiments of the present invention, the composition includes a solvent such as acetonitrile and at least one of additional compounds, for example, K2CO3, Na2CO3, potassium oxalate, or tetraethylammonium bicarbonate. In certain embodiments of the present invention, the composition includes an acid such as at least one of HCl, HF, HBr, HI, or acetic acid. In certain embodiments of the present invention, the composition is 18 F AraG:

Chemical formula

[0007] Another embodiment of the present invention is a method for preparing a PET probe composition, the method comprising reacting a compound containing an isotope (Ist) with a compound having the general formula:

Chemical formula

Chemical formula

[0008] Other objects, features, and advantages of the present invention will become apparent to those skilled in the art from the following detailed description. However, it should be understood that the detailed description and specific examples, while indicating some embodiments of the present invention, are illustrative only and not limiting. Many changes and modifications within the scope of the present invention can be made without departing from its spirit, and the present invention includes all such modifications.

[0009] A further aspect of the present disclosure will be more readily understood by considering the following detailed description of its various embodiments in conjunction with the accompanying drawings.

Brief Description of Drawings

[0010]

Figure 1A

Figure 1B

Figure 1C

[0011]

Figure 2

[0012]

Figure 3

Modes for Carrying Out the Invention

[0013] Detailed Description Before describing the present disclosure in more detail, it should be understood that the present disclosure is not limited to the specific embodiments described, and accordingly, embodiments of the present invention can, of course, vary. It should also be understood that the technical terms used herein are for the purpose of describing only specific embodiments and are not intended to be limiting. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. All publications and patents cited herein are hereby incorporated by reference in this specification as if each individual publication or patent were specifically and individually indicated to be incorporated by reference, and are incorporated by reference in this specification to disclose and describe the methods and / or materials related to the cited publications.

[0014] As will be apparent to those skilled in the art upon reading this disclosure, each of the individual embodiments described and illustrated herein has separate components and features, which can be readily separated from or combined with the features of any of several other embodiments without departing from the scope and spirit of the present disclosure. Any of the recited methods can be performed in the order of the recited events or in any other order that is logically possible.

[0015] Embodiments of the present disclosure use techniques such as organic synthetic chemistry, chemistry, etc., which are within the scope of the skills in the art unless otherwise indicated. Such techniques are well described in the literature. Unless otherwise indicated, parts are parts by weight, temperature is in °C, and pressure is at or near atmospheric pressure. Standard temperature and pressure are defined as 20 °C and 1 atmosphere.

[0016] Before describing embodiments of the present disclosure in detail, it should be understood that, unless otherwise indicated, the present disclosure is not limited to specific materials, reagents, reaction materials, manufacturing processes, etc., and thus can vary. It should also be understood that the terminology used herein is for the purpose of describing only particular embodiments and is not intended to be limiting. It is also possible in the present disclosure for steps to be performed in a different order where logically possible.

[0017] As used herein, it should be noted that the singular forms "a", "an", and "the" include the plural unless the context clearly dictates otherwise. Thus, for example, reference to "a compound" includes a plurality of compounds. In this specification and the claims that follow, reference is made to several terms that are defined to have the following meanings, unless the contrary intention is indicated.

[0018] Each application and patent cited in this specification, and each document or reference cited in each application and patent (including those under examination in each issued patent; "application cited documents"), and each PCT and foreign application or patent corresponding to and / or claiming priority from any of these applications and patents, and each document cited or referenced in each application cited document are hereby expressly incorporated by reference into this specification. Further, the documents or references cited in this specification (e.g., U.S. Patent Application Publication Nos. 20150230762, 20150297760, and 20190054198, 20210030878, 20200405667, 20190255002, 20160355460, 20160176807, 20150232415, 20150152206, 20140309424, 20120053337, 20100022746, 20100016551, 20090095635, 20090036668, U.S. Patent No. 9,011,817, Jud and Micura, Chemistry 2017 23(14) 3406 - 3413, and Kang et al., J Label Compd Radiopharm 2006; 49: 1237 - 1246) and each of these documents or references ("this specification cited references"), and each document or reference cited in each this specification cited reference (including any manufacturer's specifications, instructions for use, etc.) are hereby expressly incorporated by reference into this specification.

[0019] As used herein, "alkyl" or "alkyl group" refers to a saturated aliphatic hydrocarbon radical which may be straight-chain or branched and which has from 1 to 20 carbon atoms, the specified range of carbon atoms including each integer therebetween, as well as each lower range individually. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, and s-pentyl. The term "lower alkyl" means an alkyl group having less than 10 carbon atoms.

[0020] The term "substituted" in "substituted alkyl", "substituted phenyl", etc. means that the substituent may contain a group such as hydroxy, amino, halo, trifluoromethyl, cyano, --NH(lower alkyl), --N(lower alkyl)2, lower alkoxy, lower alkylthio, or carboxy in place of one or more hydrogens, and thus, as described later includes the terms haloalkyl, alkoxy, fluorobenzyl, and sulfur- and phosphorus-containing substituents.

[0021] As used herein, "halo", "halogen", or "halogen radical" refers to fluorine, chlorine, bromine, and iodine, and their radicals. Further, when used in a compound word such as "haloalkyl" or "haloalkenyl", "halo" refers to an alkyl or alkenyl radical in which one or more hydrogens are substituted by a halogen radical. Examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl.

[0022] The term "alkoxy" represents an alkyl group as defined above in which the indicated number of carbon atoms is bonded via an oxygen bridge. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy, and s-pentoxy. The term "lower alkoxy" means an alkoxy group having less than 10 carbon atoms.

[0023] According to the present disclosure, the "detectable effective amount" of an embodiment of the present disclosure is defined as an amount sufficient to obtain an acceptable image using an apparatus available for clinical use. The detectable effective amount of an embodiment of the present disclosure can be administered in one or multiple administrations. The detectable effective amount of an embodiment of the present disclosure can vary depending on factors such as the degree of susceptibility of the individual, the age, gender, and weight of the individual, the idiosyncratic response of the individual, the dosimetry method, etc. The detectable effective amount of an embodiment of the present disclosure can also vary depending on equipment and film-related factors. Optimization of such factors can be within the scope of those skilled in the art.

[0024] The term "detectable" refers to the ability to detect a signal or the presence of an embodiment of the present disclosure that exceeds the background signal.

[0025] The term "detectable signal" or the phrase "detection of a labeled compound" or "detectable labeled compound" refers to the detection (direct or indirect) of a labeled compound in a host or sample. The detection of a labeled compound refers to the ability to detect and distinguish the presence of the labeled compound in a host or sample from other background signals originating from the host or sample. In other words, there is a measurable and statistically significant difference between the detectable signal and the background (e.g., a statistical significant difference is a difference sufficient to distinguish between the detectable signal and the background, e.g., a difference of about 0.1%, 1%, 3%, 5%, 10%, 15%, 20%, 25%, 30%, or 40% or more between the detectable signal and the background). Standards and / or calibration curves can be used to determine the relative intensities of the detectable signal and / or background. The detectable signal can be generated from labeled compounds at low to high concentrations. In one embodiment, the detectable signal may need to be the sum of each of the individual labeled compound signals. In one embodiment, the detectable signal can be generated from a sum, integral, or other mathematical process, formula or algorithm. In one embodiment, the sum, integral, or other mathematical process, formula or algorithm may be used to process the detectable signal such that the detectable signal can be distinguished from background noise and the like.

[0026] As used herein, "agent", "active agent", etc. may include the compounds of the present disclosure (e.g., labeled compounds). The agent can be disposed in a composition or a pharmaceutical composition. As used herein, "pharmaceutical composition" refers to a combination of an active agent and a pharmaceutically acceptable carrier. As used herein, "pharmaceutical composition" refers to a composition suitable for administration to a subject, such as a mammal, particularly a human. Generally, a "pharmaceutical composition" is sterile and preferably does not contain contaminants that can induce an undesirable response in the subject (e.g., the compound(s) in the pharmaceutical composition are of pharmaceutical grade). Pharmaceutical compositions can be designed for administration to a subject or patient in need thereof via several different routes of administration, including oral, intravenous, buccal, rectal, parenteral, intraperitoneal, intradermal, intratracheal, intramuscular, subcutaneous, inhalation, etc.

[0027] "Pharmaceutically acceptable excipient", "pharmaceutically acceptable diluent", "pharmaceutically acceptable carrier", or "pharmaceutically acceptable adjuvant" means excipients, diluents, carriers, and / or adjuvants that are generally safe, non-toxic, and neither biologically nor otherwise undesirable and are useful for preparing pharmaceutical compositions, including excipients, diluents, carriers, and adjuvants acceptable for veterinary use and / or human pharmaceutical use. With respect to compositions suitable for administration to humans, the term "excipient" is meant to include, but is not limited to, the ingredients described in Remington: The Science and Practice of Pharmacy, Lippincott Williams & Wilkins, 21st ed. (2006), the contents of which are incorporated herein by reference.

[0028] As used herein, the term "unit dosage form" refers to physically discrete, separate units suitable as unit dosages for human and / or animal subjects, each unit containing a predetermined amount of a compound calculated to produce the desired effect in association with a pharmaceutically acceptable diluent, carrier, or vehicle (e.g., sufficient for the weight of the host, disease, severity of the disease, etc.). The specifications for the unit dosage form are determined by the particular compound to be used, the route and frequency of administration, as well as the effect to be achieved, and the pharmacodynamics associated with each compound in the host.

[0029] As used herein, the term "effective amount" refers to the amount of an embodiment of the present disclosure (which may be referred to as a labeled compound) to be administered that can be used to image cells such as heart cells.

[0030] "Administration" means introducing an embodiment of the present disclosure into a subject. Administration can include, but is not limited to, routes such as intravenous, oral, topical, subcutaneous, intraperitoneal, intraarterial, inhalation, vaginal, rectal, nasal, etc., and introduction into the cerebrospinal fluid or infusion into a body compartment can be used.

[0031] As used herein, the terms "host" or "subject" include humans, mammals (e.g., cats, dogs, horses, etc.), and other living animals. In particular, the host is a human subject. Representative hosts to which embodiments of the present disclosure can be administered are mammals, particularly primates, particularly humans. In veterinary applications, a wide variety of subjects, such as livestock animals like beef cattle, sheep, goats, dairy cows, pigs, etc., poultry such as chickens, ducks, geese, turkeys, etc., and companion animals, particularly pets like dogs and cats, are suitable. In diagnostic or research applications, a wide variety of mammals, including rodents (e.g., mice, rats, hamsters), rabbits, primates, and pigs, such as inbred pigs, etc., are suitable subjects. Further, in vitro applications, such as in vitro diagnostic and research applications, etc., the body fluids and cell samples of the above subjects are suitable for use as "samples", such as blood, urine, or tissue samples of mammals (particularly primates such as humans).

[0032] The invention disclosed in this specification has several embodiments. Embodiments of the present invention include, for example, a general formula:

Chemical formula

Chemical formula

[0033] The composition of the present invention may have several forms. For example, in some embodiments of the present invention, a compound having a general formula (for example, precursor 1 and precursor 3):

Chemical formula

[0034] In certain embodiments of the present invention, the composition further 18 F, 131 I, 125 I, 124 I, 123 I, 121 I, 77 Br, and 75 Br and contains isotopes selected from the group consisting of. In some embodiments of the present invention, the composition contains a solvent such as acetonitrile and at least one of additional compounds such as K2CO3, Na2CO3, potassium oxalate, or tetraethylammonium bicarbonate. In certain embodiments of the present invention, the composition contains an acid such as at least one of HCl, HF, HBr, HI, or acetic acid. In certain embodiments of the present invention, the composition 18 F AraG:

Chemical formula

[0035] In certain embodiments of the present invention, the amount of the compound in the composition is at least 0.5 mg or at least 1.0 mg, for example, from 2 mg to 15 mg. In certain embodiments of the present invention, the composition is placed in a kit comprising a container for storing the composition (for example, one having a volume of 50 milliliters, 10 milliliters or less than 1 milliliter), and optionally a stabilizer (for example, an inert gas such as N2).

[0036] Another embodiment of the present invention is a method of making a PET probe composition, comprising reacting a compound containing an isotope (Ist) with a compound having a general formula (for example, precursor 1 and precursor 3):

Chemical formula

Chemical formula

[0037] In certain methodological embodiments of the present invention, the isotope is 18 F, 131 I, 125 I, 124 I, 123 I, 121 I, 77 Br, and 75 Br, selected from the group consisting of. Optionally, for example, the isotope is 18 F]KF, 131 I]NaI, 125 I]NaI, 124 I]NaI, 123 I]NaI, 121 I]NaI, 77 Br]NaBr, 77 Br]Br2, 75Br]NaBr, and 75 Br]is selected from the group consisting of Br2. In certain embodiments of the present invention, the reaction is carried out in a solvent selected from the group consisting of dimethyl sulfoxide (DMSO), acetonitrile, dimethylformamide, and combinations thereof.

[0038] Another embodiment of the present invention is a method for preparing Compound 6, which is an exemplary embodiment shown in FIG. 1A. For example, an embodiment of the present invention includes using Compound 1 as a starting material, and steps 1. O6-tert-butyl, N2(bis-[tert-butyloxycarbonyl]) protection of the guanine nucleobase; step 2. basic deprotection of the acetyl protecting group; step 3. protection of the 3’ and 5’ OH groups using a di-tert-butylsilyl clamp followed by tert-butyldimethylsilyl protection of the 2’ OH group (step 4); and step 5. selective cleavage of the 3’,5’O-di-tert-butylsilyl group to obtain Compound 6, which is a common starting point for both Precursors 1 and 3. See, for example, Jud and Micura, Chemistry 2017 23(14) 3406-3413. Related embodiments include compositions of matter containing Compound 6, for example, this compound is disposed in a solvent.

[0039] Yet another embodiment of the present invention is Precursor 1 or Precursor 3:

Chemical formula

[0040] The present disclosure also provides a packaged composition comprising a precursor compound and / or an intermediate (e.g., precursor 1 or precursor 3) for a labeled compound, as well as instructions for use and methods of use (e.g., written instructions regarding their use) for producing the labeled compound. The kit may further include suitable buffers and reagents known in the art. Exemplary methods and materials adaptable for use in the inventions disclosed herein can be found in U.S. Patent No. 9,011,817, the contents of which are incorporated herein by reference.

[0041] Embodiments of the present disclosure also include methods of imaging cells or organs using a PET probe made according to the methods disclosed herein. For example, PET 18Embodiments of the F-labeled compounds can be used to image their localization and / or amount in a subject (e.g., a human organ such as the heart, human cells such as T cells and / or T lymphoblasts, or human sub-organs such as mitochondria). The labeled compounds can be administered to the subject, and then the subject or a portion of the subject can be imaged using a device such as positron emission tomography (PET) to detect the presence and location within the subject and / or the amount of the labeled compound present. The presence and / or amount can be used to detect the presence, location, and / or number / size of T cells and / or T lymphoblasts at one or more positions within the subject. Administration of the compounds (e.g., compositions, pharmaceutical compositions, etc.) can be performed via any of the modes of administration that are acceptable as diagnostic agents. These methods include oral, parenteral, rectal, vaginal, nasal, inhalation, topical (including transdermal), parenteral, subcutaneous, and other systemic modes. Accordingly, embodiments of the present disclosure are directed to pharmaceutical compositions comprising a pharmaceutically acceptable carrier or excipient and a diagnostically effective amount of a compound of the present disclosure. Optionally, such pharmaceutical compositions may contain, if desired, other diagnostic agents and / or therapeutic agents and / or adjuvants.

[0042] As described above, embodiments of the present invention include compounds in which one or more atoms on the compound are bonded to a protecting group (“PG”) and / or a leaving group (“LG”). As is known in the art, a leaving group is generally a molecular moiety that leaves with a pair of electrons in a heterolytic bond cleavage. The leaving group can be an anion, cation, or neutral molecule that can stabilize the additional electron density resulting from the bond heterolysis. As is known in the art, a protecting group is generally a molecular moiety that is introduced into a molecule by chemical modification of a functional group to obtain chemoselectivity in subsequent chemical reactions. In exemplary embodiments of the present invention, the LG on the compounds of the present invention includes a triflate leaving group, and the PG on the compounds of the present invention includes a tert-butyloxycarbonyl alcohol protecting group, a tert-butyloxycarbonyl amine protecting group, a tetrahydropyranyl alcohol protecting group, and / or an ethoxyethyl alcohol protecting group.

[0043] In certain embodiments of the present invention, Tr is a trityl protecting group (PG), and Tf is a triflate leaving group (LG). Alternative protecting groups (PGs) that can be used include benzyl (Bn, Bnl), 6-methoxyethoxymethyl ether (MEM), methoxymethyl ether (MOM), p-methoxybenzyl ether (PMB), methylthiomethyl ether, methoxytrityl (MMT), pivaloyl (piv), tetrahydropyranyl (THP), trimethylsilyl (TMS), acetyl, difluoroacetyl, trifluoroacetyl, isobutyryl, benzoyl, 9-fluorenylmethoxycarbonyl, phenoxyacetyl, dimethylformamidine, N,N-diphenylcarbamate, acetals prepared from acyclic or cyclic alkyl vinyl or substituted alkyl vinyl ethers (including, but not limited to, ethyl vinyl ether, ethyl isopropenenyl ether, dihydropyran, 2-alkyl dihydropyran, dihydrofuran, 2-alkyl dihydrofuran, 1-methoxycyclohexane, 5,6-dihydro-4-methoxy-2H-pyran). Alternative leaving groups (LGs) that can be used include tosylate, mesylate, alkyl mesylates, phenylsulfonate , nosylate, brosylate, acetate, alkyl acetate, phenyl acetate, iodide, bromide, chloride, and the like. Alternative groups that can replace the acetyl group include carbobenzyoxy (cbz), p-methoxybenzyl carb onyl (Moz), tert (tet)-butyloxycarbonyl (BOC), 9-fluoro It includes nilomethoxycarbonyl, phenoxyacetyl, dimethylformamidine, N,N-diphenylcarbamate, etc. Alternative groups that can replace the benzoyl group include acetyl, difluoroacetyl, trifluoroacetyl, isobutyryl, 9-fluorenylmethoxycarbonyl, phenoxyacetyl, dimethylformamidine, N,N-diphenylcarbamate, etc. Therefore, for each of the described syntheses, PG, LG, Ac, and / or Bz can each be substituted as described above and in this specification.

[0044] The isotopes used in the embodiments of the present invention are 18 F, 131 I, 125 I, 124 I, 123 I, 121 I, 77 Br, 75 Br, or 75 Br and the like may be isotopes. Compounds containing isotopes include 18 F]KF, 131 I]NaI, 125 I]NaI, 124 I]NaI, 123 I]NaI, 121 I]NaI, 77 Br]NaBr, 77 Br]Br2, 75 Br]NaBr, or 75 Br]Br2 may be included. The amount of the precursor or starting material may be about 2 - 15 mg, which can be adjusted together with other similar variables according to the amount of the desired final product and the desired scale-up of the synthesis. The reaction may include an appropriate solvent, reactive compound, buffer, etc. For example, usually, the isotope is 18 F or another isotope disclosed in U.S. Patent No. 9,011,817. The fluorination reaction can be carried out at a temperature of about 70 - 165 °C. Regarding the amount of the compound used, the amount used may be scaled up or down according to the amount of the chemical substance desired to be produced.

[0045] Various solvents suitable for the compounds of the present invention are known in the art. In addition to acetonitrile, solvents such as DMSO, dimethylformamide, tert-amyl alcohol and combinations thereof can be used. Also, solvents such as THF, dioxane, sulfone and combinations thereof can be used.

[0046] In certain embodiments, the compounds of the present invention can be modified by chemical reactions. After cooling the reaction mixture to room temperature, acid deprotection can be carried out at about 85 °C for about 10 minutes using certain acids, such as about 1N HCl (or some other acids). Finally, after cooling the resulting reaction mixture to room temperature, this mixture can be neutralized to a pH of about 6 - 7, and the resulting solution is injected into a C18 reverse-phase HPLC column to separate the final product. Also, an alternative method to C18 reverse-phase HPLC column purification is the use of a series of C18 cartridges.

[0047] It should be noted that ratios, concentrations, amounts, and other numerical data may be presented herein in a range format. Such a range format is used for convenience and brevity, and thus should be interpreted in a flexible manner to include not only the numerically explicit limits of the range, but also all individual numerical values or sub-ranges subsumed within the range as if each numerical value and sub-range were explicitly recited. By way of illustration, a concentration range of "about 0.1% to about 5%" includes not only the explicitly recited concentrations of about 0.1 wt% to about 5 wt%, but also individual concentrations (e.g., 1%, 2%, 3%, and 4%) and sub-ranges within the indicated range (e.g., 0.5%, 1.1%, 2.2%, 3.3%, and 4.4%). In one embodiment, the term "about" may include conventional rounding by significant figures of the numerical value. Further, the phrase "about 'x' to 'y'" includes "about 'x' to about 'y'".

[0048] The above embodiments of the present disclosure are merely possible implementation examples and it should be emphasized that they are described only for a clear understanding of the principles of the present disclosure. Many changes and modifications can be made to the above embodiments of the present disclosure without substantially departing from the spirit and principles of the present disclosure. All such modifications and changes are intended to be included herein within the scope of the present disclosure. For example, the present invention provides the following items. (Item 1) General formula:

Chemical formula

Chemical formula

Chemical formula

Claims

1. Precursor 1: 【Chemistry 14】 (In the formula, t Bu contains a tert-butyloxycarbonyl alcohol protecting group; Boc contains a tert-butyloxycarbonylamine protecting group; THP contains a tetrahydropyranyl alcohol protecting group, and Tf contains a triflate leaving group 20. A composition of matter comprising:

2. The compound is not disposed in a solvent. the compound is placed in a solvent comprising at least one of acetonitrile, dimethyl sulfoxide, dimethylformamide, tert-amyl alcohol, tetrahydrofuran, dioxane, and a sulfone; the composition consists essentially of the compound; or the composition consists essentially of the compound disposed in a solvent; The composition of claim 1.

3. The composition of claim 1, further comprising an isotope selected from the group consisting of 18 F, 131 I, 125 I, 124 I, 123 I, 121 I, 77 Br, and 75 Br.

4. The composition of claim 1, further comprising a solvent and at least one of K 2 CO 3 , Na 2 CO 3 , potassium oxalate, or TBACO 3 .

5. The composition of claim 1, further comprising at least one of HCl, HF, HBr, HI, or acetic acid. 【Request Item 6】 【Chemistry 15】 The composition of claim 1 further comprising:

7. The composition described in claim 1, wherein the amount of the compound in the composition is 2 mg to 15 mg.

8. The composition comprising: a container for storing the composition, the container having a volume of less than 50 milliliters; and stabilizers The composition of claim 1 disposed in a kit comprising:

9. A method for making a PET probe composition, said method comprising: reacting a compound containing the isotope (Ist) with the compound of claim 1; the reaction removes the PG and LG moieties and attaches the isotope to the compound; A method whereby said PET probe composition is made.

10. The PET probe composition 【Chemistry 16】 10. The method of claim 9, comprising:

11. The method of claim 9, wherein the isotope is selected from the group consisting of 18 F, 131 I, 125 I, 124 I, 123 I, 121 I, 77 Br, and 75 Br.

12. The method of claim 9, wherein the compound containing the isotope is selected from the group consisting of [ 18 F]KF, [ 131 I]NaI, [ 125 I]NaI, [ 124 I]NaI, [ 123 I]NaI, [ 121 I]NaI, [ 77 Br]NaBr, [ 77 Br]Br 2 , [ 75 Br]NaBr, and [ 75 Br]Br 2 .

13. The method of claim 9, wherein the reaction occurs in a solvent selected from the group consisting of dimethyl sulfoxide (DMSO), acetonitrile, dimethylformamide, and combinations thereof.

14. Precursor 1: 【Chemistry 17】 (In the formula, t Bu contains a tert-butyloxycarbonyl protecting group; Boc contains a tert-butyloxycarbonyl protecting group; THP contains a tetrahydropyranyl protecting group, and Tf contains a triflate leaving group 1. A method of making a compound comprising: using compound 6 as a starting material; and (a) protecting the 3' and 5' OH groups of compound 6 using a tetrahydropyranyl ether; (b) selectively deprotecting the tert-butyldimethylsilyl group of the compound formed in (a); and (c) introducing a triflate leaving group at the 2′ position of the compound formed in step (b) to produce Precursor 1; A method comprising:

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