Theranostic fluorinated silicon heteroaromatic systems and methods thereof

Abstract

A system and method for heteroaromatic fluorinated silicon compounds as radiopharmaceuticals with theranostic properties are described.Theranostic heteroaromatic fluorinated silicon compounds can be conjugated with various disease-binding ligands and / or chelators for imaging and therapeutic applications.The present invention generally relates to a system and method for heteroaromatic fluorinated silicon receptors.More particularly, the present invention relates to a system and method for heteroaromatic fluorinated silicon receptors with theranostic properties.

Description

[Technical field]

[0001] FIELD OF THEINVENTION The present invention relates generally to systems and methods relating to heteroaromatic fluorinated silicon receptors, and more particularly to systems and methods relating to heteroaromatic fluorinated silicon receptor systems having theranostic properties. [Background technology]

[0002] 2. Background of the Invention Nuclear medicine is a branch of radiology that utilizes radiation produced by the decay of medical radioisotopes that are typically administered to the patient. Nuclear medicine has distinct therapeutic and diagnostic areas that are differentiated by the type of radiation produced upon the decay of the medical radioisotope.

[0003] In diagnostic nuclear medicine, the scintigraphic techniques single photon emission computed tomography (SPECT) and positron emission tomography (PET) are used for molecular imaging of biological processes related to various diseases at the molecular and cellular levels. These techniques rely on radiolabeled compounds called tracers or radiopharmaceuticals to detect disease-specific biological targets or biochemical processes. SPECT and PET cameras often include computed tomography (CT) capabilities, resulting in high-end hybrid tomographic imaging devices such as SPECT / CT or PET / CT. Alternatively, PET is combined with magnetic resonance imaging (PET / MRI), which is useful for brain imaging applications.

[0004] In therapeutic nuclear medicine, radiopharmaceutical agents target pathological tissue and deliver cytotoxic radiation at the cellular level. Cytotoxic α and β radiopharmaceuticals are used to destroy malignant cells to which the radiopharmaceutical binds. - A nuclide that emits radiation is used. Alpha particles have higher energy and much larger mass. Actinium-225 is a commonly used alpha-emitter, while lutetium-177 is a commonly used beta-emitter. --emitters. Therapeutic nuclear medicine treatments can be repeated multiple times to achieve maximum benefit. Therapeutic nuclear medicine may be used in combination with or as an alternative to other treatment options such as chemotherapy, radiation therapy and surgery. For many patients, therapeutic nuclear medicine can improve quality of life and cause tumor regression or stabilization.

[0005] Theranostics is a combination of the terms therapeutics and diagnostics. Theranostics can be used to describe the combined use of one radioactive drug to identify (diagnose) the primary tumor and any metastatic tumors and a second radioactive drug to provide a therapy to treat those tumors.

[0006] Theranostic refers to pairing molecular imaging with therapeutic nuclear medicine. A "see it, treat it" approach allows for the selection of patients suitable for therapeutic nuclear medicine with PET imaging. A pair of radiopharmaceuticals targeting the same disease is needed to image and treat the condition, for example, a theranostic pair targeting somatostatin receptor type 2 (SSTR2) in neuroendocrine tumors (NETs). The octapeptide TATE is a somatostatin analogue (SSA) with high affinity for SSTR2. 177 Lu label [ 177 Therapeutic nuclear medicine using [Lu]Lu-DOTA-TATE can be used. In the diagnostic aspect, 68 Ga-labeled SSA is used for molecular imaging of NETs by PET / CT. 68 PET / CT imaging with [Ga]Ga-DOTA-TATE allows for highly accurate determination of NET staging and for determining patient eligibility for therapeutic nuclear medicine. 68 Ga-DOTA-TATE (PET imaging agent) and 177The structure of Lu-DOTA-TATE (therapeutic agent) is illustrated. Another example is the diagnosis of metastatic prostate cancer using PSMA PET. One of the PSMA-targeted theranostic pairs is 68 Ga-PSMA-617, and for treatment 177 Lu-PSMA-617. 68 Precursor of Ga-PSMA-617 and 177 1 illustrates the structure of the precursor of Lu-PSMA-617. 68 Ga-PSMA-617 can be used as a PET imaging agent. 177 Lu-PSMA-617 can be used therapeutically. Glu-ureido-based peptidomimetics are high affinity PSMA binders.

[0007] Fluorine-18 is a common PET-radionuclide in clinical use. The half-life (t 1 / 2 =109.8 minutes, 97% beta + -decay) is long enough to allow radiopharmaceuticals to be produced and transported to remote imaging facilities. Production of cyclotron-produced nuclides is scalable, and up to hundreds of patient doses can be produced in a single production run. The positron energy (maximum β + The relatively low energy (=633 keV) allows imaging with high spatial resolution and few artifacts.

[0008] Conventional radiotracers used in diagnostic PET imaging 18 The incorporation of F uses nucleophilic or electrophilic substitution chemistry, including C- 18 During radiolabeling, harsh reaction conditions are usually required, including high temperatures, aprotic organic solvents, strongly basic conditions, and strongly acidic conditions during removal of protecting groups. 18Incorporation of F can also involve the generation of radioactive and non-radioactive by-products that require complex and lengthy multi-step production procedures, and time-intensive and expensive purification processes such as semi-preparative high performance liquid chromatography. Compared to conventional radiolabeling methods, silicon fluoride acceptor (SiFA) building blocks offer rapid Si- 18 Enables F bond formation, resulting in high radiochemical yields (RCY) and high molar activities (A m )in 18 F-SiFA-conjugated PET tracer is obtained. 18 The formation of the F bond can be carried out under mild reaction conditions, such as at room temperature. Protective groups to mask sensitive functional groups may not be required. Furthermore, the absence of by-products allows for simple cartridge-based purification, with the overall synthesis time being about 20 minutes. However, an inherent drawback of the conventional phenyl-SiFA technology is its high lipophilicity. The high lipophilicity can be caused by two tert-butyl substituents on silicon, and the phenyl core, which has a logP of about 2.13. The two tert-butyl substituents on silicon result in Si- 18 In order to prevent the hydrolysis of F bond in vivo, it is necessary to sterically shield this bond. (See, for example, S. Niedermoser, et al., The Journal of Nuclear Medicine, 2015, 56, 7, 1100-1105, the disclosure of which is incorporated herein by reference in its entirety). Therefore, polar (carboxylic acid, carbohydrate, polyethylene glycol) and charged (tertiary ammonium salt) linkers are required to mask the high lipophilicity of phenyl-SiFA moiety. Heteroaromatic ring-containing SiFA (HetSiFA) technology uses more hydrophilic heteroaromatic rings to replace the phenyl rings of SiFA. (See, for example, PCT application WO2020 / 220020A1 to JM Murphy et al., U.S. Pat. No. 10,800,797(B2) to C.M. Waldmann et al., the disclosures of which are incorporated herein by reference in their entirety.) HetSiFA's rapid and reliable18 F-fluorination is straightforward and production can be scaled up, thereby increasing the availability of drugs to imaging facilities and patients. Mild reaction conditions allow for sensitive labeling of substrates, including (but not limited to) peptides and peptidomimetics. Despite advances, existing SiFA systems have inherent drawbacks for therapeutic, diagnostic and / or theranostic applications. [Prior art documents] [Patent documents]

[0009] [Patent Document 1] International Publication No. 2020 / 220020 [Patent Document 2] U.S. Pat. No. 10,800,797 [Non-patent literature]

[0010] [Non-Patent Document 1] S. Niedermoser, et al., The Journal of Nuclear Medicine, 2015, 56, 7, 1100-1105 Summary of the Invention [Means for solving the problem]

[0011] Brief Summary of the Invention Many embodiments are directed to systems and methods relating to heteroaromatic fluorinated silicon receptor systems. In some embodiments, systems and methods relating to heteroaromatic fluorinated silicon receptor systems with theranostic properties are described. Some embodiments are directed to systems and methods relating to heteroaromatic fluorinated silicon receptor systems with theranostic capabilities for targeting various types of metastatic cancer, including (but not limited to) prostate cancer.

[0012] One embodiment of the present invention comprises a compound comprising a fluorinated silicon acceptor and a heteroaromatic ring, the heteroaromatic ring being selected from the group consisting of pyridine, pyridine oxide, pyridinium, pyrazole, fused pyrazole derivatives, benzofuran, benzothiophene, indole, azaindole, imidazole and pyrimidine; The pyridine, pyridine oxide or pyridinium compound may be represented by the following formula I: [ka] having The pyrazole compound has the following formula II: [ka] having The fused pyrazole derivative compound has the following formula III: [ka] having The benzofuran, benzothiophene, indole or azaindole compound may be represented by the following formula IV: [ka] having The imidazole compound has the following formula V: [ka] having The pyrimidine compound has the following formula VI: [ka] having During the ceremony, Each F is independently F or 18 F or 19 F, Each A is independently H, CH 3、 CH 2 -CH 3、 CH 3 -CH 2 -CH(CH 3), CH(CH 3 ) 2 and C(CH 3 ) 3 and Each U is independently O-CH 3 , C.H. 3 , C.H. 2 CH 3 , H, I, Br, Cl, F, N(CH 3 ) 2 and C.H. 2 CH(NH 2 )CO 2 H, Each X is independently O, S, or N; Each Y is independently C and N; R 1 or R 2 or R 3 are each independently 3 , C.H. 2 -CH 3 , H, L 1 -CH 2 -C≡C,L 1 -CH 3 , L 1 -G, L 1 -H, L 1 -L 2 -CH 2 -C≡C,L 1 -L 2 -CH 3 , L 1 -L 2 -G, L 1 -L 2 -H, L 1 -L 2 -H 2 , L 1 -L 2 -L 3 -G, L 1 -L 2 -L 3 -H, L 1 -L 2 -L 3 -L 4 -G, L 1 -L 2 -L 3 -L 4 -H, L 1 -L2 -L 3 -L 4 -Q-L 5 -G, L 1 -L 2 -L 3 -Q, L 1 -L 2 -L 3 -Q-L 4 -G, L 1 -L 2 -N 3 , L 1 -L 2 -OH, L 1 -L 2 -Q, L 1 -L 2 -Q-G, L 1 -L 2 -Q-L 3 -G, L 1 -L 2 -Q-L 3 -L 4 -G, L 1 -L 2 -Q-L 3 -L 4 -H, L 1 -OH, L 1 -Q, L 1 -Q-L 2 -L 3 -L 4 -G, L 1 -Q-L 2 -G, NH 2 , O - , O-CH 3 , OH, [Chemical formula] and is L 1 or L 2 or L 3 or L 4 or L 5 is each independently -(O-CH 2 -CH 2 ) p -, -(CH 2 -CH 2 -O) p -, -(Glu-His) p -, -(His-Glu)p -、-(Glu-Trp) p -、-(Trp-Glu) p -、-NH-CH 2 -C 6 H 4 -NH-(C=O)-CH 2 -O-CH 2 -(C=O)-、-(C=O)-CH 2 -O-CH 2 -(C=O)-NH-C 6 H 4 -CH 2 -NH-、-(C=O)-CH 2 -CH 2 -(C=O)-、-NH-C 5 H 9 N-CH 2 -(C=O)-、-(C=O)-CH 2 -NC 5 H 9 -NH-、-(Gly) p -、-CH 2 -CH 2 -NH-、-NH-CH 2 -(C=O)-、-(Glu)-、-NH-CH 2 -CH 2 -、-(C=O)-、NH-CH 2 -CH 2 -(O-CH 2 -CH 2 ) p -(C=O)-、-(C=O)-(CH 2 -CH 2 -O) p -CH 2 -CH 2 -NH-、-NH-(C=O)-CH 2 -、-NH-(C=O)-NH-CH 2 -、-NH-(C=S)-NH-CH 2 -、-NH-(CH 2 -CH 2 -O) p -CH 2 -(C=O)-、-(C=O)-CH 2 -(O-CH 2 -CH 2 ) p -NH-、-Asp-、-NH-、-NH-(CH2 -CH 2 -O) p -CH 2 -CH 2 -(C=O)-、-(C=O)-CH 2 -CH 2 -(O-CH 2 -CH 2 ) p -NH-、-CH 2 -(C=O)-、-(C=O)-CH 2 -、-O-(C=O)-、-(C=O)-O-、-CH 2 -O-、-NH-(C=O)-O-、-O-(C=O)-NH-、-(C=O)-CH 2 -(O-CH 2 -CH 2 ) p -O-CH 2 -(C=O)-、-NH-(C=O)-NH-、-NH-(C=S)-NH-、-CH 2 -N(CH 3 )-CH 2 -、-N(CH 3 )-、-(C=O)-C 6 H 4 -(C=O)-、-C 6 H 4 -(C=O)-、-(C=O)-C 6 H 4 -、-O-CH 2 -(C=O)-、-(C=O)-CH 2 -O-、-CH 2 -C 2 N 3 -CH 2 -、-CH 2 -CH 2 -(C=O)-、-(C=O)-CH 2 -CH 2 -、-CH 2 -N + (CH 3 ) 2 -CH 2 -、-CH 2 -N(CH 3 )-、-(C=O)-CH 2 -(O-CH 2 -CH 2 ) p -、-(CH2 -CH 2 -O) p -CH 2 -CH 2 -NH-, or [ka] and p=0 to 12; each G is a disease-binding ligand, where G is independently a somatostatin receptor type 2 (SSTR2)-binding ligand, a gastrin releasing peptide receptor (GRPR)-binding ligand, a prostate specific membrane antigen (PSMA)-binding ligand, a fibroblast activation protein (FAP)-binding ligand, or a CXC chemokine receptor type 4 (CXCR-4)-binding ligand; Each Q is a chelating agent.

[0013] In further embodiments, each Q is independently -DOTA, -DOTAGA, -Dap(DOTA), -Lys(DOTA), -3p-C-NETA, -bis-thioseminarabazone, -EDTA, -CHX-A"-EDTA, -DTPA, -p-SCN-DPTA, -CHX-A"-DTPA, -p-SCN-Bz-Mx-DTPA, -NOTA, -TETA, -CB-TE2 A, -p-SCN-NOTA (cNOTA), -nNOTA, -NODAGA, -p-SCN-DOTA (cDOTA), -2-cTETA, -6-cTETA, -BAT, -Diamsa, -SarAr, -PCTA, -NODIA-Me, -TRAP, -pycup1A1B, -p-SCN-DTPA, -desferrioxamine B (DFO) mesylate, -desferrioxamine-p-SCN, -DFO-Star (DFO *), -L5, -Orn3hx-NCS, -Orn4hx-NCS, -p-SCN-Bn-HOPO, -2,3-HOPO-p-Bn-NCS, -YM103, -Tc(V)oxo, -Tc(V)nitride, -Tc(V)HYNIC, -Tc(I)-fac-tricarbonyl, -Tc(VII)trioxo, -3p-C-NETA-NCS, -3p-C-DEPA-NCS, -TCMC, -p-SCN-Bn-H 4 -octapa, -HEHA-NCS or -Macropa-NCS.

[0014] In another embodiment, Q is unchelated or is optionally chelated to M, where M is 43 Sc, 44 Sc, 45 Sc, 47 Sc, 51 Cr, 52m Mn, 68 Co, 52 Fe, 56 Ni, 57 Ni, 61 Cu, 62 Cu, 63 Cu, 64 Cu, 65 Cu, 67 Cu, 66 Ga, 67 Ga, 68 Ga, 69 Ga, 71 Ga, nat Ga, 90 Zr, 91 Zr, 92 Zr, 89 Zr, 86 Y, 90 Y, 89 Y, 99m Tc, 97 Ru, 105 Rh, 109 Pd, 111 Ag, 110m In, 111 I, 113 In, 133m In, 114m In, 117m Sn, 121 Sn, 127 Te,142 Pr, 143 Pr, 149 Pm, 151 Pm, 149 Tb, 155 Tb, 153 Sm, 157 Gd, 161 Tb, 166 Ho, 165 Dy, 169 Er, 169 Yb, 175 Yb, 172 Tm, 176 Lu, 177 Lu, 177m Lu, nat Lu, 186 Re, 188 Re, 191 Pt, 197 Hg, 198 Au, 199 Au, 212 Pb, 203 Pb, 204 Pb, 206 Pb, 207 Pb, 208 Pb, 211 At, 209 Bi, 212 Bi, 213 Bi, 223 Ra, 225 Ac, 227 Th, 232 a cation of a metal selected from the group consisting of Th, and 18 Cationic molecules containing F and 18 F[AlF] 2+ It is.

[0015] In additional embodiments, A is C(CH 3 ) 3 It is.

[0016] In another further embodiment, G is: [ka] [ka] [ka] [ka] having a formula selected from the group consisting of: Z is H, CH 3 or CF 3 It is.

[0017] In yet another further embodiment, R 1 are independently 3 , H, L 1 -CH 2 -C≡C,L 1 -CH 3 , L 1 -H, L 1 -L 2 -CH 2 -C≡C,L 1 -L 2 -CH 3 , L 1 -L 2 -G, L 1 -L 2 -H, L 1 -L 2 -H 2 , L 1 -L 2 -L 3 -G, L 1 -L 2 -L 3 -H, L 1 -L 2 -L 3 -L 4 -QL 5 -G, L 1 -L 2 -L 3 -Q, L 1 -L 2 -L 3 -QL 4 -G, L 1 -L 2 -N 3 , L 1 -L 2 -OH, L 1 -L 2 -Q, L 1 -L 2 -QL 3-L 4 -G, L 1 -OH, L 1 -Q, L 1 -QL 2 -L 3 -L 4 -G, NH 2 , O-CH 3 , O.H., [ka] and R 2 are independently 3 , H, L 1 -CH 2 -C≡C,L 1 -G, L 1 -H, L 1 -L 2 -CH 2 -C≡C,L 1 -L 2 -G, L 1 -L 2 -L 3 -G, L 1 -L 2 -L 3 -L 4 -G, L 1 -L 2 -L 3 -Q, L 1 -L 2 -L 3 -QL 4 -G, L 1 -L 2 -N 3 , L 1 -L 2 -Q, L 1 -L 2 -Q.G., L. 1 -L 2 -QL 3 -G, L 1 -OH, L 1 -Q, L 1 -QL 2 -G, NH 2 , O - or O-CH 3 and R 3 are independently 3 , C.H. 2 -CH3 Or O - It is.

[0018] In another further embodiment, the compound is [ka] is a small molecule having a formula selected from the group consisting of:

[0019] In additional embodiments, the compounds are also for positron emission tomography (PET) imaging and have the following formula: [ka] has.

[0020] In yet another further embodiment, the compound is [ka] [ka] A theranostic compound having a formula selected from the group consisting of:

[0021] In yet another further embodiment, the compound also has the following formula: [ka] It is a dual targeting theranostic compound having the following structure:

[0022] In additional embodiments, the compounds are also configured for PET imaging and therapeutic radioligand therapy.

[0023] In yet a further embodiment, the disease-binding ligand G is conjugated to the compound by a process selected from the group consisting of coupling chemistry, peptide coupling chemistry, copper catalyzed azide-alkyne cycloaddition (CuAAC) and solid phase peptide synthesis (SPPS).

[0024] In yet another embodiment, 3p-C-NETA is administered for treatment: 177 DOTA and DOTAGA are configured to form a chelate with Lu for therapeutic purposes. 177 Lu or 225 DOTA and DOTAGA are configured to form chelates with Ac for PET imaging. 68 Ga, 89 Zr or 64 It is configured to form a chelate with Cu.

[0025] Another embodiment includes a method of synthesizing a radiopharmaceutical compound comprising the steps of providing a fluorosilicon compound comprising a heteroaromatic ring, and conjugating a disease-binding ligand G to the fluorosilicon compound to form the radiopharmaceutical compound, wherein the heteroaromatic ring is selected from the group consisting of pyridine, pyridine oxide, pyridinium, pyrazole, fused pyrazole derivatives, benzofuran, benzothiophene, indole, azaindole, imidazole and pyrimidine; The pyridine, pyridine oxide or pyridinium compound is Formula I below: [ka] having The pyrazole compound has the following formula II: [ka] having The fused pyrazole derivative compound has the following formula III: [ka] having The benzofuran, benzothiophene, indole or azaindole compound may be represented by the following formula IV: [ka] having The imidazole compound has the following formula V: [ka] having The pyrimidine compound has the following formula VI: [ka] having During the ceremony, Each F is independently F or 18 F or 19 F, Each A is independently H, CH 3、 CH 2 -CH 3、 CH 3 -CH 2 -CH(CH 3 ), CH(CH 3 ) 2 and C(CH 3 ) 3 and Each U is independently O-CH 3 , C.H. 3 , C.H. 2 CH 3 , H, I, Br, Cl, F, N(CH 3 ) 2 and C.H. 2 CH(NH 2 )CO 2 H, Each X is independently O, S, or N; Each Y is independently C and N; R 1 or R 2 or R 3 are each independently 3 , C.H. 2 -CH 3 , H, L 1 -CH 2 -C≡C,L 1 -CH 3 , L 1 -G, L 1 -H, L 1 -L 2 -CH 2 -C≡C,L1 -L 2 -CH 3 、L 1 -L 2 -G、L 1 -L 2 -H、L 1 -L 2 -H 2 、L 1 -L 2 -L 3 -G、L 1 -L 2 -L 3 -H、L 1 -L 2 -L 3 -L 4 -G、L 1 -L 2 -L 3 -L 4 -H、L 1 -L 2 -L 3 -L 4 -Q-L 5 -G、L 1 -L 2 -L 3 -Q、L 1 -L 2 -L 3 -Q-L 4 -G、L 1 -L 2 -N 3 、L 1 -L 2 -OH、L 1 -L 2 -Q、L 1 -L 2 -Q-G、L 1 -L 2 -Q-L 3 -G、L 1 -L 2 -Q-L 3 -L 4 -G、L 1 -L 2 -Q-L 3 -L 4 -H、L 1 -OH、L 1 -Q、L 1 -Q-L 2 -L 3 -L 4 -G、L 1 -Q-L2 -G, NH 2 , O - , O-CH 3 , O.H., [ka] and L 1 or L 2 or L 3 or L 4 or L 5 are each independently -(O-CH 2 -CH 2 ) p -, -(CH 2 -CH 2 -O) p -, -(Glu-His) p -, -(His-Glu) p -, -(Glu-Trp) p -, -(Trp-Glu) p -, -NH-CH 2 -C 6 H 4 -NH-(C=O)-CH 2 -O-CH 2 -(C=O)-, -(C=O)-CH 2 -O-CH 2 -(C=O)-NH-C 6 H 4 -CH 2 -NH-, -(C=O)-CH 2 -CH 2 -(C=O)-, -NH-C 5 H 9 N-CH 2 -(C=O)-, -(C=O)-CH 2 -NC 5 H 9 -NH-, -(Gly) p -, -CH 2 -CH 2 -NH-, -NH-CH 2 -(C=O)-, -(Glu)-, -NH-CH 2 -CH 2 -, -(C=O)-, NH-CH 2 -CH 2 -(O-CH 2 -CH2 ) p -(C=O)-、-(C=O)-(CH 2 -CH 2 -O) p -CH 2 -CH 2 -NH-、-NH-(C=O)-CH 2 -、-NH-(C=O)-NH-CH 2 -、-NH-(C=S)-NH-CH 2 -、-NH-(CH 2 -CH 2 -O) p -CH 2 -(C=O)-、-(C=O)-CH 2 -(O-CH 2 -CH 2 ) p -NH-、-Asp-、-NH-、-NH-(CH 2 -CH 2 -O) p -CH 2 -CH 2 -(C=O)-、-(C=O)-CH 2 -CH 2 -(O-CH 2 -CH 2 ) p -NH-、-CH 2 -(C=O)-、-(C=O)-CH 2 -、-O-(C=O)-、-(C=O)-O-、-CH 2 -O-、-NH-(C=O)-O-、-O-(C=O)-NH-、-(C=O)-CH 2 -(O-CH 2 -CH 2 ) p -O-CH 2 -(C=O)-、-NH-(C=O)-NH-、-NH-(C=S)-NH-、-CH 2 -N(CH 3 )-CH 2 -、-N(CH 3 )-、-(C=O)-C 6 H 4 -(C=O)-、-C 6 H 4 -(C=O)-、-(C=O)-C 6 H 4 -、-O-CH2 -(C=O)-, -(C=O)-CH 2 -O-, -CH 2 -C 2 N 3 -CH 2 -, -CH 2 -CH 2 -(C=O)-, -(C=O)-CH 2 -CH 2 -, -CH 2 -N + (CH 3 ) 2 -CH 2 -, -CH 2 -N(CH 3 )-, -(C=O)-CH 2 -(O-CH 2 -CH 2 ) p -, -(CH 2 -CH 2 -O) p -CH 2 -CH 2 -NH-, or [ka] and p=0 to 12; each G is independently a somatostatin receptor type 2 (SSTR2)-binding ligand, a gastrin releasing peptide receptor (GRPR)-binding ligand, a prostate specific membrane antigen (PSMA)-binding ligand, a fibroblast activation protein (FAP)-binding ligand, or a CXC chemokine receptor type 4 (CXCR-4)-binding ligand; Each Q is a chelating agent.

[0026] In yet another further embodiment, each Q is independently selected from the group consisting of: -DOTA, -DOTAGA, -Dap(DOTA), -Lys(DOTA), -3p-C-NETA, -bis-thiosemicarbazone, -EDTA, -CHX-A″-EDTA, -DTPA, -p-SCN-DPTA, -CHX-A″-DTPA, -p-SCN-Bz-Mx-DTPA, -NOTA, -TETA, -CB-TE2A, -p-SCN -NOTA (cNOTA), -nNOTA, -NODAGA, -p-SCN-DOTA (cDOTA), -2-cTETA, -6-cTETA, -BAT, -Diamsa, -SarAr, -PCTA, -NODIA-Me, -TRAP, -pycup1A1B, -p-SCN-DTPA, -Desferrioxamine B (DFO) mesylate, -Desferrioxamine-p-SCN, -DFO-Star (DFO * ), -L5, -Orn3hx-NCS, -Orn4hx-NCS, -p-SCN-Bn-HOPO, -2,3-HOPO-p-Bn-NCS, -YM103, -Tc(V)oxo, -Tc(V)nitride, -Tc(V)HYNIC, -Tc(I)-fac-tricarbonyl, -Tc(VII)trioxo, -3p-C-NETA-NCS, -3p-C-DEPA-NCS, -TCMC, -p-SCN-Bn-H 4 -octapa, -HEHA-NCS or -Macropa-NCS.

[0027] Another additional embodiment further comprises chelating Q to M, wherein M is 43 Sc, 44 Sc, 45 Sc, 47 Sc, 51 Cr, 52m Mn, 68 Co, 52 Fe, 56 Ni, 57 Ni, 61 Cu, 62 Cu, 63 Cu, 64 Cu, 65 Cu, 67 Cu, 66 Ga, 67 Ga, 68 Ga,69 Ga、 71 Ga、 nat Ga、 90 Zr、 91 Zr、 92 Zr、 89 Zr、 86 Y、 90 Y、 89 Y、 99m Tc、 97 Ru、 105 Rh、 109 Pd、 111 Ag、 110m In、 111 I、 113 In、 133m In、 114m In、 117m Sn、 121 Sn、 127 For, 142 Pr、 143 Pr、 149 Pm、 151 Pm、 149 Tb、 155 Tb、 153 Sm、 157 Gd、 161 Tb、 166 Ho、 165 Dy、 169 Er、 169 Yb、 175 Yb、 172 Tm、 176 Lu、 177 Lu、 177m Lu、 nat Lu、 186 Re, 188 Re, 191 Pt、 197 Hg、 198 I、 199 I、 212 Pb、 203 Pb、 204 Pb、 206 Pb、 207 Pb、 208 Pb、 211 Assets, 209 Wind、 212 Wind、 213 Wind、 223 Ra、 225 Ac、 227 Th、 232a cation of a metal selected from the group consisting of Th, and 18 Cationic molecules containing F and 18 F[AlF] 2+ It is.

[0028] In additional embodiments, A can also be C(CH 3 ) 3 It is.

[0029] In another further embodiment, G is: [ka] [ka] [ka] having a formula selected from the group consisting of: Z is H, CH 3 or CF 3 It is.

[0030] In another further embodiment, R 1 are independently 3 , H, L 1 -CH 2 -C≡C,L 1 -CH 3 , L 1 -H, L 1 -L 2 -CH 2 -C≡C,L 1 -L 2 -CH 3 , L 1 -L 2 -G, L 1 -L 2 -H, L 1 -L 2 -H 2 , L 1 -L 2 -L 3 -G, L 1 -L 2 -L 3 -H, L 1 -L2 -L 3 -L 4 -Q-L 5 -G, L 1 -L 2 -L 3 -Q, L 1 -L 2 -L 3 -Q-L 4 -G, L 1 -L 2 -N 3 , L 1 -L 2 -OH, L 1 -L 2 -Q, L 1 -L 2 -Q-L 3 -L 4 -G, L 1 -OH, L 1 -Q, L 1 -Q-L 2 -L 3 -L 4 -G, NH 2 , O-CH 3 , OH, [Chemical formula] and R 2 is independently CH 3 , H, L 1 -CH 2 -C≡C, L 1 -G, L 1 -H, L 1 -L 2 -CH 2 -C≡C, L 1 -L 2 -G, L 1 -L 2 -L 3 -G, L 1 -L 2 -L 3 -L 4 -G, L 1 -L 2 -L 3 -Q, L 1 -L 2 -L 3 -Q-L 4 -G, L 1 -L2 -N 3 , L 1 -L 2 -Q, L 1 -L 2 -Q.G., L. 1 -L 2 -QL 3 -G, L 1 -OH, L 1 -Q, L 1 -QL 2 -G, NH 2 , O - or O-CH 3 and R 3 are independently 3 , C.H. 2 -CH 3 Or O - It is.

[0031] In a further embodiment, the radiopharmaceutical compound also comprises [ka] is a small molecule having a formula selected from the group consisting of:

[0032] In yet another embodiment, the radiopharmaceutical compound is also for positron emission tomography (PET) imaging and has the following formula: [ka] has.

[0033] In yet another embodiment, the radiopharmaceutical compound is [ka] [ka] [ka] A theranostic compound having a formula selected from the group consisting of:

[0034] In additional further embodiments, the radiopharmaceutical compound has the following formula: [ka] It is a dual targeting theranostic compound having the following structure:

[0035] In a further embodiment, the radiopharmaceutical compound is also configured for PET imaging and therapeutic radioligand therapy.

[0036] In additional yet further embodiments, the conjugation is by a process selected from the group consisting of coupling chemistry, peptide coupling chemistry, copper catalyzed azide-alkyne cycloaddition (CuAAC) and solid phase peptide synthesis (SPPS).

[0037] Another yet further embodiment provides a combination of 3p-C-NETA and 177 and forming a chelate with Lu; and forming a chelate with DOTA and DOTAGA for treatment. 177 Lu or 225 and chelation with Ac for PET imaging, and 68 Ga, 89 Zr and 64 The method further comprises forming a chelate with one of Cu.

[0038] Additional embodiments and features are set forth in part in the description which follows, and in part will become apparent to those skilled in the art upon examination of the specification or may be learned by the practice of the present disclosure. A further understanding of the nature and advantages of the present disclosure may be realized by reference to the remaining portions of the specification and the drawings which form a part of this disclosure.

[0039] The present specification will be more fully understood by reference to the following figures, which are illustrated as exemplary embodiments of the invention and should not be construed as a complete description of the scope of the invention. [Brief description of the drawings]

[0040] [Figure 1] FIG. 1 illustrates the structures of 68Ga-DOTA-TATE and 177Lu-DOTA-TATE according to the prior art.

[0041] [Diagram 2] FIG. 2 illustrates the structures of 68Ga-PSMA-617 and 177Lu-PSMA-617 according to the prior art.

[0042] [Diagram 3] FIG. 3 illustrates an exemplary HPLC chromatogram of a HetSiFA hydrolytic stability assay according to an embodiment of the present invention.

[0043] [Figure 4-1] FIG. 4 illustrates the structures of pyridine-HetSiFAs and their properties according to embodiments of the present invention. [Figure 4-2] Same as above.

[0044] [Diagram 5] FIG. 5 illustrates the hydrolytic stability and radiochemical conversion (RCC) of pyridyl-HetSiFA, according to an embodiment of the invention.

[0045] [Figure 6] FIG. 6 illustrates the hydrolytic stability and radiochemical conversion (RCC) of pyridyl-HetSiFA, according to an embodiment of the invention.

[0046] [Figure 7] FIG. 7 illustrates the structures of N-modified pyridine-HetSiFAs and their properties according to embodiments of the present invention.

[0047] [Figure 8] FIG. 8 illustrates the structures of pyrazole-HetSiFAs and their properties according to embodiments of the present invention.

[0048] [Figure 9] FIG. 9 illustrates the hydrolytic stability and radiochemical conversion (RCC) of pyrazole-HetSiFA, according to an embodiment of the invention.

[0049] [Figure 10-1] FIG. 10 illustrates structures of [6+5] fused HetSiFAs and their properties according to an embodiment of the present invention. [Figure 10-2] Same as above.

[0050] [Figure 11] FIG. 11 illustrates the structures and properties of fused HetSiFA, furan-HetSiFA and pyrrole-HetSiFA according to an embodiment of the present invention.

[0051] [Figure 12] FIG. 12 illustrates a schematic diagram for synthesizing an 18F-labeled PET imaging tracer comprising HetSiFA and a disease-binding ligand according to an embodiment of the present invention.

[0052] [Figure 13] FIG. 13 illustrates a synthesis scheme of a pyrazole-HetSiFA building block for on-resin conjugation to a disease-binding ligand according to an embodiment of the present invention.

[0053] [Figure 14] FIG. 14 illustrates the structure of 18F-labeled HetSiFA conjugated with TATE for PET imaging of SSTR2 in cancer according to an embodiment of the present invention.

[0054] [Figure 15] FIG. 15 illustrates the structure of 18F-labeled HetSiFA conjugated with JR11 for PET imaging of SSTR2 in cancer according to an embodiment of the present invention.

[0055] [Figure 16]FIG. 16 illustrates a scheme for synthesizing a theranostic couple comprising a HetSiFA-chelator construct and a disease-binding ligand, according to an embodiment of the present invention.

[0056] [Figure 17] FIG. 17 illustrates the structure of a HetSiFA-chelator construct that is capped with a biologically inactive moiety for testing, according to an embodiment of the present invention.

[0057] [Figure 18] FIG. 18 illustrates a synthetic scheme for FTX-165, a HetSiFA theranostic, in accordance with an embodiment of the present invention.

[0058] [Figure 19] FIG. 19 illustrates a HetSiFA-chelator-ligand construct that forms a chemically identical PET diagnostic agent and RLT therapeutic agent, according to an embodiment of the present invention.

[0059] [Figure 20] FIG. 20 illustrates radiolabeling results of 18F-FTX-165, according to an embodiment of the present invention.

[0060] [Figure 21] FIG. 21 illustrates ex vivo biodistribution data of 18F-FTX-165 in healthy mice, according to an embodiment of the present invention.

[0061] [Figure 22] FIG. 22 illustrates radiolabeling results of 18F-FTX-164 showing radiolysis, according to an embodiment of the present invention.

[0062] [Diagram 23] FIG. 23 illustrates radiolabeling results of 18F-FTX-181, according to an embodiment of the present invention.

[0063] [Figure 24]FIG. 24 illustrates ex vivo biodistribution data of 18F-FTX-181 in healthy mice, according to an embodiment of the present invention.

[0064] [Diagram 25] FIG. 25 illustrates PET images of 18F-FTX-181 in healthy mice, according to an embodiment of the present invention.

[0065] [Figure 26] FIG. 26 illustrates the results of an HSA binding assay of HetSiFA compounds, according to an embodiment of the present invention.

[0066] [Figure 27] 27A-27N illustrate various HetSiFA theranostic couples, according to embodiments of the present invention.

[0067] [Figure 28] FIG. 28 illustrates a dual targeting HetSiFA theranostic pair, according to an embodiment of the present invention.

[0068] [Figure 29] FIG. 29 illustrates a synthetic scheme for PPI-24069 / FTX-175, according to an embodiment of the invention.

[0069] [Diagram 30] FIG. 30 illustrates a synthetic scheme for PPI-24073 / FTX-181, according to an embodiment of the invention.

[0070] [Diagram 31] FIG. 31 illustrates a synthetic scheme for PPI-24082 / FTX-219, according to an embodiment of the invention. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0071] Detailed Description of the Invention In the description of the embodiments, reference may be made to the accompanying drawings, which form a part of this specification, and in which specific embodiments in which the present invention may be implemented are shown by way of example. It should be understood that other embodiments may be utilized and structural changes may be made without departing from the scope of the present invention. Unless otherwise defined, all terms, notations, and other scientific or technical terms used in the present specification are intended to have the meanings commonly understood by those skilled in the art to which the present invention pertains. In some cases, terms having commonly understood meanings are defined herein for clarity and / or ease of reference, and the inclusion of such definitions herein should not necessarily be interpreted as representing a substantial difference from what is commonly understood in the art. Many aspects of the techniques and procedures described or referenced herein are well understood and commonly used by those skilled in the art. The following presents exemplary embodiments of the present invention.

[0072] 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 invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are described.

[0073] As used herein, each of the following terms has the meaning associated with it in this section.

[0074] The articles "a" and "an" are used herein to refer to one or to more than one (e.g., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

[0075] "About" and "approximately" are used to describe and take into account small variations. When used in conjunction with an event or circumstance, the term can refer to instances where the event or circumstance occurs exactly, as well as instances where the event or circumstance occurs to approximately the same extent. When used in conjunction with a numerical value, the term can refer to a range of variation of less than or equal to ±10% of that numerical value, such as less than or equal to ±5%, less than or equal to ±4%, less than or equal to ±3%, less than or equal to ±2%, less than or equal to ±1%, less than or equal to ±0.5%, less than or equal to ±0.1%, or less than or equal to ±0.05%.

[0076] Furthermore, amounts, ratios and other numerical values ​​may sometimes be presented in range format herein. It should be understood that such range format is used for convenience and brevity, and includes numerical values ​​explicitly specified as the boundaries of a range, but should be understood flexibly to include all individual numerical values ​​or subranges contained within the range as if each numerical value and subrange were explicitly specified. For example, a ratio range of about 1 to about 200 should be understood to include the explicitly stated boundaries of about 1 and about 200, but also include individual ratios such as about 2, about 3 and about 4, and subranges such as about 10 to about 50, about 20 to about 100, etc.

[0077] As used herein, the term "pharmaceutical acceptable" refers to a material, such as a carrier or diluent, that does not abolish the biological activity or properties of a compound and is relatively non-toxic, i.e., the material may be administered to an individual without causing biological effects or interacting undesirably and adversely with any of the components in the composition in which it is contained. In the case of compositions suitable for administration to humans, the term "pharmaceutical acceptable" is intended to include, but is not limited to, the components listed in Remington: The Science and Practice of Pharmacy, Lippincott Williams & Wilkins, 21st ed. (2006).

[0078] As used herein, the expression "pharmaceutical acceptable salt" refers to a salt of the compound to be administered prepared from a pharmaceutical acceptable non-toxic acid, including inorganic acids, organic acids, solvates, hydrates or clathrates thereof. Examples of such inorganic acids are hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid and hexafluorophosphoric acid. Suitable organic acids can be selected, for example, from the aliphatic, aromatic, carboxylic and sulfonic classes of organic acids, examples of which are formic acid, acetic acid, propionic acid, succinic acid, camphorsulfonic acid, citric acid, fumaric acid, gluconic acid, isethionic acid, lactic acid, malic acid, mucic acid, tartaric acid, para-toluenesulfonic acid, glycolic acid, glucuronic acid, maleic acid, furoic acid, glutamic acid, benzoic acid, anthranilic acid, salicylic acid, phenylacetic acid, mandelic acid, embonic acid (pamoic acid), methanesulfonic acid, ethanesulfonic acid, pantothenic acid, benzenesulfonic acid (besylate), stearic acid, sulfanilic acid, alginic acid, galacturonic acid, etc. Additionally, pharma- ceutically acceptable salts include, by way of non-limiting example, alkaline earth metal salts (e.g., calcium or magnesium), alkali metal salts (e.g., sodium or potassium) and ammonium salts.

[0079] As used herein, the term "imaging agent", "imaging probe" or "imaging compound" refers to a molecule that can be detected by its luminescent signal, such as positron emission, autofluorescence, or optical properties, unless otherwise specified. Methods of detection of the compound can include, but are not limited to, nuclear scintigraphy, positron emission tomography (PET), single photon emission computed tomography (SPECT), magnetic resonance imaging (MRI), magnetic resonance spectroscopy, computed tomography (CT), or combinations thereof, depending on the intended use and the imaging methods available to medical or research personnel.

[0080] As used herein, the term "biomolecule" refers to any molecule produced by a living organism and may be selected from the group consisting of proteins, peptides, polysaccharides, carbohydrates, lipids, and analogs and fragments thereof.

[0081] As used herein, the terms "bioconjugation" and "conjugation" refer to the chemical derivatization of a macromolecule with another molecular entity, unless otherwise specified. The molecular entity can be any molecule, and can include a small molecule or another macromolecule. Examples of molecular entities include, but are not limited to, the compounds of the present invention, other macromolecules, polymers or resins (such as polyethylene glycol (PEG) or polystyrene), non-immunogenic high molecular weight compounds, fluorescent, chemiluminescent radioisotopes and bioluminescent marker compounds, antibodies, biotin, diagnostic detection molecules (such as maleimide-derivatized fluorescein), coumarins, metal chelators or any other modifying groups. The terms bioconjugation and conjugation are used interchangeably throughout this specification.

[0082] As used herein, the term “alkyl,” by itself or as part of another substituent, has the specified number of carbon atoms, unless otherwise stated (e.g., C 1~6means 1 to 6 carbon atoms), straight or branched chain hydrocarbon containing straight, branched or cyclic substituents. Examples include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, pentyl, neopentyl, hexyl and cyclopropylmethyl.

[0083] As used herein, the term "substituted alkyl" refers to any group that is substituted with halogen, -OH, alkoxy, -NH 2 , -N(CH 3 ) 2 , -C(=O)OH, trifluoromethyl, -C≡N, -C(=O)O(C 1 ~C 4 ) alkyl, -C(=O)NH 2 , -SO 2 NH 2 and -C(=NH)NH 2 means an alkyl as defined above substituted with one, two or three substituents selected from the group consisting of: Examples of substituted alkyl include, but are not limited to, 2,2-difluoropropyl, 2-carboxycydopentyl and 3-chloropropyl.

[0084] As used herein, the term "heteroalkyl," alone or in combination with another term, means, unless otherwise specified, a stable straight or branched chain alkyl group consisting of the specified number of carbon atoms and one or two heteroatoms selected from the group consisting of O, N and S, where the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. The heteroatom(s) may be located at any position of the heteroalkyl group, including between the remainder of the heteroalkyl group and the fragment to which it is attached, and at the most distal carbon atom in the heteroalkyl group.

[0085] As used herein, unless otherwise stated, the term "alkoxy," employed alone or in combination with other terms, means an alkyl group, as defined above, having the designated number of carbon atoms, linked to the remainder of the molecule via an oxygen atom (e.g., methoxy, ethoxy, 1-propoxy, 2-propoxy (isopropoxy), and the higher homologs and isomers, etc.).

[0086] The terms "halo" or "halogen," as used herein, by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.

[0087] As used herein, the term "aromatic" refers to a carbocyclic or heterocyclic ring having one or more polyunsaturated rings and having aromatic properties, e.g., having (4n+2) delocalized π (pi) electrons, where n is an integer.

[0088] As used herein, the term "aryl," used alone or in combination with other terms, unless otherwise specified, means a carbocyclic aromatic system containing one or more rings (usually one, two or three rings), which may be joined together in a pendant fashion, such as biphenyl, or may be fused, such as naphthalene. Examples of aryl groups include phenyl, anthracyl and naphthyl.

[0089] As used herein, the term "substituted" means that an atom or group of atoms is replaced with hydrogen as a substituent attached to another group. The term "substituted" further refers to any level of substitution, i.e., mono-, di-, tri-, tetra-, or penta-substitution, where such substitution is permitted. The substituents are independently selected, and the substitution may be at any chemically available position. In one embodiment, the number of substituents varies between 1 and 4. In another embodiment, the number of substituents varies between 1 and 3. In yet another embodiment, the number of substituents varies between 1 and 2.

[0090] As used herein, the term "optionally substituted" means that the group referred to is substituted or may be substituted.In one embodiment, the group referred to is optionally substituted with zero substituents, for example, the group referred to is unsubstituted.In another embodiment, the group referred to is optionally substituted with one or more additional groups, each of which is individually and independently selected from the groups described herein.

[0091] Ranges: Throughout this disclosure, various aspects of the invention may be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity, and should not be construed as an inflexible limitation on the scope of the invention. Thus, the description of a range should be considered to specifically disclose all possible subranges within that range, as well as individual numerical values. For example, the description of a range such as 1-6 should be considered to specifically disclose subranges such as 1-3, 1-4, 1-5, 2-4, 2-6, 3-6, and individual numbers within that range, such as 1, 2, 2.7, 3, 4, 5, 5.3, and 6. This applies regardless of the breadth of the range.

[0092] Systems and methods are described for heteroaromatic fluorinated silicon receptor (HetSiFA) systems with theranostic properties. Many embodiments include systems and methods for HetSiFA systems with theranostic capabilities to obtain conjugates that bind to biological targets overexpressed in cancer. Theranostics has the ability to combine diagnostic PET imaging with therapeutic radioligand therapy (RLT). Theranostic couples according to some embodiments may have the same chemical structure and are suitable for PET diagnostic agents. 18Therapeutic couples may include heteroaromatic fluorinated silicon receptor systems incorporating F, and chelators incorporating radiometals for RLT. In some embodiments, theranostic couples may enable the diagnosis and treatment of patients with various types of metastatic cancer, including (but not limited to) metastatic prostate cancer.

[0093] In many embodiments, various HetSiFA compounds for imaging can be used.In some embodiments, HetSiFA compounds for PET imaging can be used.HetSiFA compounds can include heteroaryl rings substituted with various side chains, linkers and disease targeting ligands for PET imaging. [ka] In the formula, F is F, 18 F or 19 F. Each A is independently H, methyl, ethyl, sec-butyl, isopropyl, and tert-butyl.

[0094] In many embodiments, various HetSiFA compounds for theranostics can be used.In some embodiments, HetSiFA compounds can comprise a single disease-binding ligand that targets receptors that are overexpressed in cancer cells.Single-targeted theranostic compounds can comprise heteroaryl rings that are substituted with various side chains, linkers, disease targeting ligands, and chelators for radiometallation. [ka] In the formula, F is F, 18 F or 19 F. Each A is independently H, methyl, ethyl, sec-butyl, isopropyl, and tert-butyl.

[0095] In many embodiments, various HetSiFA compounds for theranostics can be used.In some embodiments, the HetSiFA compound can comprise two disease-binding ligands as a dual-targeting theranostic compound.The two disease-binding ligands can target different receptors that are overexpressed in cancer cells.The dual-targeting theranostic compound can comprise heteroaryl rings that are substituted with various side chains, linkers, disease-targeting ligands, and chelators for radiometallation. [ka] In the formula, F is F, 18 F or 19 F. Each A is independently H, methyl, ethyl, sec-butyl, isopropyl, and tert-butyl.

[0096] In many embodiments, the HetSiFA compounds can include heteroaryl rings, including (but not limited to) pyridine, pyridinium, pyrazole, fused pyrazole, benzofuran, benzothiophene, indole, azaindole, imidazole, and pyrimidine. As can be easily understood, any type of heteroaryl ring can be utilized as appropriate for the requirements of a particular application according to various embodiments of the present invention.

[0097] In some embodiments, the HeSiFA compound comprises a heteroaryl ring, such as pyridine or pyridinium or a salt thereof: [ka] Can include Alternatively, the HetSiFA compound may have a heteroaryl ring, such as a pyrazole or a salt thereof: [ka] Can include Alternatively, the HetSiFA compound may comprise a heteroaryl ring, such as a fused pyrazole derivative or a salt thereof: [ka] Can include Alternatively, the HetSiFA compound may have a heteroaryl ring such as benzofuran, benzothiophene, indole, azaindole or salts thereof: [ka] Can include Alternatively, the HetSiFA compound may have a heteroaryl ring, such as imidazole or a salt thereof: [ka] Can include Alternatively, the HetSiFA compound may have a heteroaryl ring, such as a pyrimidine or a salt thereof: [ka] may include During the ceremony, F is independently F or 18 F or 19 F, A is independently H, CH 3、 CH 2 -CH 3、 CH 3 -CH 2 -CH(CH 3 ), CH(CH 3 ) 2 and C(CH 3 ) 3 and U is independently O-CH 3 , C.H. 3 , C.H. 2 CH 3 , H, I, Br, Cl, F, N(CH 3 ) 2 and C.H. 2 CH(NH 2 )CO 2 H, X is independently O, S, or N; Y is independently C and N; R 1 or R 2 or R 3 are independently 3 , C.H. 2 -CH 3 , H, L 1 -CH 2 -C≡C,L 1 -CH 3 , L 1 -G, L 1 -H, L 1 -L 2 -CH 2 -C≡C,L 1 -L 2 -CH 3 , L 1 -L 2 -G, L 1 -L 2 -H, L 1 -L 2 -H 2 , L 1 -L 2 -L 3 -G, L 1 -L 2 -L 3 -H, L 1 -L 2 -L 3 -L 4 -G, L 1 -L 2 -L 3 -L 4 -H, L 1 -L 2 -L 3 -L 4 -QL 5 -G, L 1 -L 2 -L 3 -Q, L 1 -L 2 -L 3 -QL 4 -G, L 1 -L 2 -N 3 , L 1 -L 2 -OH, L 1 -L 2-Q, L 1 -L 2 -Q.G., L. 1 -L 2 -QL 3 -G, L 1 -L 2 -QL 3 -L 4 -G, L 1 -L 2 -QL 3 -L 4 -H, L 1 -OH, L 1 -Q, L 1 -QL 2 -L 3 -L 4 -G, L 1 -QL 2 -G, NH 2 , O - , O-CH 3 , O.H., [ka] and L 1 or L 2 or L 3 or L 4 or L 5 are each independently -(O-CH 2 -CH 2 ) p -, -(CH 2 -CH 2 -O) p -, -(Glu-His) p -, -(His-Glu) p -, -(Glu-Trp) p -, -(Trp-Glu) p -, -NH-CH 2 -C 6 H 4 -NH-(C=O)-CH 2 -O-CH 2 -(C=O)-, -(C=O)-CH 2 -O-CH 2 -(C=O)-NH-C 6 H 4 -CH 2 -NH-, -(C=O)-CH 2-CH 2 -(C=O)-、-NH-C 5 H 9 N-CH 2 -(C=O)-、-(C=O)-CH 2 -NC 5 H 9 -NH-、-(Gly) p -、-CH 2 -CH 2 -NH-、-NH-CH 2 -(C=O)-、-(Glu)-、-NH-CH 2 -CH 2 -、-(C=O)-、NH-CH 2 -CH 2 -(O-CH 2 -CH 2 ) p -(C=O)-、-(C=O)-(CH 2 -CH 2 -O) p -CH 2 -CH 2 -NH-、-NH-(C=O)-CH 2 -、-NH-(C=O)-NH-CH 2 -、-NH-(C=S)-NH-CH 2 -、-NH-(CH 2 -CH 2 -O) p -CH 2 -(C=O)-、-(C=O)-CH 2 -(O-CH 2 -CH 2 ) p -NH-、-Asp-、-NH-、-NH-(CH 2 -CH 2 -O) p -CH 2 -CH 2 -(C=O)-、-(C=O)-CH 2 -CH 2 -(O-CH 2 -CH 2 ) p -NH-、-CH 2 -(C=O)-、-(C=O)-CH 2 -、-O-(C=O)-、-(C=O)-O-、-CH 2-O-, -NH-(C=O)-O-, -O-(C=O)-NH-, -(C=O)-CH 2 -(O-CH 2 -CH 2 ) p -O-CH 2 -(C=O)-, -NH-(C=O)-NH-, -NH-(C=S)-NH-, -CH 2 -N(CH 3 )-CH 2 -, -N(CH 3 )-, -(C=O)-C 6 H 4 -(C=O)-, -C 6 H 4 -(C=O)-, -(C=O)-C 6 H 4 -, -O-CH 2 -(C=O)-, -(C=O)-CH 2 -O-, -CH 2 -C 2 N 3 -CH 2 -, -CH 2 -CH 2 -(C=O)-, -(C=O)-CH 2 -CH 2 -, -CH 2 -N + (CH 3 ) 2 -CH 2 -, -CH 2 -N(CH 3 )-, -(C=O)-CH 2 -(O-CH 2 -CH 2 ) p -, -(CH 2 -CH 2 -O) p -CH 2 -CH 2 -NH-, [ka] and p=0 to 12; G is a disease-binding ligand, each G is independently Somatostatin receptor type 2 (SSTR2) binding ligand G1 [ka] SSTR2-binding ligand G 2 [ka] SSTR2-binding ligand G 3 [ka] SSTR2-binding ligand G 4 [ka] Gastrin-releasing peptide receptor (GRPR) binding ligand G 5 [ka] (Wherein, Z is H, CH 3 or CF 3 is) GRPR-binding ligand G 6 [ka] (Wherein, Z is H, CH 3 or CF 3 is) Prostate-specific membrane antigen (PSMA)-binding ligand G 7 [ka] PSMA-binding ligand G 8 [ka] PSMA-binding ligand G 9 [ka] PSMA-binding ligand G 10 [ka] PSMA-binding ligand G 11 [ka] Fibroblast activation protein (FAP) binding ligand G 12 [ka] FAP-binding ligand G 13 [ka] FAP-binding ligand G 14 [ka] FAP-binding ligand G 15 [ka] CXC chemokine receptor type 4 (CXCR-4) binding ligand G 16 [ka] CXCR-4 binding ligand G 17 [ka] and Q is a chelating agent, each Q is independently -DOTA [ka] -DOTAGA [ka] -Dap(DOTA) [ka] -Lys (DOTA) [ka] -3p-C-NETA [ka] -Bis-thiosemicarbazone [ka] (wherein R can be methyl) 2 ATSM), or R is NH 2 (H 2 ATSM / A)) -EDTA [ka] -CHX-A”-EDTA [ka] -DTPA [ka] -p-SCN-DPTA [ka] -CHX-A”-DTPA [ka] -p-SCN-Bz-Mx-DTPA [ka] -NOTA [ka] -TETA [ka] -CB-TE2A [ka] where R can be (C=O)-OH (CB-TE2A), or R can be P(O)(OH) 2 (CB-TE1A1P) -p-SCN-NOTA (cNOTA) [ka] -nNOTA [ka] -NODAGA [ka] -p-SCN-DOTA(cDOTA) [ka] -2-cTETA [ka] -6-cTETA [ka] -BAT [ka] -Diamsar [ka] -SarAr [ka] -PCTA [ka] -NODIA-Me [ka] -TRAP [ka] -pycup1A1B [ka] where R can be phenyl (pycup1A1B) or R can be (C=O)OH (pycup2A). -p-SCN-DTPA [ka] -Desferrioxamine B (DFO) mesylate [ka] -Desferrioxamine-p-SCN [ka] -DFO-Star (DFO * ) [ka] -L5 [ka] -Orn3hx-NCS [ka] (wherein n=1) -Orn4hx-NCS [ka] (wherein n=2) -p-SCN-Bn-HOPO [ka] -2,3-HOPO-p-Bn-NCS [ka] -YM103 [ka] (In the formula, R is [ka] is) -Tc(V)oxo [ka] -Tc(V) nitride [ka] -Tc(V)HYNIC [ka] -Tc(I)-fac-tricarbonyl [ka] -Tc(VII) trioxo [ka] -3p-C-NETA-NCS [ka] -3p-C-DEPA-NCS [ka] -TCMC [ka] -p-SCN-Bn-H 4 October [ka] -HEHA-NCS [ka] -Macropa-NCS [ka] It is.

[0098] In some embodiments, Q can be unchelated. In some embodiments, Q can be optionally chelated to a metal cation M, where M is 43 Sc, 44 Sc, 45 Sc, 47 Sc, 51 Cr, 52m Mn, 68 Co, 52 Fe, 56 Ni, 57 Ni, 61 Cu, 62 Cu, 63 Cu, 64 Cu, 65 Cu, 67 Cu, 66 Ga, 67 Ga, 68 Ga, 69 Ga, 71 Ga, nat Ga, 90 Zr, 91 Zr, 92 Zr, 89 Zr, 86 Y, 90 Y, 89 Y, 99m Tc, 97 Ru, 105 Rh, 109 Pd, 111 Ag, 110m In, 111 I, 113 In, 133m In, 114m In, 117m Sn, 121 Sn, 127 Te, 142 Pr, 143 Pr, 149 Pm, 151 Pm, 149 Tb, 155 Tb, 153 Sm,157 Gd, 161 Tb, 166 Ho, 165 Dy, 169 Er, 169 Yb, 175 Yb, 172 Tm, 176 Lu, 177 Lu, 177m Lu, nat Lu, 186 Re, 188 Re, 191 Pt, 197 Hg, 198 Au, 199 Au, 212 Pb, 203 Pb, 204 Pb, 206 Pb, 207 Pb, 208 Pb, 211 At, 209 Bi, 212 Bi, 213 Bi, 223 Ra, 225 Ac, 227 Th, 232 Th cation, and 18 F[AlF] 2+ etc. 18 Q is a cationic molecule containing F. The following non-limiting examples illustrate chelating agents with metal cations chelated. As can be readily appreciated, any of the above chelating agents can be chelated as well. The chelated Q can be any of the following: DOTA chelated with M: [ka] DOTAGA chelated with M: [ka] Dap(DOTA) chelated with M: [ka] Lys(DOTA) chelated with M: [ka] and 3p-C-NETA chelated with M: [ka] It can be said that:

[0099] In some embodiments, various small molecule HetSiFA compounds can be used to synthesize radiopharmaceuticals. Various types of disease-binding ligands and / or chelators can be attached to the small molecule HetSiFA compounds during synthesis for individual applications of the small molecule HetSiFA compounds. In some embodiments, the small molecule HetSiFA compounds have the formula: [ka] [ka] may have the following structure:

[0100] Various HetSiFA compounds for PET imaging can be used. Various types of disease-binding ligands are conjugated to the radiolabeled HetSiFA compounds. In some embodiments, the HetSiFA compound for PET imaging has the formula: [ka] may have the following structure:

[0101] Various HetSiFA compounds are theranostic compounds. Various types of disease-binding ligands are conjugated to radiolabeled HetSiFA compounds. Theranostic compounds have the same chemical structure but differ in nuclide. Theranostic compounds can be used for PET imaging and / or as therapeutic agents. In some embodiments, theranostic HetSiFA compounds have the formula: [ka] [ka] [ka] may have the following structure:

[0102] Various HetSiFA compounds are dual targeting theranostic compounds. Two types of disease binding ligands are conjugated to the radiolabeled HetSiFA compounds. Theranostic compounds can be used for PET imaging and / or as therapeutic agents. In some embodiments, theranostic HetSiFA compounds have the formula: [ka] may have the following structure:

[0103] Many embodiments provide HetSiFA systems with desirable properties for making radiopharmaceuticals, including (but not limited to) radiolabeling efficiency, hydrophilicity, chemical versatility, hydrolytic stability, plasma protein binding capacity, kinetic solubility, target binding affinity and biodistribution in mice. In some embodiments, HetSiFAs with heteroaromatic groups, including (but not limited to) pyrazole, pyridine, pyridine oxide and azaindole, show better properties than phenyl-SiFAs for making radiopharmaceuticals. Various HetSiFAs with heteroaromatic groups, including (but not limited to) indole, benzothiophene, benzofuran, furan and pyrrole, show less favorable properties than pyrazole, pyridine, pyridine oxide and azaindole.

[0104] HetSiFAs, including (but not limited to) pyrazole-HetSiFAs, pyridine-HetSiFAs, pyridine oxide-HetSiFAs, and azaindole-HetSiFAs, can be conjugated to disease-binding ligands. Examples of disease-binding ligands include:18 Somatostatin receptor type 2 (SSTR2) binding ligands (G 1 , G 2 , G 3 and G 4 ), gastrin releasing peptide receptor (GRPR) binding ligand (G 5 and G 6 etc.), prostate-specific membrane antigen (PSMA)-binding ligand (G 7 , G 8 , G 9 , G 10 and G 11 ), fibroblast activation protein (FAP) binding ligand (G 12 , G 13 , G 14 and G 15 ) and CXC chemokine receptor type 4 (CXCR-4) binding ligands (G 16 and G 17 Various HetSiFA compounds can be conjugated to disease-binding ligands by a variety of processes, including (but not limited to) coupling chemistry, peptide coupling chemistry, copper-catalyzed azide-alkyne cycloaddition (CuAAC), and solid-phase peptide synthesis (SPPS).

[0105] Prostate cancer cells may become PSMA negative during malignant tumors at the stage of metastatic castration-resistant prostate cancer (mCRPC). GRPR is a member of the G-protein-coupled receptor superfamily and part of the family of bombesin receptors. GRPR is overexpressed in various malignant entities, including neuroblastoma, lung cancer, pancreatic cancer, gastric cancer, colorectal cancer, esophageal cancer, breast cancer and prostate cancer, and therefore may be a potential specific target for various malignant tumors. This overexpression of GRPR, as well as its rather low expression in normal organs and healthy tissues, makes this receptor a promising diagnostic and therapeutic target for PET and RLT, respectively. Considering the difference in expression patterns of PSMA and GRPR and overexpression of GRPR in cell membranes of prostate cancer and prostatic intraepithelial neoplasia, in contrast to healthy prostate tissue and benign prostatic hyperplasia, targeting GRPR with theranostic radiopharmaceuticals may be favorable in patients who do not respond to PSMA theranostics and may be PSMA negative.

[0106] In many embodiments, systems and methods are described for theranostic HetSiFA systems with dual targeting capabilities. HetSiFA systems can be conjugated with two different disease-binding ligands to target receptors that are overexpressed in cancer cells. Dual targeting capabilities can improve the accuracy of imaging and / or treatment. In some embodiments, HetSiFA systems can be conjugated with dual disease-binding ligands for receptors PSMA and GRPR for imaging and treatment of metastatic prostate cancer. In certain embodiments, HetSiFA systems can be conjugated with dual disease-binding ligands for receptors GRPR and SSTR2 for imaging and treatment of metastatic breast or lung cancer.

[0107] Various HetSiFA compounds can be conjugated, according to some embodiments, to small molecules that have no biological function (otherwise known as caps). The resulting compounds can be used in radiolabeling studies and / or other assays.

[0108] HetSiFAs combined with metal chelators can be made into theranostic HetSiFAs. In many embodiments, various HetSiFA compounds are available, including but not limited to, DOTA, DOTAGA, Dap(DOTA), Lys(DOTA), 3p-C-NETA, AAZTA, bis-thiosemicarbazones, H 2 A.T.S.M., H. 2 ATSM / A, EDTA, CHX-A”-EDTA, DTPA, p-SCN-DPTA, CHX-A”-DTPA, p-SCN-Bz-Mx-DTPA, NOTA, TETA, CB-TE2A, CB-TE1A1P, p-SCN-NOTA, nNOTA, NODAGA, p-SCN-DOTA, 2-cTETA, 6-cTETA, BAT, Diamsar, SarAr, PCTA, NODIA-Me, TRAP, pycup1A1B, pycup2A, p-SCN-DTPA, desferrioxamine, desferrioxamine B, desferrioxamine B (DFO) mesylate, desferrioxamine-p-SCN, DFO-Star (DFO * ), L5, Orn3hx-NCS, Orn4hx-NCS, p-SCN-Bn-HOPO, 2,3-HOPO-p-Bn-NCS, YM103, Tc(V) oxo, Tc(V) nitride, Tc(V) HYNIC, Tc(I)-fac-tricarbonyl, Tc(VII) trioxo, 3p-C-NETA-NCS, 3p-C-DEPA-NCS, TCMC, p-SCN-Bn-H 4 It is provided that it can be conjugated with chelating agents including octapa, HEHA-NCS, and Macropa-NCS.

[0109] The chelating agent is 18 The combination of HetSiFA and a metal chelator may, according to certain embodiments, enhance the lipophilicity of the F-PET-radiopharmaceutical.18 It can be used in F-PET imaging radiopharmaceuticals. Chelating agents can be added to increase the overall polarity of the HetSiFA moiety. In some embodiments, the chelating agent can remain free without binding any metal ions. In some embodiments, the chelating agent can be (but is not limited to) nat Ga and nat It can form chelates with non-radioactive metals, including Lu.

[0110] In many embodiments, the chelating agents are capable of forming chelates with metal cations. The chelating agents are each 43 Sc, 44 Sc, 45 Sc, 47 Sc, 51 Cr, 52m Mn, 68 Co, 52 Fe, 56 Ni, 57 Ni, 61 Cu, 62 Cu, 63 Cu, 64 Cu, 65 Cu, 67 Cu, 66 Ga, 67 Ga, 68 Ga, 69 Ga, 71 Ga, 90 Zr, 91 Zr, 92 Zr, 89 Zr, 86Y, 90 Y, 89 Y, 99m Tc, 97 Ru, 105 Rh, 109 Pd, 111 Ag, 110m In, 111 I, 113 In, 133m In, 114m In, 117m Sn, 121 Sn, 127 Te, 142 Pr, 143 Pr, 149 Pm,151 Pm, 149 Tb, 155 Tb, 153 Sm, 157 Gd, 161 Tb, 166 Ho, 165 Dy, 169 Er, 169 Yb, 175 Yb, 172 Tm, 176 Lu, 177 Lu, 177m Lu, 186 Re, 188 Re, 191 Pt, 197 Hg, 198 Au, 199 Au, 212 Pb, 203 Pb, 204 Pb, 206 Pb, 207 Pb, 208 Pb, 211 At, 209 Bi, 212 Bi, 213 Bi, 223 Ra, 225 Ac, 227 Th, 232 a cation selected from the group consisting of Th, and 18 F[AlF] 2+ etc. 18 It can form chelates with F-containing cationic molecules.

[0111] In some embodiments, the 3p-C-NETA chelator is used for therapeutic applications, including but not limited to: 177 The 3p-C-NETA can be labeled with a nuclide containing Lu. The 3p-C-NETA can be incubated at room temperature for about 5 minutes. 177 Lu is efficiently labeled. 177 Lu-3p-C-NETA complexes can be formed. In some embodiments, DOTA and DOTAGA chelators can be used for PET imaging applications, including but not limited to: 68 Ga, 89 Zr or 64In some embodiments, the DOTA and DOTAGA chelators can be labeled with nuclides including, but not limited to, for therapeutic applications. 177 Lu or 225 They can be labeled with Ac-containing nuclides. DOTA- and DOTAGA- 177 Lu labeling can be carried out at about 95° C. for about 15-45 minutes.

[0112] In many embodiments, an amino acid spacer can be added to the HetSiFA tracer. In some embodiments, an amino acid spacer including (but not limited to) histidine (H or His) / glutamic acid (E or Glu) and / or tryptophan (W or Trp) / glutamic acid (E or Glu) can increase the affinity of the HetSiFA tracer for the target receptor, resulting in good in vivo imaging properties.

[0113] In many embodiments, the HetSiFA-chelator constructs can be conjugated to disease-binding ligands to form precursors for theranostic applications. The theranostic couple induced by HetSiFA in some embodiments can be identical twins with true "see and treat" capabilities. The diagnostic and therapeutic couples have the same chemical composition but different nuclides. Properties of HetSiFA compounds

[0114] Many embodiments provide theranostic HetSiFA compounds with unexpected properties, including (but not limited to) radiolabeling efficiency, hydrophilicity, chemical versatility, hydrolytic stability, human serum albumin (HSA) binding capacity, plasma protein binding capacity, kinetic solubility, target binding affinity, and biodistribution properties in mice.

[0115] In many embodiments, the pyrazole-HetSiFA compounds have the desired radiolabeling properties, kinetic solubility, chemical diversity, hydrophilicity and in vivo stability. The pyridine-HetSiFAs according to some embodiments have the desired hydrophilicity and chemical diversity. In certain embodiments, the azaindole-HetSiFAs have the desired radiolabeling properties, are hydrolytically stable and are chemically diverse. A brief description of each property and the characterization of each property are set forth below. a) Hydrophilicity. Hydrophilicity is related to the strength of dissolution or absorption in aqueous solutions. Hydrophilicity indicates a preference for liquids, solutions or surfaces with a high dipole moment, such as water. Lipophilicity indicates a preference for liquids, solutions or surfaces with a low dipole moment, such as lipid solutions. The more polar the HetSiFA, the less lipophilicity may need to be masked by the introduction of cumbersome and long linkers into the radiopharmaceutical. The hydrophilicity of HetSiFA is assessed by calculating and / or measuring the octanol / water partition coefficient, logP. LogD measures the lipophilicity of an ionizable compound, with the partition being a function of pH. The reversed-phase HPLC retention time t R can be used to qualitatively compare the polarity of HetSiFAs. b) Hydrolytic stability. Si- 18 The F bond is susceptible to hydrolysis in aqueous media and can form silanols. The design of the HetSiFA molecule is based on the Si- 18 The hydrolytic stability of the F bond may be affected. The hydrolytic stability of the synthesized HetSiFA can be tested in pH 10 carbonate buffer (0.1 M aqueous, 0.05 M in mixture). The HetSiFA substrate (100 μM in 1:1 MeCN / pH 10 carbonate buffer) is aged at room temperature (25 °C). At various time points, the substrate is quantified by HPLC UV monitoring. HetSiFA is dissolved at 100 μM in a 1:1 mixture of acetonitrile-aqueous buffer (pH 7.4 or 10). Hydrolysis is monitored by HPLC (approximately 7 time points). Hydrolytic stability refers to the stability at pH 10 and is the half-life (t1 / 2(pH10) 3 illustrates an HPLC chromatogram of HetSiFA, in which hydrolyzed HetSiFA is illustrated according to an embodiment. Typical HPLC conditions: Phenomenex Prodigy ODS-3 column (250×4.6 mm, 10 μm), mobile phase: MeCN / H 2 O(0.1% HCO 2 H), gradient, 20:80 to 50:50 (15 min), hold (5 min), 0.8 mL / min. T=25° C. Additionally, the stability of the compounds can be evaluated in rat and human plasma and in microsomes. c) Radiolabeling. For HetSiFA-based PET tracers to be clinically useful, they need to be radiolabeled with high radiochemical yield (RCY). The radiolabeling properties of the synthesized HetSiFA can be assessed using low amounts of radioactivity. Radio-thin layer chromatography (radio-TLC) can be used to 18 The rate of F-fluoride incorporation, i.e. the radiochemical conversion rate (RCC), is measured. d) Chemical diversity. The availability of aromatic heterocycles allows for HetSiFAs with different ring sizes, heteroatom cores and substitution patterns. Modification of the HetSiFA core allows for fine tuning of steric and electronic properties, as well as the addition of linkers and other functional groups. e) Human serum albumin and plasma protein binding. Binding to plasma proteins such as human serum albumin (HSA) affects the blood circulation time of a radiopharmaceutical and influences its binding ability to biological targets. The HSA binding properties of HetSiFA can be assessed by an HPLC method using a Chiralpak HSA column. For calibration of the HSA column, nine reference substances showing HSA binding ranging from 13% to 99% are measured and a standard curve is established. The reference substances are p-benzyl alcohol (literature HSA% = 13.15), aniline (literature HSA% = 14.06), phenol (literature HSA% = 20.69), benzoic acid (literature HSA% = 34.27), carbamazepine (literature HSA% = 75.00), p-nitrophenol (literature HSA% = 77.65), estradiol (literature HSA% = 64.81), probenecid (95.00) and glibenclamide (literature HSA% = 99.00). HSA% binding of the compounds was derived from a standard curve. The plasma protein binding properties of HetSiFA can be evaluated using mouse and human plasma proteins. f) Dynamic solubility. Solubility is an important parameter that influences pharmacokinetic behavior. Dynamic solubility can be evaluated in phosphate buffered saline (PBS) at pH 7.4. g) Target binding affinity. Binding affinity indicates the strength of the drug-target interaction. It can be measured in cells stably expressing the target of interest by displacing iodine-125 labeled ligand in a dose-dependent manner. h) Biodistribution in mice. Ex vivo biodistribution studies in mice reveal the distribution of an injected tracer in certain organs after a predefined time post-injection (pi). In a typical ex vivo biodistribution experiment, four healthy mice were dosed with 3.7-10 MBq of 18 F-labeled HetSiFA tracer is injected. One mouse is imaged by PET 10-90 min pi and then euthanized. Three mice are imaged by PET 70-90 min pi and then euthanized. Organs are weighed and activity is measured in a gamma counter. 18 HetSiFA compounds for F radiolabeling

[0116] In many embodiments, 18 A series of HetSiFAs for F radiolabeling are provided. In some embodiments, HetSiFAs with heteroaromatics, including (but not limited to) pyridine, pyridinium, pyridine oxide, pyrazole, fused pyrazole, imidazole, pyrimidine and azaindole, exhibit better properties than phenyl-SiFA for radiopharmaceutical production. Some embodiments provide that HetSiFAs with heteroaromatics, including (but not limited to) indole, benzothiophene, benzofuran, furan and pyrrole, exhibit less favorable radiolabeling properties than phenyl-SiFA.

[0117] FIG. 4 illustrates the structure of a pyridine-HetSiFA compound according to an embodiment of the present invention. The hydrolytic stability at pH 10 is calculated based on the half-life of the Si-F bond at pH 10 (t 1 / 2(pH10) ) is reported as the reversed-phase HPLC retention time t R can be used to qualitatively compare the polarity of HetSiFAs. Pyridyl-HetSiFAs have a shorter t R It is more polar than phenyl-SiFA, as evidenced by the logP of the aromatic core (logP ピリジン = 0.65; log P ベンゼン =2.13). 18 F 19 By isotope exchange with F 18 The rate of F incorporation (SiFEx) can be reported as the rate of radiochemical conversion (RCC).

[0118] Many embodiments provide that the substituent effect can increase the Si-F bond stability. The methoxy group ortho to silicon increases the Si-F stability. 3-(di-tert-butylfluorosilyl)-4-methoxypyridine has slightly lower hydrolytic stability than phenyl-SiFA. 5-(di-tert-butylfluorosilyl)-6-methoxypyridine has higher hydrolytic stability than phenyl-SiFA. Figure 5 illustrates the hydrolytic stability and radiochemical conversion rate (RCC) of pyridyl-HetSiFA according to an embodiment.

[0119] FIG. 6 illustrates the hydrolytic stability and radiochemical conversion (RCC) of pyridyl-HetSiFA according to an embodiment. FIG. 6 shows that the substituent para to silicon affects Si-F stability. Pyridine-HetSiFA is 18 It is efficiently radiolabeled with F. The radiochemical conversion rates (RCC) are comparable to phenyl-SiFA, with RCCs often exceeding 80%.

[0120] Pyridine-HetSiFAs are chemically diverse and, in some embodiments, substitution at both oxygen and nitrogen allows for extensive regioselective modification of the pyridine core. Functionalized side chains can be added to provide attachment points for disease-binding ligands.

[0121] In many embodiments, pyridine-HetSiFAs are converted to the corresponding N-modified derivatives to increase their polarity. Figure 7 illustrates the structure of pyridyl N-modified HetSiFA compounds according to embodiments. In many embodiments, N-modified pyridine-HetSiFAs provide an attachment point at the nitrogen. Pyridine-oxide and pyridinium HetSiFAs are more polar than their pyridine counterparts. Pyridine-oxide and pyridinium HetSiFAs are efficiently radiolabeled, but tend to decompose over time in solution.

[0122] Many embodiments provide pyrazole-HetSiFA compounds that have better radiolabeling properties, kinetic solubility and hydrophilicity. Pyrazole-HetSiFA compounds are smaller and more polar (logP ピラゾール = 0.26; log P ベンゼン = 2.13). Figure 8 illustrates the structure of a pyrazole-HetSiFA compound according to an embodiment of the invention.

[0123] Up to three side chains can be attached to the pyrazole-HetSiFA, thus making a wide range of different molecules accessible. Pyrazole-HetSiFAs offer good chemical diversity.

[0124] The hydrolytic stability of pyrazole-HetSiFA evaluated by stability assay at pH 10 is relatively low. However, the pH 10 environment cannot be reached in a physiological environment. Figure 9 illustrates the hydrolytic stability and radiochemical conversion rate (RCC) of pyrazole-HetSiFA. Figure 9 shows that the substituent of pyrazole-HetSiFA can affect the hydrolytic stability.

[0125] Many embodiments provide [6+5] fused HetSiFA compounds with advantageous radiolabeling properties, hydrolytic stability, kinetic solubility and hydrophilicity. Figure 10 illustrates the structure of a [6+5] fused HetSiFA compound according to an embodiment of the present invention.

[0126] Some embodiments present several [6+5] fused HetSiFAs that are effectively radiolabeled, hydrolytically stable, and chemically diverse. [6+5] fused HetSiFAs are generally larger than pyrazole- and pyridine-HetSiFAs, but some remain more polar than phenyl-SiFAs.

[0127] Many [6+5] fused HetSiFAs have an azaindole core. Azaindole-HetSiFAs according to some embodiments can be successfully radiolabeled and exhibit high hydrolytic stability depending on how the azaindole core is modified.

[0128] Some embodiments provide that the nitrogen of the pyridine moiety in the azaindole can be at position 7, 6, 5 or 4. Azaindole-HetSiFAs offer high chemical diversity.

[0129] In some embodiments, azaindoles are converted to their N-oxides or N-substitutions. The modification increases the polarity of the core. They are often efficiently radiolabeled at the expense of hydrolytic stability. Due to their large size and relatively low hydrophilicity, azaindoles are of low priority as the HetSiFA core for radiopharmaceutical development.

[0130] Many embodiments suggest that indoles, benzothiophenes and benzofurans may be less polar and less chemically diverse than phenyl-SiFAs. Some furan- and pyrrole-HetSiFAs lack chemical diversity and have high lipophilicity. Some furan-HetSiFAs radiolabel efficiently, but the stability of the Si-F bond is low. Some pyrrole-HetSiFAs are less efficient. 18 These compounds may not be ideal for the development of radiopharmaceuticals of HetSiFA.

[0131] FIG. 11 illustrates the structures of fused HetSiFA, furan-HetSiFA and pyrrole-HetSiFA, and their properties, according to an embodiment of the present invention. HetSiFA constructs for PET imaging

[0132] HetSiFAs with various physicochemical and labeling properties can be conjugated with disease targeting ligands for PET imaging. 18 F-labeled precursors can be generated. Figure 12 illustrates a schematic diagram of synthesizing HetSiFA PET tracers according to an embodiment. Disease targeting ligands can be conjugated via the N-terminus of the peptide on the resin. Any type of disease targeting ligand, such as (but not limited to) peptides or peptidomimetics that can target cancer cells, can be implemented. Examples of targets for disease binding ligands include (but are not limited to): GRPR, PSMA, SSTR2, FAP and CXCR4. HetSiFA compounds with various aromatic cores, such as (but are not limited to) pyrazole, pyridine, pyridinium, azaindole, imidazole and pyrimidine, as well as polar linkers, can be conjugated with disease targeting ligands. The aromatic core of the HetSiFA compound can affect the pharmacological properties of the HetSiFA-ligand construct. Candidates to be conjugated can differ in terms of physicochemical and labeling characteristics and can be screened for their radiolabeling, hydrolytic stability, binding affinity and other properties. The HetSiFA-ligand constructs can then be used for PET imaging. 18 Radiolabeled with F, it can provide doses for up to several hundred patients.

[0133] FIG. 13 shows a synthetic scheme for pyrazole-HetSiFA building blocks that can be conjugated to disease-binding ligands, according to an embodiment of the invention.

[0134] Figure 14 illustrates the structure of HetSiFA conjugated to TATE for PET imaging of SSTR2 according to an embodiment of the present invention. Figure 15 illustrates HetSiFA conjugated to JR11 for PET imaging of SSTR2 according to an embodiment of the present invention. HetSiFA constructs for theranostics

[0135] For theranostic applications, HetSiFA can be combined with a chelator for (radio)metal complexation. Figure 16 illustrates a schematic diagram of the conjugation of HetSiFA-chelator constructs with disease targeting ligands according to an embodiment. HetSiFA-chelator constructs can be conjugated with disease targeting ligands to generate precursors for PET imaging and RLT as theranostic pairs. Disease targeting ligands can be conjugated via the N-terminus of a peptide on a resin. Any type of disease targeting ligand, such as (but not limited to) peptides or peptidomimetics that can target cancer cells, can be implemented. Examples of targets for disease binding ligands include (but are not limited to): GRPR, PSMA, SSTR2, FAP and CXCR4. HetSiFAs with various aromatic cores can be applied, including (but are not limited to) pyrazole, pyridine, pyridinium, azaindole, imidazole and pyrimidine. The HetSiFA-chelator constructs can vary in terms of aromatic core, polar linker and chelator. The HetSiFA-chelator constructs can affect the pharmacological properties of the HetSiFA-chelator-ligand construct. The conjugated candidates can differ in terms of physicochemical and labeling characteristics and can be screened for their radiolabeling, hydrolytic stability, binding affinity and other properties. The conjugated candidates can be used for PET imaging. 18 F, or for RLT 177 Lu / 225 In addition, the chelator can be used to label the nucleosomes, including but not limited to: 68 Ga, 64 Cu or 89 It will be possible to label with other PET isotopes, including Zr.

[0136] Historically, the development of theranostic partners has required separate and lengthy development processes for both the imaging and therapeutic companions. 68 GaPET / 177 The fact that only one precursor is needed to produce the Lu theranostic couple is likely one of the reasons why this theranostic couple has been so popular. 18 To increase the use of F, 18 F / 177 There may be a need for Lu pairs to become more readily available. 68 Instead of Ga 18 Substitution with F can improve patient care (through higher resolution imaging) and may increase the availability of radiopharmaceuticals (through scale-up). Precursors derived from HetSiFA-chelators can be used to treat, but are not limited to, 18 F, 177 Lu or 225 It is possible to label with nuclides including Ac. 68 Ga or 64 Labeling with Cu is also possible if desired.

[0137] In some embodiments, HetSiFA combined with a metal chelator can be made into a theranostic HetSiFA. The combination of HetSiFA and a metal chelator can also be made into a non-theranostic HetSiFA according to some embodiments. 18 It can be used as a F-PET imaging radiopharmaceutical. In such an embodiment, a chelator can be added to reduce the overall polarity of the HetSiFA moiety. The chelator can be left empty or a non-radioactive metal can be chelated.

[0138] Chelators that can be conjugated to a HetSiFA moiety to yield a HetSiFA-chelator conjugate include (but are not limited to) DOTA, DOTAGA, NOTA, and NODAGA. DOTA and DOTAGA chelators can be conjugated to a PET ( 68 Ga or 64 Cu) or treatment ( 177 Lu or 225 3p-C-NETA may be labeled with a nuclide for HetSiFA. 3p-C-NETA may also be conjugated to HetSiFA. Examples of chelators include (but are not limited to) EDTA, CHX-A"-EDTA, DTPA, p-SCN-DTPA, CHX-A"-DTPA, pSCN-Bz-Mx-DTPA, TETA, CB-TE2A, CB-TE1A1P, p-SCN-NOTA, nNOTA, NODAGA, p-SCN-DOTA, DOTAGA, 2-cTETA, 6-cTETA, BAT, Diamsar, SarAr, PCTA, NODIA-Me, TRAP, pycup1A1B, pycup2A, p-SCN-DTPA, DFO, DFO B, DFO B mesylate, DFO-p-SCN, DFO-Star, L5, Orn3hx-NCS, Orn4hx-NCS, p-SCN-Bn-HOPO, YM103, 2,3-HOPO-p-Bn-NCS, oxo, nitride, HYNIC, fac-tricarbonyl, trioxo, 3p-C-NETA-NCS, 3p-C-DEPA-NCS, TCMC, p-SCN-Bn-H 4 octapa, HEHA-NCS and Macropa-NCS.

[0139] The cations that the chelating group can chelate are: 43 Sc, 44 Sc, 45 Sc, 47 Sc, 51 Cr, 52m Mn, 68 Co, 52 Fe, 56 Ni, 57 Ni, 61 Cu, 62 Cu, 63 Cu, 64 Cu,65 Cu、 67 Cu、 66 Ga、 67 Ga、 68 Ga、 69 Ga、 71 Ga、 90 Zr、 91 Zr、 92 Zr、 89 Zr、 86 Y、 90 Y、 89 Y、 99m Tc、 97 Ru、 105 Rh、 109 Pd、 111 Ag、 110m In、 111 I、 113 In、 133m In、 114m In、 117m Sn、 121 Sn、 127 For, 142 Pr、 143 Pr、 149 Pm、 151 Pm、 149 Tb、 155 Tb、 153 Sm、 157 Gd、 161 Tb、 166 Ho、 165 Dy、 169 Er、 169 Yb、 175 Yb、 172 Tm、 176 Lu、 177 Lu、 177m Lu、 186 Re, 188 Re, 191 Pt、 197 Hg、 198 I、 199 I、 212 Pb、 203 Pb、 204 Pb、 206 Pb、 207 Pb、 208 Pb、 211 Assets, 209 Wind、 212 Wind、 213 Wind、 223 Ra、 225Ac, 227 Th, 232 Th cation, or 18 F[AlF] 2+ etc. 18 It is a cationic molecule containing F.

[0140] FIG. 17 illustrates the structure of a HetSiFA theranostic compound that has no biological function for radiolabeling studies, according to an embodiment of the present invention.

[0141] FIG. 18 illustrates a synthetic scheme for theranostic HetSiFA targeting SSTR2, according to an embodiment of the present invention.

[0142] FIG. 19 illustrates an SSTR2-ligand conjugated with a HetSiFA-chelator construct to form an SSTR2-targeting HetSiFA theranostic, according to an embodiment of the present invention. nat When Lu is complexed in a chelating agent, this compound is useful for PET diagnosis. 18 It can be labeled with F ( 18 F-Pyrazole-HetSiFA- 176 Lu-DOTAGA-TATE ( 18 F-FTX-165). When the chelator is empty, this compound is 177 can be labeled with Lu ( 19 F-Pyrazole-HetSiFA- 177 Lu-DOTAGA-TATE ( 177 The theranostic pair induced by HetSiFA according to some embodiments can be identical twins with a bona fide "see and treat" capability. The diagnostic and therapeutic pair differ in nuclide but not chemical composition. FIG. 18 F PET diagnosis and 177 Lu treatment illustrates that the only difference is the radioactive label. 68 Ga-DOTA-TATE and 177Other theranostic pairs, such as Lu-DOTA-TATE (Figure 1), are not chemically identical but differ in the radiometal. Substitution of the radiometal may affect biodistribution, target affinity, metabolic stability and other properties.

[0143] FIG. 20 is a block diagram of an embodiment of the present invention. 18 F-labeled pyrazole-HetSiFA compound, 18 FIG. 20 illustrates the compound F-FTX-165. 18 Radio-HPLC and radio-TLC chromatograms of F-pyrazole-HetSiFA-Lu-DOTAGA-TATE are shown. RCC (low activity) is equal to about 80% (rTLC, 5 min). RCY (medium activity) is equal to about 54% (isolated). RCY (high activity) is equal to about 47% (isolated). Maximum isolated activity is equal to about 23.9 GBq (645 mCi). A m is greater than approximately 159 GBq / μmol (4.3 Ci / μmol).

[0144] FIG. 21 shows a graph of the IL-16 expression in healthy mice, according to an embodiment. 18 F-Pyrazole-HetSiFA-Lu-DOTAGA-TATE( 18 The chemical structure of this compound is shown in FIG. 20. Ex vivo biodistribution data are collected in three Balb / c female mice. Little uptake into bone was observed, and in vivo, Si- 18 This indicates that the F bond is sufficiently stable.

[0145] FIG. 22 is a block diagram of an embodiment of the present invention. 18 F-labeled pyridine-HetSiFA compound, 18 FIG. 22 illustrates the compound F-FTX-164. 18Radio-HPLC and radio-TLC chromatograms of F-pyridine-HetSiFA-Lu-DOTAGA-TATE are shown. The compound decomposes upon radiolabeling with a starting activity of about 77 GBq. RCC (low activity) is equal to about 65%. RCY (medium activity) is equal to about 15%. RCY (high activity) is less than about 1%. Radiolysis may have occurred.

[0146] The lipophilicity of the HetSiFA in a radiopharmaceutical may need to be considered. 18 FIG. 23 illustrates the compound Lu-DOTAGA- 18 F-Pyrazole-HetSiFA-PEG 12 -TATE( 18 Radio-HPLC and radio-TLC chromatograms of F-FTX-181) are shown, in which polyethylene glycol (PEG) chains are added to increase solubility and hydrophilicity. 18 F-labeled compounds can be isolated with high activity yields of up to 41 GBq. RCC (low activity) is equal to about 75% (rTLC, 5 min). RCY (medium activity) is equal to about 31% (isolated). RCY (high activity) is equal to about 51% (isolated). Maximum isolated activity is equal to about 41 GBq (1.1 Ci). A m is greater than approximately 273 GBq / μmol (7.33 Ci / μmol).

[0147] FIG. 24 shows Lu-DOTAGA- in healthy mice, according to an embodiment. 18 F-Pyrazole-HetSiFA-PEG 12 Illustrates ex vivo biodistribution data for compound -TATE. 18 The chemical structure of F-FTX-181 is shown in Figure 23. Ex vivo biodistribution data are collected in three Balb / c female mice. 18 Compared with F-FTX-165, little uptake into bone was observed, and in vivo, Si- 18 This shows that the F bond is stable enough. 18Factors other than the hydrolytic stability of the F bond may explain the in vivo Si- 18 This suggests that the enzyme metabolism in the liver may affect F bond stability. Even if the HetSiFA is stable to hydrolysis, it may contribute to the defluorination of lipophilic HetSiFA (see, for example, S. Otaru, et al., Mol. Pharmaceutics, 2020, 17, 3106-3115; S. Otaru, et al., Molecules, 2020, 25, 5, 1208, the disclosures of which are incorporated herein by reference). The favorable renal excretion of HetSiFA radiopharmaceuticals may help reduce defluorination in the liver. 18 Accumulation of F-FTX-181 is low and is washed out of non-targeted organs, except for the gallbladder. 18 F-FTX-181 exhibits promising biodistribution, warranting further development.

[0148] Figure 25 shows the results of the study in healthy mice 70 to 90 minutes after injection. 18 1 illustrates a maximum intensity PET image of F-FTX-181.

[0149] (Het)SiFAs are known to bind to plasma proteins. Binding to plasma proteins can affect the blood circulation time of a radiopharmaceutical and affect its ability to bind to biological targets. HetSiFAs can modify plasma protein binding properties in two ways: 1) Many different heterocycles in the chemical space allow for a search for candidates with desired plasma protein binding properties. 2) The plasma protein binding HetSiFA moieties can be placed in different parts of the radiopharmaceutical. HetSiFAs can either protrude from the radiopharmaceutical and become more accessible to plasma proteins, or be "sandwiched" by other parts of the molecule and become less accessible. The phenyl in phenyl-SiFAs cannot be chemically modified to affect its plasma protein binding. Phenyl-SiFAs are generally linked to radiopharmaceuticals via side chains that are generally para-positioned away from the silicon substituent. Thus, all phenyl-SiFAs protrude from the molecular framework, making a "sandwich" structure impossible.

[0150] FIG. 26 illustrates the results of a human serum albumin (HSA) binding assay of HetSiFA compounds according to an embodiment. A standard curve can be first established using a reference compound (see, for example, Valko, K. et al., J. Pharm. Sci. 2003, 92 (11), 2236-2248; Wurzer, AJ et al., PSMA binding dual mode radiotracer and therapeutic. 2020, WO2020157177A1, the disclosures of which are incorporated herein by reference). The results of the HSA binding assay include four HetSiFA theranostic compounds, FTX-164, FTX-165, FTX-168 and FTX-181 (structures shown in FIG. 26), and two therapeutic agents, Lutathera and Lu-NeoB. As shown in FIG. 26, the four HetSiFA compounds have HSA% ranging from about 84% to about 98%. Test conditions for the HSA binding assay included: Column: Chiralpak HSA (100 × 2.1 mm, 5 μm, Cat. No. HSA5LM-C0004), Flow rate: 0.3 mL / min, Mobile phase: A - NH 4 OAc buffer (50 mM, pH = 7), prepared fresh daily; B - isopropanol (HPLC grade); 0-3 min: isocratic 100% A, 0% B; 3-40 min: gradient to 80% A, 20% B; 40-60 min: isocratic 80% A, 20% B. Samples: 9 reference compounds, concentrations i-PrOH / NH 4 0.5 mg / mL (50 mM) in OAc pH=7, 50:50. All retention time measurements are performed in triplicate for each sample. Exemplary embodiments

[0151] The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the present invention, and are not intended to limit the scope of what the inventors regard as their invention, nor are they intended to represent that the following experiments are all or the only experiments performed. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperatures, etc.), but some experimental error and deviation should be accounted for. EXAMPLES

[0152] Example 1 HetSiFA compounds In certain embodiments, the HetSiFA compound can include a pyridine ring with various side chains, linkers and / or chelators. An example of a HetSiFA compound is di(tert-butyl)(fluoro)(2-pyridyl)silane, which has the following structure: [ka] Di(tert-butyl)(fluoro)(2-methoxy-3-pyridyl)silane, having the following structure: [ka] Di(tert-butyl)(fluoro)(4-pyridyl)silane having the following structure: [ka] Di(tert-butyl)(fluoro)(2-methoxy-4-pyridyl)silane, having the following structure: [ka] Di(tert-butyl)(fluoro)(6-methoxy-3-pyridyl)silane, having the following structure: [ka] Di(tert-butyl)(fluoro)(3-methoxy-4-pyridyl)silane, having the following structure: [ka] Di(tert-butyl)(fluoro)(3-methoxy-2-pyridyl)silane, having the following structure: [ka] Di(tert-butyl)(fluoro)(4-methoxy-3-pyridyl)silane, having the following structure: [ka] Di(tert-butyl)(fluoro)(3-pyridyl)silane having the following structure: [ka] [2-({N-5-[di(tert-butyl)(fluoro)silyl]-4-methoxy-2-pyridylcarbamoyl}methoxy)ethoxy]acetic acid, having the following structure: [ka] tert-Butyl {[(3-{5-[di(tert-butyl)(fluoro)silyl]-4-methoxy-2-pyridyl}ureido)methyl]carbonylamino}acetate, having the following structure: [ka] N-methyl{5-[di(tert-butyl)(fluoro)silyl]-4-methoxy-2-pyridyl}amine, having the following structure: [ka] 5-[di(tert-butyl)(fluoro)silyl]-2-pyridylamine, having the following structure: [ka] 5-[di(tert-butyl)(fluoro)silyl]-2-{[(2-carboxymethoxyethoxy)methyl]carbonylamino}-4-methoxy-1-pyridinium-1-olate, having the following structure: [ka] 5-[di(tert-butyl)(fluoro)silyl]-2-({[2-(tert-butoxycarbonylmethoxy)ethoxy]methyl}carbonylamino)-4-methoxy-1-pyridinium-1-olate, having the following structure: [ka] Di(tert-butyl)(fluoro)(4-methoxy-6-methyl-3-pyridyl)silane, having the following structure: [ka] Di(tert-butyl)[6-(dimethoxymethyl)-3-pyridyl](fluoro)silane, having the following structure: [ka] 5-[di(tert-butyl)(fluoro)silyl]-2-pyridinol, having the following structure: [ka] tert-Butyl [2-({N-5-[di(tert-butyl)(fluoro)silyl]-2-pyridylcarbamoyl}methoxy)ethoxy]acetate, having the following structure: [ka] 3-[di(tert-butyl)(fluoro)silyl]-1-methyl-1-pyridinium, having the following structure: [ka] 4-[di(tert-butyl)(fluoro)silyl]-1-methyl-1-pyridinium, having the following structure: [ka] 5-[di(tert-butyl)(fluoro)silyl]-4-methoxy-2-pyridylamine, having the following structure: [ka] 5-[di(tert-butyl)(fluoro)silyl]-2-({[2-(tert-butoxycarbonylmethoxy)ethoxy]methyl}carbonylamino)-1-pyridinium-1-olate, having the following structure: [ka] [2-({N-5-[di(tert-butyl)(fluoro)silyl]-2-pyridylcarbamoyl}methoxy)ethoxy]acetic acid, having the following structure: [ka] {5-[di(tert-butyl)(fluoro)silyl]-4-methoxy-2-pyridyl}-N-methylamino-tert-butylformate having the following structure: [ka] N-{5-[di(tert-butyl)(fluoro)silyl]-4-methoxy-2-pyridyl}acetamide, having the following structure: [ka] (3-{5-[di(tert-butyl)(fluoro)silyl]-4-methoxy-2-pyridyl}thioureido)acetic acid, having the following structure: [ka] [4-({5-[di(tert-butyl)(fluoro)silyl]-4-methoxy-2-pyridylamino}methyl)-1H-1,2,3-triazol-1-yl]acetic acid, having the following structure: [ka] ((5-(di-tert-butylfluorosilyl)-4-methoxypyridin-2-yl)carbamoyl)glycine, having the following structure: [ka] tert-Butyl 4-[N-(S)-1,2-bis{N-2-[2-({N-5-[di(tert-butyl)(fluoro)silyl]-4-methoxy-2-pyridylcarbamoyl}methoxy)ethoxy]ethylcarbamoyl}ethylcarbamoyl]-2-[4,7,10-tris(tert-butoxycarbonylmethyl)-1,4,7,10-tetraaza-1-cyclododecyl]butyrate, having the following structure: [ka] (S)-3-{N-2-[2-({N-5-[di(tert-butyl)(fluoro)silyl]-4-methoxy-2-pyridylcarbamoyl}methoxy)ethoxy]ethylcarbamoyl}-3-{4-tert-butoxycarbonyl-4-[4,7,10-tris(tert-butoxycarbonylmethyl)-1,4,7,10-tetraaza-1-cyclododecyl]butyrylamino}propionic acid, having the following structure: [ka] (4-{[N-(S)-1,2-bis{N-2-[2-({N-5-[di(tert-butyl)(fluoro)silyl]-4-methoxy-2-pyridylcarbamoyl}methoxy)ethoxy]ethylcarbamoyl}ethylcarbamoyl]methyl}-7,10-bis(carboxymethyl)-1,4,7,10-tetraaza-1-cyclododecyl)acetic acid, having the following structure: [ka] (S)-3-[N-(S)-2-carboxy-1-{[(3-pyridyl)methyl]carbamoyl}ethylcarbamoyl]-3-[3-(3-{5-[di(tert-butyl)(fluoro)silyl]-4-methoxy-2-pyridyl}ureido)propionylamino]propionic acid, having the following structure: [ka] {5-[di(tert-butyl)(fluoro)silyl]-2-pyridyl}-N-methylamino-tert-butylformate having the following structure: [ka] N-(3-pyridyl)methyl 3-(3-{5-[di(tert-butyl)(fluoro)silyl]-4-methoxy-2-pyridyl}ureido)propionamide, having the following structure: [ka] {N-5-[di(tert-butyl)(fluoro)silyl]-4-methoxy-2-pyridylcarbamoyl}(trimethylammonio)methane iodide, having the following structure: [ka] N-{5-[di(tert-butyl)(fluoro)silyl]-4-methoxy-2-pyridyl}(dimethylamino)acetamide, having the following structure: [ka] 3-{N-2-[2-({N-5-[di(tert-butyl)(fluoro)silyl]-4-methoxy-2-pyridylcarbamoyl}methoxy)ethoxy]ethylcarbamoyl}-3-({[4,7,10-tris(tert-butoxycarbonylmethyl)-1,4,7,10-tetraaza-1-cyclododecyl]methyl}carbonylamino)propionic acid, having the following structure: [ka] Benzyl 3-{N-2-[2-({N-5-[di(tert-butyl)(fluoro)silyl]-4-methoxy-2-pyridylcarbamoyl}methoxy)ethoxy]ethylcarbamoyl}-3-({[4,7,10-tris(tert-butoxycarbonylmethyl)-1,4,7,10-tetraaza-1-cyclododecyl]methyl}carbonylamino)propionate, having the following structure: [ka] N-{5-[di(tert-butyl)(fluoro)silyl]-4-methoxy-2-pyridyl}[2-(2-azidoethoxy)ethoxy]acetamide, having the following structure: [ka] 3-(3-{5-[di(tert-butyl)(fluoro)silyl]-4-methoxy-2-pyridyl}ureido)propionic acid, having the following structure: [ka] 2-Amino-5-[di(tert-butyl)(fluoro)silyl]-4-methoxy-1-pyridinium-1-olate, having the following structure: [ka] 3-[di(tert-butyl)(fluoro)silyl]-2-methoxy-1-pyridinium-1-olate having the following structure: [ka] 5-[di(tert-butyl)(fluoro)silyl]-2-(tert-butoxycarbonylamino)-4-methoxy-1-pyridinium-1-olate having the following structure: [ka] 5-[di(tert-butyl)(fluoro)silyl]-4-methoxy-2-(2-propynylamino)-1-pyridinium-1-olate having the following structure: [ka] 2-(N-tert-butoxycarbonyl-N-2-propynylamino)-5-[di(tert-butyl)(fluoro)silyl]-4-methoxy-1-pyridinium-1-olate having the following structure: [ka] {5-[di(tert-butyl)(fluoro)silyl]-4-methoxy-2-pyridyl}-N-2-propynylamino-tert-butylformate having the following structure: [ka] 4-[di(tert-butyl)(fluoro)silyl]-3-methoxy-1-pyridinium-1-olate, having the following structure: [ka] 3-[di(tert-butyl)(fluoro)silyl]-4-methoxy-1-pyridinium-1-olate having the following structure: [ka] 5-[di(tert-butyl)(fluoro)silyl]-2-methoxy-1-pyridinium-1-olate having the following structure: [ka] 4-[di(tert-butyl)(fluoro)silyl]-1-(tert-butoxycarbonylmethyl)-3-methoxy-1-pyridinium, having the following structure: [ka] tert-Butyl {3-[di(tert-butyl)(fluoro)silyl]-4-oxo-1-pyridyl}acetate, having the following structure: [ka] 3-[di(tert-butyl)(fluoro)silyl]-1-(tert-butoxycarbonylmethyl)-4-methoxy-1-pyridinium bromide, having the following structure: [ka] N-(3-pyridyl)methyl(3-{5-[di(tert-butyl)(fluoro)silyl]-4-methoxy-2-pyridyl}ureido)acetamide, having the following structure: [ka] 5-[di(tert-butyl)(fluoro)silyl]-2-pyridylamino-tert-butyl formirate having the following structure: [ka] N-(3-pyridyl)methyl[4-({5-[di(tert-butyl)(fluoro)silyl]-4-methoxy-2-pyridylamino}methyl)-1H-1,2,3-triazol-1-yl]acetamide, having the following structure: [ka] N-(3-pyridyl)methyl(3-{5-[di(tert-butyl)(fluoro)silyl]-4-methoxy-2-pyridyl}thioureido)acetamide, having the following structure: [ka] tert-Butyl 3-(3-{5-[di(tert-butyl)(fluoro)silyl]-4-methoxy-2-pyridyl}ureido)propionate, having the following structure: [ka] tert-Butyl (3-{5-[di(tert-butyl)(fluoro)silyl]-4-methoxy-2-pyridyl}thioureido)acetate, having the following structure: [ka] N-(3-pyridyl)methyl{5-[di(tert-butyl)(fluoro)silyl]-4-methoxy-2-pyridylamino}acetamide, having the following structure: [ka] {5-[di(tert-butyl)(fluoro)silyl]-4-methoxy-2-pyridylamino}acetic acid, having the following structure: [ka] tert-Butyl-5-[fluorobis(isopropyl)silyl]-4-methoxy-2-pyridylaminoformate having the following structure: [ka] N-2-propynyl{5-[di(tert-butyl)(fluoro)silyl]-4-methoxy-2-pyridyl}amine, having the following structure: [ka] tert-Butyl (3-{5-[di(tert-butyl)(fluoro)silyl]-4-methoxy-2-pyridyl}ureido)acetate, having the following structure: [ka] N-benzyl{5-[di(tert-butyl)(fluoro)silyl]-4-methoxy-2-pyridylamino}acetamide, having the following structure: [ka] N-{5-[di(tert-butyl)(fluoro)silyl]-4-methoxy-2-pyridyl}-N-butylsuccinamide, having the following structure: [ka] N-benzyl-N-{5-[di(tert-butyl)(fluoro)silyl]-4-methoxy-2-pyridyl}succinamide, having the following structure: [ka] tert-Butyl 3-{N-5-[di(tert-butyl)(fluoro)silyl]-4-methoxy-2-pyridylcarbamoyl}propionate, having the following structure: [ka] 5-[di(tert-butyl)(fluoro)silyl]-4-methoxy-2-pyridylamino-tert-butylformate having the following structure: [ka] may include.

[0153] In certain embodiments, the HetSiFA compound can include a pyrazole ring with various side chains, linkers and / or chelators. An example of a HetSiFA compound is di(tert-butyl)(fluoro)(1-methyl-5-pyrazolyl)silane, which has the following structure: [ka] Di(tert-butyl)(fluoro)(5-pyrazolyl)silane having the following structure: [ka] Di(tert-butyl)(fluoro){1-[(2-methoxyethoxy)methyl]-5-pyrazolyl}silane, having the following structure: [ka] Di(tert-butyl)(fluoro){1-[(2-methoxyethoxy)methyl]-4-methyl-5-pyrazolyl}silane, having the following structure: [ka] {5-[di(tert-butyl)(fluoro)silyl]-1-methyl-3-pyrazolylamino}acetic acid, having the following structure: [ka] N-(3-pyridyl)methyl{5-[di(tert-butyl)(fluoro)silyl]-1-methyl-3-pyrazolylamino}acetamide, having the following structure: [ka] {5-[di(tert-butyl)(fluoro)silyl]-1-{2-[2-(tert-butoxycarbonylamino)ethoxy]ethyl}-3-pyrazolylamino}acetic acid, having the following structure: [ka] 3-[di(tert-butyl)(fluoro)silyl]-5-(carboxymethyl)-2,5-dimethyl-4,5,6,7-tetrahydro-2H-1,2,5-triazainden-5-ium formate salt having the following structure: [ka] N-(3-pyridyl)methyl{3-[di(tert-butyl)(fluoro)silyl]-2-methyl-4,5,6,7-tetrahydro-2H-1,2,5-triazainden-5-yl}acetamide, having the following structure: [ka] {3-[di(tert-butyl)(fluoro)silyl]-2-methyl-4,5,6,7-tetrahydro-2H-1,2,5-triazainden-5-yl}acetic acid, having the following structure: [ka] [({5-[di(tert-butyl)(fluoro)silyl]-1-methyl-3-pyrazolylamino}methyl)carbonylamino]acetic acid, having the following structure: [ka] tert-Butyl 3-[di(tert-butyl)(fluoro)silyl]-2-methyl-4,5,6,7-tetrahydro-2H-1,2,5-triazaindene-5-carboxylate, having the following structure: [ka] tert-Butyl 3-[fluorobis(isopropyl)silyl]-2-methyl-4,5,6,7-tetrahydro-2H-1,2,4-triazaindene-4-carboxylate, having the following structure: [ka] 5-[di(tert-butyl)(fluoro)silyl]-3-(tert-butoxycarbonylamino)-1-methylpyrazole, having the following structure: [ka] ({5-[di(tert-butyl)(fluoro)silyl]-1-(2-{2-[(9H-fluoren-9-yl)methoxycarbonylamino]ethoxy}ethyl)-3-pyrazolyl}[(9H-fluoren-9-yl)methoxycarbonyl]amino)acetic acid, having the following structure: [ka] N-[2-(2-{5-[di(tert-butyl)(fluoro)silyl]-3-[({[(3-pyridyl)methyl]carbamoyl}methyl)amino]-1-pyrazolyl}ethoxy)ethyl](3,16,19-trioxo-2,17,18-trioxa-5,8,11,14-tetraaza-1-tetratetracyclo[9.6.3.2]) having the structure 5 , 14 ]docosa-8-yl)acetamide: [ka] 4-[N-2-(2-{5-[di(tert-butyl)(fluoro)silyl]-3-[({[(3-pyridyl)methyl]carbamoyl}methyl)amino]-1-pyrazolyl}ethoxy)ethylcarbamoyl]-2-[4,7,10-tris(carboxymethyl)-1,4,7,10-tetraaza-1-cyclododecyl]butyric acid, having the following structure: [ka] 4-[N-2-(2-{5-[di(tert-butyl)(fluoro)silyl]-3-[({[(3-pyridyl)methyl]carbamoyl}methyl)amino]-1-pyrazolyl}ethoxy)ethylcarbamoyl]-2-(3,16,19-trioxo-2,17,18-trioxa-5,8,11,14-tetraaza-1-galatricyclo[9.6.3.2]) having the structure 5 , 14 ]Docos-8-yl)butyric acid: [ka] N-(3-pyridyl)methyl[({5-[di(tert-butyl)(fluoro)silyl]-1-methyl-3-pyrazolylamino}methyl)carbonylamino]acetamide, having the following structure: [ka] Methyl [({5-[di(tert-butyl)(fluoro)silyl]-1-{2-[2-({(3,16,19-trioxo-2,17,18-trioxa-5,8,11,14-tetraaza-1-galatricyclo[9.6.3.2 5 , 14 ]docosa-8-yl)methyl}carbonylamino)ethoxy]ethyl}-3-pyrazolylamino}methyl)carbonylamino]acetate: [ka] Methyl({[({5-[di(tert-butyl)(fluoro)silyl]-1-methyl-3-pyrazolylamino}methyl)carbonylamino]methyl}carbonylamino)acetate, having the following structure: [ka] 1-{5-[di(tert-butyl)(fluoro)silyl]-1-methyl-3-pyrazolyl}-2,5-piperazinedione having the following structure: [ka] (4-{[N-2-(2-{5-[di(tert-butyl)(fluoro)silyl]-3-({[(methoxycarbonylmethyl)carbamoyl]methyl}amino)-1-pyrazolyl}ethoxy)ethylcarbamoyl]methyl}-7,10-bis(carboxymethyl)-1,4,7,10-tetraaza-1-cyclododecyl)acetic acid, having the following structure: [ka] Methyl [({5-[di(tert-butyl)(fluoro)silyl]-1-{2-[2-({[4,7,10-tris(tert-butoxycarbonylmethyl)-1,4,7,10-tetraaza-1-cyclododecyl]methyl}carbonylamino)ethoxy]ethyl}-3-pyrazolylamino}methyl)carbonylamino]acetate, having the following structure: [ka] N-[2-(2-{5-[di(tert-butyl)(fluoro)silyl]-3-[({[(3-pyridyl)methyl]carbamoyl}methyl)amino]-1-pyrazolyl}ethoxy)ethyl](3,16,19-trioxo-2,17,18-trioxa-5,8,11,14-tetraaza-1-galatricyclo[9.6.3.2]) having the structure 5 , 14 ]docosa-8-yl)acetamide: [ka] (4-{[N-2-(2-{5-[di(tert-butyl)(fluoro)silyl]-3-[({[(3-pyridyl)methyl]carbamoyl}methyl)amino]-1-pyrazolyl}ethoxy)ethylcarbamoyl]methyl}-7,10-bis(carboxymethyl)-1,4,7,10-tetraaza-1-cyclododecyl)acetic acid, having the following structure: [ka] 13-[di(tert-butyl)(fluoro)silyl]-4-oxa-1,7,10,14-tetraazabicyclo[9.2.1]tetradec-11(14),12-dien-8-one having the following structure: [ka] tert-Butyl (4-{[N-2-(2-{5-[di(tert-butyl)(fluoro)silyl]-3-[({[(3-pyridyl)methyl]carbamoyl}methyl)amino]-1-pyrazolyl}ethoxy)ethylcarbamoyl]methyl}-7,10-bis(tert-butoxycarbonylmethyl)-1,4,7,10-tetraaza-1-cyclododecyl)acetate, having the following structure: [ka] {5-[di(tert-butyl)(fluoro)silyl]-1-{2-[2-({[4,7,10-tris(tert-butoxycarbonylmethyl)-1,4,7,10-tetraaza-1-cyclododecyl]methyl}carbonylamino)ethoxy]ethyl}-3-pyrazolylamino}acetic acid, having the following structure: [ka] may include.

[0154] In certain embodiments, the HetSiFA compound can include an azaindole ring with various side chains, linkers and / or chelators. An example of a HetSiFA compound is {2-[di(tert-butyl)(fluoro)silyl]-1-methyl-1H-1,7-diazainden-5-yloxy}acetic acid having the following structure: [ka] {{2-[di(tert-butyl)(fluoro)silyl]-1-methyl-1H-1,7-diazainden-6-ylamino}acetic acid, having the following structure: [ka] Di(tert-butyl)(fluoro)(1-{1-[(p-methoxyphenyl)methyl]-3-azetidinyl}-1H-1,7-diazainden-2-yl)silane, having the following structure: [ka] 2-[di(tert-butyl)(fluoro)silyl]-1-methyl-1H-1,7-diazainden-7-ium-7-olate having the following structure: [ka] 2-[di(tert-butyl)(fluoro)silyl]-1-methyl-1H-1,4-diazainden-4-ium-4-olate having the following structure: [ka] N-(3-pyridyl)methyl{2-[di(tert-butyl)(fluoro)silyl]-1-methyl-1H-1,7-diazainden-5-yloxy}acetamide, having the following structure: [ka] 2-[di(tert-butyl)(fluoro)silyl]-1,4-dimethyl-1H-1,4-diazainden-4-ium, having the following structure: [ka] Di(tert-butyl)(fluoro)(6-methoxy-1-methyl-1H-1,7-diazainden-2-yl)silane, having the following structure: [ka] tert-Butyl {2-[di(tert-butyl)(fluoro)silyl]-1-methyl-1H-1,7-diazainden-5-yloxy}acetate, having the following structure: [ka] 2-[di(tert-butyl)(fluoro)silyl]-1-methyl-1H-1,7-diazainden-5-ol, having the following structure: [ka] tert-Butyl 3-{2-[di(tert-butyl)(fluoro)silyl]-1H-1,7-diazainden-1-yl}-1-azetidinecarboxylate, having the following structure: [ka] N-methyl{2-[di(tert-butyl)(fluoro)silyl]-1-methyl-1H-1,4-diazainden-5-yl}amine, having the following structure: [ka] {2-[di(tert-butyl)(fluoro)silyl]-1-methyl-1H-1,4-diazainden-6-yl}-N-methylamino-tert-butylformate having the following structure: [ka] {2-[di(tert-butyl)(fluoro)silyl]-1-methyl-1H-1,4-diazainden-5-yl}-N-methylamino-tert-butyl formirate having the following structure: [ka] N-methyl{2-[di(tert-butyl)(fluoro)silyl]-1-methyl-1H-1,4-diazainden-6-yl}amine, having the following structure: [ka] Di(tert-butyl)(fluoro)[1-(2-methoxyethyl)-1H-1,4-diazainden-2-yl]silane, having the following structure: [ka] Di(tert-butyl)(fluoro)(5-methoxy-1-methyl-1H-1,7-diazainden-2-yl)silane, having the following structure: [ka] may include.

[0155] Example 2 Theranostic HetSiFA Compounds 27A-27N illustrate HetSiFA theranostic pairs, according to embodiments of the present invention. FIG. 27A shows the structures of GRPR-targeting HetSiFA theranostics FTX-216 and FTX-219. FIG. 27B shows the structure of the pyridine-HetSiFA-DOTA-TATE theranostic pair. FIG. 27C shows the structure of the pyrazole-HetSiFA-DOTAGA-TATE theranostic pair. FIG. 27D shows the structure of the pyridine-HetSiFA-DOTAGA-TATE theranostic pair. FIG. 27E shows the structure of the pyrazole-HetSiFA-DOTAGA-(HE) i FIG. 27F shows the structure of the pyridine-HetSiFA-DOTAGA-(HE) theranostic couple. i Figure 27G shows the structure of the pyrazole-HetSiFA-DOTAGA-(HE) theranostic couple. iFIG. 27H shows the structure of the pyridine-HetSiFA-DOTAGA-(HE) theranostic couple. i FIG. 27I shows the structure of the pyrazole-HetSiFA-DOTAGA-(HE) theranostic couple. i FIG. 27J shows the structure of the pyridine-HetSiFA-DOTAGA-(HE) theranostic couple. i FIG. 27K shows the structure of the pyrazole-HetSiFA-DOTAGA-(HE) theranostic couple. i Figure 27L shows the structure of the pyridine-HetSiFA-DOTAGA-(HE) theranostic couple. i Figure 27M shows the structure of the pyrazole-HetSiFA-DOTAGA-(HE) theranostic couple. i Figure 27N shows the structure of the pyridine-HetSiFA-DOTAGA-(HE) theranostic couple. i The structures of the -FAP (i = 0 to 3) theranostic couples are shown.

[0156] FIG. 28 illustrates a dual targeting HetSiFA theranostic pair, according to an embodiment of the present invention.

[0157] Example 3 Regarding HetSiFA compounds 18 F-Radiolabeling Procedure Below are some general information about HetSiFA compounds: 18 A F-radiolabelling procedure is described, but as can be easily understood, in order to radiofluorinate the HetSiFA precursor molecule, [ 18Any radiolabeling procedure can be used, such as a method that relies on azeotropic drying of [F]fluoride. Prior to the start of the synthesis, the reaction vessel is charged with a solution of the HetSiFA precursor (150 nmol) in anhydrous dimethylsulfoxide (150 μL) and a 1 M solution of oxalic acid in anhydrous acetonitrile (MeCN) (30 μL). This solution must be freshly prepared by dissolving oxalic acid (9 mg) in anhydrous MeCN (0.1 mL). 18 [F]fluoride is captured on a QMA cartridge (Sep-Pak Accell Plus QMA Carbonate Plus Light cartridge, 46 mg, 40 μm, Waters) preconditioned with 10 mL of ultrapure water. The cartridge is dried with a nitrogen stream, rinsed with MeCN (10 mL) and dried again with a nitrogen stream. Activity is assayed from the QMA cartridge by elution of [K + ⊂ 2.2.2] OH - The solution of [K]-cryptate is eluted into the precharged reactor. + ⊂ 2.2.2] OH - -For the preparation of cryptates, Kryptofix® 222 (343 mg, 910 μmol, 1.1 equiv., Sigma-Aldrich) and 1 M KOH (830 μL, 830 μmol, 1.0 equiv., 99.99% semiconductor grade, Sigma Aldrich) are dissolved in water (10 mL) and aliquots are taken into Eppendorf vials (1 mL or 1.5 mL, respectively). The contents of each vial are lyophilized and the individual doses of [K + ⊂ 2.2.2] OH - The complex is obtained as an off-white solid. The smaller volume vial contains 91 μmol K222 and 83 μmol KOH and is typically used for manual radiolabeling experiments where liquid loss is minimal. The larger volume vial contains 137 μmol K222 and 125 μmol KOH and is typically used for automated radiolabeling experiments where liquid loss in the delivery lines is expected. Lyophilized [K + ⊂ 2.2.2] OH- -Cryptates must be dissolved in anhydrous MeCN. The reaction is maintained at room temperature for 10 min. Formulation buffer (10 mL of phosphate buffered saline (PBS), pH 7.4, containing 0.5% (w / v) Na ascorbate) is added to the reactor and the resulting mixture is passed through an HLB cartridge (Oasis HLB cartridge Plus Short, 225 mg sorbent, 60 μm particle size, Waters) preconditioned with 10 mL of water and transferred to waste. The reactor is rinsed with additional formulation buffer (10 mL) and all of the contents are passed through the HLB cartridge and transferred to waste. The HLB cartridge is washed with formulation buffer (10 mL) and placed in waste. The product is eluted from the cartridge through a 0.22 μm sterile filter into a sterile vial containing ethanol (2 mL). Alternatively, aqueous ethanol (50% v / v, 4 mL) can be used. The product mixture is diluted with formulation buffer (20 mL). (See, e.g., Wurzer et al. EJNMMI radiopharm. chem. 6, 4 2021, the disclosure of which is incorporated herein by reference).

[0158] Example 4 Synthesis of HetSiFA compounds The synthesis process for the pyrazole-HetSiFA compound is detailed below. As can be easily understood, various HetSiFA compounds can be synthesized by similar processes.

[0159] Commercially available reactants / reagents purchased from suppliers such as Sigma-Aldrich, TCI, Combi-Blocks, AK Scientific, Gelest, Ambeed, Macrocyclics, Chempep or AAPPTec were used without further purification unless otherwise stated. All reactions were carried out in air-dried (unless flame-dried specified) reaction tubes / flasks at room temperature and under positive nitrogen / argon pressure unless otherwise stated. Reactions were monitored by using a waters HPLC system equipped with a diode array detector and an ESI-MS detector. Reactions were carried out in commercially available reagent grade solvents without further purification or drying of the solvents unless otherwise stated in the procedure. Crude products were worked up before purification, if performed.

[0160] Purification by reversed-phase HPLC is performed under standard conditions using a Biotage® Isolera one high-performance flash purification system. Elution is performed using a linear gradient of acetonitrile in water (10 mM AmF or AmBic in deionized water). The solvent system is adjusted according to the polarity and stability of the compound, and the flow rates used for purification are less than or equal to those suggested by the manufacturer and vary depending on the size of the C18 column used. Compounds are collected by either UV or waters mass detection (ESI positive mode). Fractions containing the desired compound are combined and concentrated (rotary evaporator) and the excess CH 3 The CN was removed and the resulting aqueous solution was lyophilized to give the desired material.

[0161] Nuclear magnetic resonance (NMR) spectra are recorded on a JEOL 400 MHz spectrometer instrument. 1 H) was used as the reference standard for chemical shifts. The following solvents were used: CDCl 3 , methanol-d 4 , DMSO-d 6 , acetone-d 6 and CDs 3 C.N. 1H-NMR data are presented as follows: chemical shifts (in ppm) downfield from tetramethylsilane (multiplicity, coupling constants, integrals). The following abbreviations are used in reporting NMR data: s, singlet; d, doublet; t, triplet; q, quartet; p, pentuplet; h, hextuplet; dd, doublet of doublet; ddd, doublet of doublet of doublet; dddd, doublet of doublet of doublet of doublet; dt, doublet of triplet; dtd, doublet of triplet of doublet; ddt, doublet of triplet of triplet; dq, doublet of quartet; dp, doublet of pentaplet; td, triplet of doublet; qd, quintet of doublet; m, multiplet. Where appropriate, the following abbreviations are used in reporting NMR data to account for any singlets or any multiplicities: br, broad; app, apparent. First-order coupling constants are reported using Hz as the unit of frequency and were measured using the distance between the center of one peak and the center of the other peak.

[0162] Unless otherwise stated, purification is performed by normal phase flash column chromatography on silica gel under standard conditions using, but not limited to, the following equipment and supplies: Biotage® SP1 or SP2 purification system with Biotage® SNAP cartridge KP-Sil column 10 g, 25 g, 50 g, 100 g or 340 g, and CombiFlash® Rf Teledyne Isco purification system with SilicaRediSep® Rf normal phase column 12 g, 24 g, 40 g, 80 g, 120 g, 220 g or 330 g. When the crude material was purified by vacuum-liquid chromatography (scale-up procedure), technical grade Supelco (Sigma Aldrich) silica was used as the stationary phase and conditioned with copious amounts of hexane before use. The solvent system is adjusted according to the polarity and stability (reverse phase) of the compound. The fractions containing the desired compound are combined and concentrated (rotary evaporator) to remove the solvent and obtain the desired material (usually in the case of normal phase purification) or the fractions are concentrated under reduced pressure and then lyophilized (usually in the case of reversed phase purification) to obtain the desired material. 3 CN) or the residue from the normal phase separation (after evaporation of the solvent at reduced pressure) was 3 It was suspended in a mixture of CN (a few drops) / water and then lyophilized (whichever was deemed more appropriate to obtain good physical properties of the desired compound). The LCMS method is as follows:

[0163] LCMS (Method 8B): Column: Waters Acquity UPLC CSH C18, 1.8 μm, 2.1 × 30 mm, 40 °C; Gradient: 5% to 100% B in 5.2 min; hold 100% B for 1.8 min; Run time = 7.0 min; Flow rate = 0.9 mL / min; Eluent: A = Milli-Q HO + 10 mM ammonium formate pH = 3.8 (Am.F); Eluent B: acetonitrile (no additives).

[0164] LCMS (Method 10A): Column: Waters Acquity UPLC CSH C18, 1.8 μm, 2.1 × 30 mm, 40 °C; Gradient: 5% to 100% B in 2.0 min; hold 100% B for 0.7 min; Run time = 2.7 min; Flow rate = 0.9 mL / min; Eluent: A = Milli-Q HO + 10 mM ammonium formate pH = 3.8 (Am.F); Eluent B: acetonitrile (no additives).

[0165] Synthesis of 1-(2-(2-azidoethoxy)ethyl)-3-nitro-1H-pyrazole (5a) and 1-(2-(2-azidoethoxy)ethyl)-5-nitro-1H-pyrazole (5b). [ka]

[0166] A flame-dried round-bottom flask was charged with 3-nitro-1H-pyrazole (4, 2.00 g, 17.3 mmol) and DMF (40.0 mL). The solution was cooled to 0° C., and then sodium hydride 60% (797 mg, 19.9 mmol) dispersed in mineral oil was added in small portions. The mixture was stirred at 0° C. for 30 minutes, and then 2-bromoethyl ether (3.44 mL, 26.0 mmol) was added dropwise. The resulting mixture was then allowed to warm to room temperature.

[0167] After stirring at room temperature for 2 hours, the reaction was cooled to 0° C. and slowly quenched with saturated aqueous ammonium chloride, and the mixture was extracted with ethyl acetate. The aqueous phase was extracted twice more with ethyl acetate. The combined organic layers were washed with brine and diluted with Na 2 SO 4The crude alkylated product was obtained after drying at 40° C., filtration and concentration under reduced pressure. To the crude material from the first step was added DMF (20.0 mL) and sodium azide (2.38 g, 36.4 mmol). The resulting mixture was heated to 80° C. After stirring at 80° C. for 2 h, the mixture was cooled to room temperature and then poured into water and extracted with ethyl acetate. The aqueous layer was extracted three more times with ethyl acetate and the combined organic layers were washed with saturated aqueous ammonium chloride and added with Na 2 SO 4 The crude oil was diluted with 25 g of SiO 2 The product was purified by normal phase chromatography using a column eluted with a gradient of ethyl acetate / hexanes. The product was eluted with 35% ethyl acetate and concentrated to give 1-(2-(2-azidoethoxy)ethyl)-3-nitro-1H-pyrazole (5a, 2.11 g, 54%) as a clear liquid. 1 H-NMR (400 MHz, CDCl 3 ) δ 7.56 (d, J = 2.5 Hz, 1H), 6.88 (d, J = 2.5 Hz, 1H), 4.38 (t, J = 4.8 Hz, 2H), 3.87 (t, 4.8 Hz), 3.60 (t, J = 4.7 Hz, 2H), 3.32 (t, J = 4.7 Hz, 2H).LCMS (Method 10A):C 7 H 10 N 6 O 3 Na + Calculated value of [M+H] + : 249.1, measured value: 249.2. Rt = 0.80 min.

[0168] Scale-up: A flame-dried, three-necked round-bottom flask equipped with a mechanical stirrer, condenser, and temperature probe was charged with 2-(2-azidoethoxy)ethyl 4-methylbenzenesulfonate (3, 63.9 g, 224 mmol) (Delmas, AF et. al., Angew. Chem. Int. Ed., 2012, 51, 11320-11324) in DMF (290 mL), followed by 3-nitro-1H-pyrazole (4, 26.6 g, 231 mmol) and potassium carbonate (63.2 g, 448 mmol) at room temperature. The resulting suspension was stirred and heated at 60° C. (external temperature) and maintained at internal temperature (approximately 55° C.) for 90 minutes.

[0169] The reaction mixture was cooled to room temperature and the mixture was diluted with ethyl acetate (400 mL). The diluted solution was washed three times with water (150 mL×3) and partitioned. The combined aqueous layer was extracted with ethyl acetate (400 mL×3), and then the combined organic layer was pre-dried with brine and added Na 2 SO 4 After drying at 40° C., filtration and concentration under reduced pressure, 60.4 g of a crude light yellow liquid (rr ca. 8:1, favoring the desired N-alkylated regioisomer) was obtained. 2The crude liquid was purified by normal phase chromatography using a column (using a vacuum-liquid chromatography apparatus) and the desired regioisomer, 1-(2-(2-azidoethoxy)ethyl)-3-nitro-1H-pyrazole (5a), was eluted with a gradient of ethyl acetate / hexanes. The desired regioisomer was eluted with approximately 50% ethyl acetate in hexanes to give the desired pure regioisomer (11.5 g, 23%) as a clear, colorless liquid, and another fraction contained both regioisomers in a ratio of approximately 85:15 major:minor regioisomer (36.6 g, 72% combined). NOTE: We found in separate parallel reactions that the undesired regioisomer does not react in the subsequent reaction step (silylation) and that good separation can be achieved in the silylation step, but if desired, impure fractions can be purified again using the same gradient to give the additional desired regioisomer 1-(2-(2-azidoethoxy)ethyl)-3-nitro-1H-pyrazole (5a). Characterization of the pure 1-(2-(2-azidoethoxy)ethyl)-3-nitro-1H-pyrazole (5a) obtained here is consistent with that previously (small scale, see above).

[0170] Synthesis of 1-(2-(2-azidoethoxy)ethyl)-5-(di-tert-butylsilyl)-3-nitro-1H-pyrazole (6). [ka]

[0171] A flame-dried round-bottom flask was charged with diisopropylamine (1.37 mL, 9.75 mmol) and THF (15.0 mL). The solution was cooled to 0° C. and n-butyllithium (2.5 M in hexanes, 3.57 mL, 8.93 mmol) was added slowly. After stirring the solution at 0° C. for 30 min, it was added dropwise to a solution of 1-(2-(2-azidoethoxy)ethyl)-3-nitro-1H-pyrazole (5a, 1.68 g, 7.44 mmol) in THF (30.0 mL) at −78° C. The resulting mixture was stirred at −78° C. for 1 h, followed by the addition of di-tert-butylchlorosilane (1.67 mL, 8.18 mmol) at the same temperature. The cold bath was removed and the mixture was allowed to warm gradually to room temperature. After stirring for 21 h, the mixture was cooled to 0° C. and quenched with saturated ammonium chloride. Extract with ethyl acetate and wash with brine to remove Na 2 SO 4 The crude oil was diluted with 25 g of SiO 2 The product was purified by normal phase chromatography using a column eluted with a gradient of ethyl acetate / hexanes. The product was eluted with 15% ethyl acetate, which was then concentrated to give 1-(2-(2-azidoethoxy)ethyl)-5-(di-tert-butylsilyl)-3-nitro-1H-pyrazole (6, 1.97 g, 72%) as a light yellow solid. 1 H-NMR (400 MHz, CDCl 3 ) δ 7.03 (s, 1H), 4.52 (t, J = 5.8 Hz. 2H), 4.14 (s, 1H), 3.98 (t, J = 5.8 Hz, 2H), 3.62 - 3.57 (m, 2H), 3.33 - 3.26 (m, 2H), 1.06 (s, 18H).LCMS (Method 10A):C 15 H 29 N 6 O 3 S + Calculated value of [M+H] + : 369.2, measured value: 369.3. Rt = 1.73 min.

[0172] Scale-up. A flame-dried round-bottom flask equipped with a stir bar was charged with 1-(2-(2-azidoethoxy)ethyl)-3-nitro-1H-pyrazole (5a, 14.3 g, 56.9 mmol) in THF (330 mL). The solution was cooled to -78°C and lithium diisopropylamide (57.5 mL, 57.5 mmol) was added slowly over 40 min. The resulting mixture was stirred at -78°C for 1 h, followed by the dropwise addition of di-tert-butylchlorosilane (14.2 mL, 68.3 mmol) over 30 min at the same temperature. The reaction mixture was allowed to reach room temperature overnight (16 h) over the course of the reaction by removing the cooling bath.

[0173] The mixture was cooled to 0° C. and quenched with saturated ammonium chloride. It was extracted with ethyl acetate, predried with brine, and washed with Na 2 SO 4 The mixture was dried over SiO, filtered and concentrated under reduced pressure. 2 The crude oil was purified by normal phase chromatography using a column (vacuum-liquid chromatography apparatus) eluting with a gradient of ethyl acetate / hexane (10-55%). The desired product was eluted with about 45% ethyl acetate, whereupon the fractions containing the desired compound were concentrated under reduced pressure (the solution was placed in a water bath at about 75°C) until the weight of the oil was observed to be constant, and the desired compound was finally solidified upon standing at room temperature. The desired compound was then finally resuspended in an ACN / water mixture and lyophilized to give 1-(2-(2-azidoethoxy)ethyl)-5-(di-tert-butylsilyl)-3-nitro-1H-pyrazole (6, 7.60 g, 34%) as a yellow powder. The characterization of the desired compound obtained here is consistent with that previously (small scale, see above).

[0174] Synthesis of tert-butyl (2-(2-(5-(di-tert-butylsilyl)-3-nitro-1H-pyrazol-1-yl)ethoxy)ethyl)carbamate (7). [ka]

[0175] To a stirred solution of 1-(2-(2-azidoethoxy)ethyl)-5-(di-tert-butylsilyl)-3-nitro-1H-pyrazole (6, 1.97 g, 5.35 mmol) in THF (20.0 mL) was added trimethylphosphine (1 M in THF, 8.02 mL, 8.02 mmol) dropwise. The mixture was stirred at room temperature for 45 minutes, then water (5.00 mL) was added slowly. The reaction was stirred for an additional 30 minutes at room temperature, then sodium carbonate (1.14 g, 10.7 mmol) and di-tert-butyl dicarbonate (1.84 mL, 8.02 mmol) were added to the mixture at room temperature (Caution: Vigorous bubbling is observed upon addition of trimethylphosphine. The reaction is exothermic upon addition of water). After stirring the resulting mixture at room temperature for 30 minutes, the mixture was extracted with ethyl acetate, washed with brine, and diluted with Na 2 SO 4 The crude oil was diluted with 25 g of SiO 2 The product was purified by normal phase chromatography using a column eluted with a gradient of ethyl acetate / hexanes. The product was eluted with 15% ethyl acetate, which was then concentrated to give tert-butyl (2-(2-(5-(di-tert-butylsilyl)-3-nitro-1H-pyrazol-1-yl)ethoxy)ethyl)carbamate (7, 2.01 g, 85%) as a yellow oil. 1 H-NMR (400 MHz, CDCl 3 ) δ 7.03 (s, 1H), 4.69 (br s, 1H), 4.49 (t, J = 5.7 Hz, 2H), 4.11 (s, 1H), 3.91 (t, J = 5.7 Hz, 2H), 3.47 (t, J = 5.2 Hz, 2H), 3.22 (dd, J = 10.1, 5.0 Hz, 2H), 1.41 (s, 9H), 1.06 (s, 18H).LCMS (Method 10A):C 20 H 39 N 4 O 5 S + Calculated value of [M+H] +: 443.3, actual value: 443.4. Rt=1.75 min.

[0176] Scale-up. A round-bottom flask equipped with a stir bar was charged with a solution of 1-(2-(2-azidoethoxy)ethyl)-5-(di-tert-butylsilyl)-3-nitro-1H-pyrazole (6, 27.0 g, 73.3 mmol) in THF (200 mL) and a solution of trimethylphosphine in THF (1 M, 110 mL, 110 mmol) was added dropwise at 0° C. After the addition was complete or until bubbling ceased, the reaction mixture was stirred at 0° C. for approximately an additional 5 minutes and then at room temperature for 1 hour. The reaction mixture was cooled to 0° C. and the reaction mixture was stirred with H 2 2H2O (83.5 mL) was slowly introduced and then stirred at room temperature for another 30 min before the next step was started. Sodium carbonate (16.2 g, 152 mmol) and di-tert-butyl dicarbonate (16.8 mL, 73.3 mmol) were added to the reaction mixture at room temperature. After stirring overnight at room temperature, a large amount of ethyl acetate / water biphasic mixture was added to the reaction mixture until all the sodium carbonate was dissolved, the reaction mixture was partitioned, the organic layer was washed thoroughly with water, and then pre-dried with brine to obtain Na2O. 2 SO 4 Drying at 40° C., filtering, concentrating under reduced pressure to constant weight, then drying under high vacuum overnight afforded tert-butyl (2-(2-(5-(di-tert-butylsilyl)-3-nitro-1H-pyrazol-1-yl)ethoxy)ethyl)carbamate (7, 32.4 g, 100%, 96% purity by LCMS, Method 10A) as a light orange oil (quantitative) deemed pure enough for the next step. This oil was carried on to the next step without purification. The LCMS characterization of the desired compound obtained here is consistent with that previously obtained (small scale, see above).

[0177] Synthesis of tert-butyl (2-(2-(3-amino-5-(di-tert-butylsilyl)-1H-pyrazol-1-yl)ethoxy)ethyl)carbamate (8). [ka]

[0178] To a round-bottom flask containing tert-butyl (2-(2-(5-(di-tert-butylsilyl)-3-nitro-1H-pyrazol-1-yl)ethoxy)ethyl)carbamate (7, 2.01 g, 4.53 mmol) was added MeOH (30.0 mL) and palladium (10% on activated carbon, wet, 48.2 mg, 45.3 μmol). The mixture was flushed with nitrogen before being fitted with a hydrogen balloon. The reaction mixture was stirred at room temperature under a hydrogen atmosphere. After stirring for 19 h at room temperature, the reaction mixture was filtered through a Celite pad and the filter cake was rinsed three additional times with methanol. The filtrate was concentrated to give tert-butyl (2-(2-(3-amino-5-(di-tert-butylsilyl)-1H-pyrazol-1-yl)ethoxy)ethyl)carbamate (8, 1.87 g, 92%) as a light green oil. LCMS (Method 10A):C 20 H 41 N 4 O 3 S + Calculated value of [M+H] + : 413.4, measured value: 413.6. Rt = 1.54 min.

[0179] Scale-up. A round-bottom flask equipped with a stir bar was charged with tert-butyl (2-(2-(5-(di-tert-butylsilyl)-3-nitro-1H-pyrazol-1-yl)ethoxy)ethyl)carbamate (7, 32.4 g, 73.2 mmol) in MeOH (500 mL). Nitrogen gas was bubbled through the solution with one good balloon (1 atm) for 30 min, then palladium (10% on activated carbon, 849 mg, 798 μmol) was added to the reaction mixture in one portion. The nitrogen gas atmosphere and saturation was replaced with a hydrogen atmosphere by attaching a two-skinned hydrogen balloon (1 atm), then the reaction mixture was placed under vacuum (hydrogen balloon removed), followed by flushing with hydrogen (vacuum released), and this cycle was repeated multiple times. After about 6 hours, another hydrogen balloon was attached to the reaction mixture so that the reaction mixture was connected to two (double membrane) hydrogen balloons. The reaction mixture was stirred at room temperature under hydrogen atmosphere for 36 hours. After the reaction was complete after 36 hours, the hydrogen gas atmosphere of the reaction mixture was replaced with nitrogen gas, which was then placed under vacuum (removing nitrogen) and then flushed with nitrogen gas (released vacuum). This cycle was repeated multiple times. The reaction mixture was filtered through a Celite pad and the filter cake was rinsed three more times with copious amounts of methanol. The filtrate containing the desired product was concentrated under reduced pressure to give crude tert-butyl (2-(2-(3-amino-5-(di-tert-butylsilyl)-1H-pyrazol-1-yl)ethoxy)ethyl)carbamate (8, 30.2 g, 95%, 95% purity by LCMS, Method 10A) as a yellow oil, which was used in the next step without purification. Characterization of the desired compound obtained here by LCMS is consistent with that previously obtained (small scale, see above).

[0180] Synthesis of (1-(2-(2-((tert-butoxycarbonyl)amino)ethoxy)ethyl)-5-(di-tert-butylsilyl)-1H-pyrazol-3-yl)glycine (9). [ka]

[0181] To a solution of tert-butyl (2-(2-(3-amino-5-(di-tert-butylsilyl)-1H-pyrazol-1-yl)ethoxy)ethyl)carbamate (8, 1.87 g, 4.17 mmol) in MeOH (30.0 mL) was added acetic acid (482 μL, 8.34 mmol) and glyoxylic acid monohydrate (392 mg, 4.17 mmol) at 0° C. After stirring the mixture at 0° C. for 30 min, sodium cyanoborohydride (276 mg, 4.17 mmol) was added and the reaction mixture was then allowed to warm to room temperature. After stirring the reaction mixture at room temperature for 1 h, it was concentrated under reduced pressure and the crude residue was subjected to purification by reverse phase chromatography using a 40 g C18 column and eluting with a gradient of 10 mM ammonium formate / acetonitrile. The product was eluted with 55% ACN, which was concentrated to a suspension, diluted with water, then diluted with water and lyophilized over the weekend to give (1-(2-(2-((tert-butoxycarbonyl)amino)ethoxy)ethyl)-5-(di-tert-butylsilyl)-1H-pyrazol-3-yl)glycine (9, 1.54 g, 69%) as a white powder. 1 H-NMR (400 MHz, CD 3 CN) δ 5.76 (s, 1H), 5.37 (br s, 1H), 4.49 (t, J = 6.0 Hz, 2H), 4.17 (t, J = 5.6 Hz, 2H), 3.98 (s, 1H), 3.83 (s, 2H), 3.70 (t, J = 5.6 Hz, 2H), 3.36 (t, J = 5.5 Hz, 2H), 3.08 (q, J = 5.6 Hz, 2H), 1.37 (s, 9H), 1.01 (s, 18H), COOH and NHBoc proton signals are weak. LCMS (Method 10A): C 22 H 43 N 4 O 5 S + Calculated value of [M+H] + : 471.3, measured value: 471.4. Rt = 1.46 min.

[0182] Scale-up. To a solution of tert-butyl (2-(2-(3-amino-5-(di-tert-butylsilyl)-1H-pyrazol-1-yl)ethoxy)ethyl)carbamate (8, 30.2 g, 65.9 mmol) in MeOH (508 mL) was added acetic acid (7.54 mL, 132 mmol) and glyoxylic acid monohydrate (6.38 g, 65.9 mmol) at 0° C. After the mixture was stirred at 0° C. for 1 h, sodium cyanoborohydride (2.40 g, 36.2 mmol) was added in small portions (approximately 500 mg each) (CAUTION). Upon completion of the addition, the mixture was stirred at 0° C. for an additional 30 min. The reaction mixture was diluted with H 2 HO (150 mL) was added slowly and as much methanol as possible was removed under reduced pressure (to facilitate partitioning). The crude solution was partitioned between a large amount of ethyl acetate and water and the organic layer was pre-dried with brine. The aqueous layer was back-extracted two more times with ethyl acetate (Note: the aqueous layer obtained after extraction and the methanol-rich fraction after evaporation of the solvent in vacuo were treated with bleach before being discarded). The combined organic layers were washed with Na 2 SO 4 Drying at 40° C., filtration and concentration under reduced pressure gave (1-(2-(2-((tert-butoxycarbonyl)amino)ethoxy)ethyl)-5-(di-tert-butylsilyl)-1H-pyrazol-3-yl)glycine (9, 33.0 g, 82% purity, 3 min run on LC10) as a white foam which was carried on to the next step without purification. Characterization of the desired compound obtained here is consistent with that previously given (small scale, see above).

[0183] Synthesis of (1-(2-(2-((tert-butoxycarbonyl)amino)ethoxy)ethyl)-5-(di-tert-butylfluorosilyl)-1H-pyrazol-3-yl)glycine (PPI-24068). [ka]

[0184] To a round bottom flask containing (1-(2-(2-((tert-butoxycarbonyl)amino)ethoxy)ethyl)-5-(di-tert-butylsilyl)-1H-pyrazol-3-yl)glycine (9, 1.54 g, 2.88 mmol) was added potassium fluoride (253 mg, 4.32 mmol), 18-crown-6 (1.16 g, 4.32 mmol) and THF (30.0 mL). Acetic acid (499 μL, 8.64 mmol) was then added and the mixture was heated to 40° C. After 4 h at 40° C., the mixture was then concentrated under reduced pressure, dissolved in minimal DMF and subjected to reverse phase chromatography (25 g C18 column, eluted with 10 mM ammonium formate / acetonitrile). The product was eluted with 67% ACN, concentrated to a suspension, diluted with minimal ACN, and lyophilized overnight to give (1-(2-(2-((tert-butoxycarbonyl)amino)ethoxy)ethyl)-5-(di-tert-butylfluorosilyl)-1H-pyrazol-3-yl)glycine (PPI-24068, 1.07 g, 76%) as a white powder. 1 H-NMR (400 MHz, CD 3 CN) δ 5.77 (s, 1H), 5.39 (br s, 1H), 4.54 (br s, 1H), 4.14 (t, J = 5.5 Hz, 2H), 3.81 (s, 2H), 3.70 (t, J = 5.4 Hz, 2H), 3.36 (t, J = 5.4 Hz, 2H), 3.08 (q, J = 5.6 Hz, 2H), 1.37 (s, 9H), 1.02 (s, 18H), the COOH proton signal is weak and the NH proton at 4.54 ppm is very broad. 19 F-NMR (376 MHz, CD 3 CN) δ -181.96 (s).LCMS (Method 10A):C 22 H 42 FN 4 O 5 S + Calculated value of [M+H] + : 489.3, Actual value: 489.4. C 22 H 40 FN 4 O5 S - Calculated value [MH] - : 487.3, measured value: 487.4. Rt = 1.43 min.

[0185] Scale-up. To a round-bottom flask containing (1-(2-(2-((tert-butoxycarbonyl)amino)ethoxy)ethyl)-5-(di-tert-butylsilyl)-1H-pyrazol-3-yl)glycine (9, 33.0 g, 70.1 mmol) and THF (275 mL) was added potassium fluoride (6.17 g, 105 mmol) and 18-crown-6 (28.4 g, 105 mmol). After addition of potassium fluoride and crown ether, bubbling and an exotherm (from room temperature to approximately 5° C.) were observed.

[0186] After stirring at room temperature for 2 hours, the reaction was deemed complete. The reaction mixture was concentrated under reduced pressure and the crude residue was partitioned between a large amount of ethyl acetate and water. The aqueous layer was extracted twice more with ethyl acetate and the combined organic layers were washed with Na 2 SO 4The crude residue was purified by reverse phase chromatography using a 400 g C18 column and the desired compound was eluted with a gradient of 10 mM ammonium formate / acetonitrile (0-55%). The product eluted at approximately 45% ammonium formate. The desired fractions were pooled and concentrated to remove as much ACN / water as possible, then split according to purity (2 fractions). A small second fraction (approximately 5 g, approximately 80% pure) was repurified using the same gradient, but with a slower elution rate and using a 120 g C18 column instead of the 400 g C18 column. In total, after two purification runs, (1-(2-(2-((tert-butoxycarbonyl)amino)ethoxy)ethyl)-5-(di-tert-butylfluorosilyl)-1H-pyrazol-3-yl)glycine (PPI-24068, 21 g, approx. 30% over 4 steps, approx. 93% purity by LC10 in 3 min run) was obtained as a white powder after lyophilization. Characterization of the desired compound obtained here is consistent with previous one (small scale, see above). Note: This compound showed some instability after long storage and under basic medium, and attempts to purify the title compound using a gradient with 10 mM AmB in deionized water and ACN were unsuccessful.

[0187] Synthesis of N-(((9H-fluoren-9-yl)methoxy)carbonyl)-N-(1-(2-(2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)ethoxy)ethyl)-5-(di-tert-butylfluorosilyl)-1H-pyrazol-3-yl)glycine (PPI-24069). [ka]

[0188] In a round bottom flask equipped with a stir bar, (1-(2-(2-((tert-butoxycarbonyl)amino)ethoxy)ethyl)-5-(di-tert-butylfluorosilyl)-1H-pyrazol-3-yl)glycine (PPI-24068, 3.19 g, 5.87 mmol) was dissolved in DCM (70.0 mL), then trifluoroacetic acid (TFA) (5.72 mL, 74.0 mmol) was added dropwise at room temperature, and the reaction mixture was continuously stirred at 40° C. for 90 min. After 90 min, the reaction mixture was cooled to room temperature and then concentrated to give the Boc-deprotected intermediate (not shown). The reaction was concentrated under reduced pressure, the residue was resuspended in about 50 mL of DCM, sonicated, then concentrated under reduced pressure, and this cycle was repeated three more times to give a colorless gum, which was further dried under vacuum overnight and then used in the next step (Fmoc coupling) without purification. The gum was dissolved in DCM (70.0 mL) and Fmoc chloride (3.10 g, 11.7 mmol) was added in two equal portions (one equivalent was added before the addition of DIPEA and another equivalent was added after the addition of about 4 equivalents of DIPEA or partway through completion) and N,N-diisopropylethylamine (DIPEA) (8.00 mL, 45.5 mmol) (about 1.0 mL every 15 min up to 30 min) was added in small portions every 15 min up to 30 min at 0° C. The progress of the reaction was followed using an LC10 until the starting material was completely consumed.

[0189] After about 3 h at 0° C., the reaction mixture was diluted with a large amount of DCM and washed with saturated aqueous ammonium chloride. 2 SO 4The crude residue was purified by reverse phase chromatography (C18, 120 g) eluting with a gradient of 10 mM ammonium formate / acetonitrile (50-100%). The title compound was eluted with 90-100% ACN and fractions were then concentrated and lyophilized to give N-(((9H-fluoren-9-yl)methoxy)carbonyl)-N-(1-(2-(2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)ethoxy)ethyl)-5-(di-tert-butylfluorosilyl)-1H-pyrazol-3-yl)glycine (PPI-24069, 2.90 g, 56%, ca. 95% pure by LCMS, Method 10A) as a white powder, which was used for peptide coupling without further purification. LCMS (Method 10A): C 47 H 54 FN 4 O 7 S + Calculated value of [M+H] + : 833.4, actual value: 833.6. Rt=2.01 min. [ka]

[0190] Resin activation and first amino acid coupling. PPI-24073 was synthesized on the solid phase using an Fmoc-based approach. In a fritted glass reactor, 2-chlorotrityl chloride resin (10, 1.2 mmol / g, 100-200 mesh, 12 mmol) was activated by swelling in dichloromethane, draining, and shaking in 100 mL of dichloromethane for 10 min, then draining again. In a separate flask, Fmoc-Thr(tBu)-OH (8.60 g, 21.0 mmol) was dissolved in dichloromethane (80 mL), DIPEA (12.6 mL, 72 mmol) was added, and the solution was mixed for 5 min (sonication was used to aid dissolution). The solution was then poured into the activated 2-chlorotrityl chloride resin (10) and allowed to react by shaking for 4.5 h. Methanol (20 mL, HPLC grade) was then added and the mixture was shaken for 30 minutes (this step is done to cap any unreacted resin). The reaction vessel was drained and the resin was washed with dichloromethane (2×120 mL), DMF (2×120 mL), methanol (2×120 mL) and again with dichloromethane (2×120 mL). Resin 11 was used in the next step. [ka]

[0191] Peptide chain elongation. Resin 11 was treated twice with a mixture of piperidine and DMF (1:2 ratio) for 45 min each to deprotect the Fmoc group. Fmoc removal was confirmed by a positive Kaiser test. After the resin was successfully washed with DMF (2×120 mL), methanol (2×120 mL) and dichloromethane (2×120 mL), Fmoc-Cys(Trt)-OH (1.5 eq.) was preactivated with HATU (1.5 eq.), HOAt (1.5 eq.) and DIPEA (4 eq.) in DMF (100 mL), and then the above obtained solution was added to the reaction vessel containing the resin and shaken at room temperature for at least 4 h between two reaction cycles. Amino acid coupling was confirmed by a negative Kaiser test. Using a similar procedure, Fmoc-Thr(tBu)-OH, Fmoc-Lys(Boc)-OH, Fmoc-D-Trp(Boc)-OH, Fmoc-L-Tyr(tBu)-OH, Fmoc-Cys(Trt)-OH and Fmoc-D-Phe-OH were sequentially coupled to the peptide sequence to give 12. The resin was washed sequentially with DMF (2 x 120 mL), methanol (2 x 120 mL) and dichloromethane (2 x 120 mL). When necessary, the reaction was quenched with air after amino acid coupling and the dry resin was stored in a refrigerator. The sequence was resumed after activating the resin with DCM for 30 min.

[0192] Preparation of Kaiser test solution. [(0.5 g ninhydrin in 10 mL ethanol) + 0.4 mL 0.001 M aqueous KCN in 20 mL pyridine]. These two solutions were mixed in a 1:1 ratio, the resin was suspended, heated and the color of the resin was observed. [ka]

[0193] Coupling of the PEG12-linker. Resin 12 (1.2 mmol / g, 0.4 mmol) was treated twice with a 1:2 mixture of piperidine and DMF (3 mL) to deprotect the Fmoc group, then washed successively with DMF, methanol and dichloromethane (positive Kaiser test). Fmoc-NH-PEG(12)-COOH (1.0 equiv.) was preactivated with HATU (1.0 equiv.), HOAt (1.0 equiv.) and DIPEA (2.7 equiv.) in DMF (3 mL), then the resulting solution was added to the reaction vessel containing the resin and shaken overnight at room temperature. The resin was washed successively with DMF (2×120 mL), methanol (2×120 mL) and dichloromethane (2×120 mL). Completion of the reaction was confirmed by a negative Kaiser test. [ka]

[0194] Peptide cross-linking. To a stirred solution of iodine (500 mg, 1.97 mmol) in DMF (40.0 mL) in a glass reactor, resin 13 (1.2 mmol / g, 0.4 mmol) suspended in DMF (20.0 mL) was added in small portions over 30 min. The entire mixture was gently shaken at room temperature for 4 h. The resin was then drained and excess iodine was washed away using DMF (3×20 mL) and DCM (3×20 mL). After overnight treatment with a small amount of deprotection cocktail containing TFA, a small amount of resin was analyzed using LCMS. [ka]

[0195] Coupling of N-(((9H-fluoren-9-yl)methoxy)carbonyl)-N-(1-(2-(2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)ethoxy)ethyl)-5-(di-tert-butylfluorosilyl)-1H-pyrazol-3-yl)glycine (PPI-24069).

[0196] Resin 14 (1.2 mmol / g, 0.4 mmol) was treated twice with a 1:2 mixture of piperidine and DMF (3 mL) to deprotect the Fmoc group, then washed successively with DMF, methanol and dichloromethane (positive Kaiser test). PPI-24069 (1.0 equiv.) was preactivated with ATU (1.0 equiv.), HOAt (1.0 equiv.) and DIPEA (2.7 equiv.) in HDMF (3 mL), then the resulting solution was added to the reaction vessel containing the resin and shaken overnight at room temperature. The resin 15 was washed successively with DMF (2×10 mL), methanol (2×10 mL) and dichloromethane (2×10 mL). Completion of the reaction was confirmed by a negative Kaiser test. [ka]

[0197] DOTAGA-tetra(t-Bu)-COOH coupling. Resin 15 (1.2 mmol / g, 0.4 mmol) was treated twice with a 1:2 mixture of piperidine and DMF (3 mL) to deprotect the Fmoc group, then washed successively with DMF, methanol and dichloromethane (positive Kaiser test). DOTAGA-tetra(t-Bu)-COOH (1.4 equiv.) was preactivated with HATU (1.4 equiv.), HOAt (1.4 equiv.) and DIPEA (3.8 equiv.) in DMF (3 mL), then the resulting solution was added to the reaction vessel containing the resin and shaken overnight at room temperature. The resin 16 was washed successively with DMF (2×10 mL), methanol (2×10 mL) and dichloromethane (2×10 mL). Completion of the reaction was confirmed by a negative Kaiser test. [ka]

[0198] Deprotection of the peptide and removal from the resin. 2,2',2"-(10-(4-((2-(2-(3-(((R)-45-(((4R,7S,10S,13R,16S,19R)-13-((1H-indol-3-yl)methyl)-10-(4-aminobutyl)-4-(((1S,2R)-1-carboxy-2-hydroxypropyl)carbamoyl)-16-(4-hydroxybenzyl)-7-((R)-1-hydroxyethyl)-6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,17-pentaazacylate Synthesis of leucosan-19-yl)amino)-44-benzyl-2,42,45-trioxo-6,9,12,15,18,21,24,27,30,33,36,39-dodecaoxa-3,43-diazapentatetracontyl)amino)-5-(di-tert-butylfluorosilyl)-1H-pyrazol-1-yl)ethoxy)ethyl)amino)-1-carboxy-4-oxobutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (PPI-24074).

[0199] Resin 16 was treated with a pre-prepared deprotection cocktail (15 mL, 446 μmol) at room temperature overnight as follows. The solvent was collected by filtration and the volume was reduced on a rotavapor. The peptide was precipitated by adding cold diethyl ether, centrifuged, and the solid was washed twice with cold diethyl ether to give the desired peptide product PPI-24074 (650 mg, 59% yield). The resulting solid was analyzed by using LCMS and used directly in the next step.

[0200] LCMS (Method 8B): EM=C 112 H 178 FN 19 O 36 S 2 Si; Calculated value [M+2H] 2+ = 1239.1, Measured value = 1239.5; Calculated value [M+3H] 3+ = 826.4, Measured value = 826.4; Calculated value [M-2H] 2- = 1237.1, actual = 1237.5; Rt = 2.02 min.

[0201] Deprotection cocktail: [88% TFA + 5% water + 5% phenol + 2% triisopropylsilane]. [ka]

[0202] Formation of the lutetium chelate (PPI-24073). A solution of PPI-24074 (50.0 mg, 20.2 μmol) in DMSO (1.00 mL) was diluted with aqueous LuCl 3 (250 μL, 200 mM) was added and the mixture was stirred at 90° C. for 1 h. The reaction was then stopped, cooled to room temperature and directly purified using a reversed-phase column (C18, 30 g) eluted with a gradient of 10 mM ammonium formate (pH 3.8) and acetonitrile. The pure product fractions collected at 36% acetonitrile were combined and lyophilized overnight to give the desired product PPI-24073 (7 mg, 13% yield).

[0203] LCMS (Method 8B): EM=C 112 H 175 FLuN 19 O 36 S 2 Si; Calculated value [M+2H] 2+ = 1325.1, Measured value = 1325.2; Calculated value [M+3H] 3+ = 883.7, Observed = 883.7; Rt = 2.05 min.

[0204] HRMS: [M+2Na-2H] observed mass 2692.0625, calculated mass 2692.0689. [M+3Na-3H] observed mass 2714.0625, calculated mass 2714.0508. [M+4Na-4H] observed mass 2736.0313, calculated mass 2736.0327. [ka]

[0205] BAL resin synthesis. In a glass reactor equipped with a fret, MBHA resin (17, 0.8-1.6 mmol / g, 3.50 g, 4.20 mmol) was activated in dichloromethane (50 mL) for 30 min and drained. The resin showed a positive Kaiser test. In a separate flask, 5-(4-formyl-3,5-dimethoxyphenoxy)pentanoic acid (18, 1.5 equiv.), DIC (1.5 equiv.) and HOBt (1.5 equiv.) were mixed in DMF (25.0 mL) for 5 min and this solution was added to the resin. The resin was shaken at room temperature for 4 h, drained and the resin was treated again with fresh reagents as above. The solvent was drained and the resulting BAL resin 19 was washed successively with DMF (3×25 mL), methanol (3×25 mL) and dichloromethane (3×25 mL). Completion of the reaction was confirmed by a negative Kaiser test. [ka]

[0206] Synthesis of product resin 23. The synthesis of product resin 23 from Bal-resin 19 was achieved using the protocol described in the reference paper (ACS Omega 2019, 4, 1470-1478). After coupling of the Fmoc-protected pABzA-DIG linker, the resulting resin 23 was used for further functionalization. [ka]

[0207] Synthesis of product resin 24. Next, Fmoc-L-His(Trt)-OH (3 eq.), preactivated with HATU (3 eq.), HOAt (3 eq.) and DIEA (8 eq.) in DMF (6 mL), was added in two equal portions to the reaction vessel containing resin 23 and shaken at room temperature for 4 h and overnight, respectively. Fmoc deprotection was performed using a piperidine / DMF (1:2) solution for a total of 1.5 h over two reaction cycles. A similar procedure was used to sequentially couple Fmoc-L-Glu(tBu)-OH, Fmoc-L-His(Trt)-OH and again Fmoc-L-Glu(tBu)-OH to the peptide sequence. The formation of product resin 24 was confirmed by Kaiser test. [ka]

[0208] Coupling of N-(((9H-fluoren-9-yl)methoxy)carbonyl)-N-(1-(2-(2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)ethoxy)ethyl)-5-(di-tert-butylfluorosilyl)-1H-pyrazol-3-yl)glycine (PPI-24069).

[0209] Resin 24 (1.2 mmol / g, 0.65 mmol) was treated twice with a 1:2 mixture of piperidine and DMF (3 mL) to deprotect the Fmoc group, then washed successively with DMF, methanol and dichloromethane (positive Kaiser test). PPI-24069 (1.5 equiv.) was preactivated with HATU (1.0 equiv.), HOAt (1.5 equiv.) and DIPEA (4 equiv.) in DMF (3 mL), then the resulting solution was added to the reaction vessel containing the resin and shaken overnight at room temperature. The resin 25 was washed successively with DMF (2×10 mL), methanol (2×10 mL) and dichloromethane (2×10 mL). Completion of the reaction was confirmed by a negative Kaiser test. [ka]

[0210] DOTA-Tris(t-Bu)-COOH coupling. Resin 25 (1.2 mmol / g, 0.65 mmol) was treated twice with a 1:2 mixture of piperidine and DMF (3 mL) to deprotect the Fmoc group, then washed sequentially with DMF, methanol and dichloromethane (positive Kaiser test). DOTA-Tris(t-Bu)-COOH (1.5 equiv.) was preactivated with HATU (1.5 equiv.), HOAt (1.5 equiv.) and DIPEA (4 equiv.) in DMF (3 mL), then the resulting solution was added to the reaction vessel containing the resin and shaken overnight at room temperature. The resulting resin 26 was washed sequentially with DMF (2×10 mL), methanol (2×10 mL) and dichloromethane (2×10 mL). Completion of the reaction was confirmed by a negative Kaiser test. [ka]

[0211] Deprotection of the peptide and removal from the resin. 2,2',2"-(10-(2-((2-(2-(3-(((4R,7R,10R,13R)-4,10-bis((1H-imidazol-4-yl)methyl)-1-(4-((7R,10S,13S,16S,19S,25S)-25-((1H-imidazol-5-yl)methyl)-13-((1H-indol-3-yl)methyl)-10-(3-amino-3-oxopropyl)-7-benzyl-28-isobutyl-19-isopropyl-16,30-dimethyl-5,8,11,14,17,20,23,26-octyl)-2,4-diamino-1,5-dimethyl-2,6-diamino-1,5-dimethyl-2,7-diamino-1,5-dimethyl-2,8-diamino-1,6-diamino-1,7-diamino-1,5-dimethyl-2,8-diamino-1,5-dimethyl-2 ... Synthesis of tetraoxo-3-oxa-6,9,12,15,18,21,24,27-octaazahentriacontanamido)phenyl)-7,13-bis(2-carboxyethyl)-3,6,9,12,15-pentaoxo-2,5,8,11,14-pentaazahexadecan-16-yl)amino)-5-(di-tert-butylfluorosilyl)-1H-pyrazol-1-yl)ethoxy)ethyl)amino)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (27).

[0212] Resin 26 from the previous step was treated overnight at room temperature with a pre-made deprotection cocktail (15 mL, 446 μmol) as follows. The solvent was collected by filtration and the volume reduced on a rotavapor. The peptide was precipitated by addition of cold diethyl ether, centrifuged, and the solid was washed twice with cold diethyl ether to give the desired product 27, which was used directly in the next step.

[0213] The deprotection cocktail was prepared by mixing the following reagents: [88% TFA + 5% water + 5% phenol + 2% triisopropylsilane]. [ka]

[0214] Formation of the lutetium chelate (PPI-24082). A solution of 27 (69.0 mg, 20.2 μmol) in DMSO (1.38 mL) was diluted with aqueous LuCl 3 (552 μL, 200 mM) was added and the mixture was stirred at 90° C. for 1 h. The reaction was then stopped, cooled to room temperature, and directly purified using preparative HPLC eluting with a gradient of 0.1% TFA and acetonitrile. The pure product fractions collected at 30% acetonitrile were combined and lyophilized overnight to give the desired product PPI24082 (1.04 mg, optimized yield).

[0215] LCMS (Method 8B): EM=C 116 H 166 FLuN 30 O 28 Si; Calculated value [M+2H] 2+ = 1325.6, actual = 1325.5; Rt = 2.79 min.

[0216] FIG. 29 illustrates a synthetic scheme for PPI-24069, according to an embodiment of the present invention.

[0217] FIG. 30 illustrates a synthetic scheme for PPI-24073 / FTX-181, according to an embodiment of the invention.

[0218] FIG. 31 illustrates a synthetic scheme for PPI-24082 / FTX-219, according to an embodiment of the invention. Doctrine of Equivalents

[0219] As can be inferred from the above discussion, the above concepts can be implemented in various arrangements according to the embodiments of the present invention. Thus, while the present invention has been described in certain specific embodiments, numerous additional modifications and variations will be apparent to those skilled in the art. Thus, it should be understood that the present invention can be implemented otherwise than as specifically described. The present embodiments are therefore to be considered in all respects as illustrative and not restrictive.

Claims

1. Silicon fluoride receptors, and Heteroaromatic ring A compound comprising: the heteroaromatic ring is selected from the group consisting of pyridine, pyridine oxide, pyridinium, pyrazole, fused pyrazole derivatives, benzofuran, benzothiophene, indole, azaindole, imidazole and pyrimidine; The pyridine, pyridine oxide or pyridinium compound has the following formula I: 【Chemical 264】 having The pyrazole compound has the following formula II: 【Chemistry 265】 having The fused pyrazole derivative compound has the following formula III: 【Chemical 266】 having The benzofuran, benzothiophene, indole, or azaindole compound has the following formula IV: 【Chemical 267】 having The imidazole compound has the following formula V: 【Chemical 268】 having The pyrimidine compound has the following formula VI: 【Chemical 269】 having During the ceremony, Each F is independently F or １８ F or １９ F, Each A is independently H, CH ３、 CH ２ -CH ３、 CH ３ -CH ２ -CH(CH ３ ), CH(CH ３ ) ２ and C(CH ３ ) ３ and Each U is independently O-CH ３ , C.H. ３ , C.H. ２ CH ３ , H, I, Br, Cl, F, N(CH ３ ) ２ and C.H. ２ CH(NH ２ ) CO ２ H, Each X is independently O, S, or N; each Y is independently C or N; R １ or R ２ or R ３ each independently is CH ３ CH ２ -CH ３ H, L １ -CH ２ -C≡C, L １ -CH ３ L １ -G, L １ -H, L １ -L ２ -CH ２ -C≡C, L １ -L ２ -CH ３ L １ -L ２ -G, L １ -L ２ -H, L １ -L ２ -H ２ L １ -L ２ -L ３ -G, L １ -L ２ -L ３ -H, L １ -L ２ -L ３ -L ４ -G, L １ -L ２ -L ３ -L ４ -H, L １ -L ２ -L ３ -L ４ -Q-L ５ -G, L １ -L ２ -L ３ -Q, L １ -L ２ -L ３ -Q-L ４ -G, L １ -L ２ -N ３ L １ -L ２ -OH, L １ -L ２ -Q, L １ -L ２ -Q-G, L １ -L ２ -Q-L ３ -G、L １ -L ２ -Q-L ３ -L ４ -G、L １ -L ２ -Q-L ３ -L ４ -H、L １ -OH、L １ -Q、L １ -Q-L ２ -L ３ -L ４ -G、L １ -Q-L ２ -G、NH ２ 、O － 、O-CH ３ 、OH、 【Chemistry 270】 and L １ Or L ２ Or L ３ Or L ４ Or L ５ Each independently represents -(O-CH ２ -CH ２ ) ｐ -, -(CH ２ -CH ２ -O) ｐ -,-(Glu-His) ｐ -,-(His-Glu) ｐ -,-(Glu-Trp) ｐ -,-(Trp-Glu) ｐ --NH-CH ２ -C ６ H ４ -NH-(C=O)-CH ２ -O-CH ２ -(C=O)-, -(C=O)-CH ２ -O-CH ２ -(C=O)-NH-C ６ H ４ -CH ２ -NH-, -(C=O)-CH ２ -CH ２ -(C=O)-, -NH-C ５ H ９ N-CH ２ -(C=O)-, -(C=O)-CH ２ -NC ５ H ９ -NH-, -(Gly) ｐ --, --CH ２ -CH ２ -NH-, -NH-CH ２ -(C=O)-, -(Glu)-, -NH-CH ２ -CH ２ -, -(C=O)-, NH-CH ２ -CH ２ -(O-CH ２ -CH ２ ) ｐ -(C=O)-, -(C=O)-(CH ２ -CH ２ -O) ｐ -CH ２ -CH ２ -NH-, -NH-(C=O)-CH ２ -、-NH-(C=O)-NH-CH ２ -、-NH-(C=S)-NH-CH ２ -、-NH-(CH ２ -CH ２ -O) ｐ -CH ２ -(C=O)-、-(C=O)-CH ２ -(O-CH ２ -CH ２ ) ｐ -NH-,-Asp-,-NH-,-NH-(CH ２ -CH ２ -O) ｐ -CH ２ -CH ２ -(C=O)-、-(C=O)-CH ２ -CH ２ -(O-CH ２ -CH ２ ) ｐ -NH-、-CH ２ -(C=O)-、-(C=O)-CH ２ -、-O-(C=O)-、-(C=O)-O-、-CH ２ -O-、-NH-(C=O)-O-、-O-(C=O)-NH-、-(C=O)-CH ２ -(O-CH ２ -CH ２ ) ｐ -O-CH ２ -(C=O)-,-NH-(C=O)-NH-,-NH-(C=S)-NH-,-CH ２ -N(CH ３ )-CH ２ -、-N(CH ３ )-、-(C=O)-C ６ H ４ -(C=O)-、-C ６ H ４ -(C=O)-、-(C=O)-C ６ H ４ -、-O-CH ２ -(C=O)-、-(C=O)-CH ２ -O-、-CH ２ -C ２ N ３ -CH ２ -、-CH ２ -CH ２ -(C=O)-、-(C=O)-CH ２ -CH ２ -、-CH ２ -N ＋ (CH ３ ) ２ -CH ２ -、-CH ２ -N(CH ３ )-、-(C=O)-CH ２ -(O-CH ２ -CH ２ ) ｐ -、-(CH ２ -CH ２ -O) ｐ -CH ２ -CH ２ -NH-、または 【Chemistry 271】 and p=0 to 12; each G is a disease-binding ligand, where G is independently a somatostatin receptor type 2 (SSTR2)-binding ligand, a gastrin releasing peptide receptor (GRPR)-binding ligand, a prostate specific membrane antigen (PSMA)-binding ligand, a fibroblast activation protein (FAP)-binding ligand, or a C-X-C chemokine receptor type 4 (CXCR-4)-binding ligand; Each Q is a chelating agent; compound.

2. Q is each independently selected from -DOTA, -DOTAGA, -Dap(DOTA), -Lys(DOTA), -3p-C-NETA, -bis-thiosemicarbazone, -EDTA, -CHX-A"-EDTA, -DTPA, -p-SCN-DPTA, -CHX-A"-DTPA, -p-SCN-Bz-Mx-DTPA, -NOTA, -TETA, -CB-TE2A, -p-SCN-NOTA(cN -OTA), -nNOTA, -NODAGA, -p-SCN-DOTA (cDOTA), -2-cTETA, -6-cTETA, -BAT, -Diamsa, -SarAr, -PCTA, -NODIA-Me, -TRAP, -pycup1A1B, -p-SCN-DTPA, -desferrioxamine B (DFO) mesylate, -desferrioxamine-p-SCN, -DFO-Star (DFO ＊ ), -L5, -Orn3hx-NCS, -Orn4hx-NCS, -p-SCN-Bn-HOPO, -2,3-HOPO-p-Bn-NCS, -YM103, -Tc(V)oxo, -Tc(V)nitride, -Tc(V)HYNIC, -Tc(I)-fac-tricarbonyl, -Tc(VII)trioxo, -3p-C-NETA-NCS, -3p-C-DEPA-NCS, -TCMC, -p-SCN-Bn-H ４ The compound of claim 1, which is -octapa, -HEHA-NCS or -Macropa-NCS.

3. Q is non-chelated or optionally chelated with M, and M is ４３ Sc, ４４ Sc, ４５ Sc, ４７ Sc, ５１ Cr, ５２ｍ Mn, ６８ Co, ５２ Fe, ５６ Ni, ５７ Ni, ６１ Cu, ６２ Cu, ６３ Cu, ６４ Cu, ６５ Cu, ６７ Cu, ６６ G.A. ６７ G.A. ６８ G.A. ６９ G.A. ７１ G.A. ｎａｔ G.A. ９０ Zr, ９１ Zr, ９２ Zr, ８９ Zr, ８６ Y. ９０ Y. ８９ Y. ９９ｍ Tc, ９７ Ru, １０５ Rh, １０９ Pd, １１１ Ag, １１０ｍ In, １１１ I, １１３ In, １３３ｍ In, １１４ｍ In, １１７ｍ Sn, １２１ Sn, １２７ Te, １４２ P.R. １４３ P.R. １４９ P.M., １５１ P.M., １４９ Tb, １５５ Tb, １５３ Sm, １５７ Gd, １６１ Tb, １６６ Ho, １６５ Dy, １６９ Er, １６９ Yb, １７５ Yb, １７２ Tm, １７６ Lu, １７７ Lu, １７７ｍ Lu, ｎａｔ Lu, １８６ Re, １８８ Re, １９１ Pt, １９７ Hg, １９８ Au, １９９ Au, ２１２ Pb, ２０３ Pb, ２０４ Pb, ２０６ Pb, ２０７ Pb, ２０８ Pb, ２１１ At, ２０９ Bi, ２１２ Bi, ２１３ Bi, ２２３ Ra, ２２５ A c, ２２７ Th, ２３２ a cation of a metal selected from the group consisting of Th, and １８ Cationic molecules containing F, and １８ F[AlF] ２＋ 2. The compound of claim 1,

4. A is C (CH ３ ) ３ 2. The compound of claim 1,

5. G is the following: 【Chemical 272】 【Chemical 273】 【Chemical 274】 【Chemistry 275】 and Z is H, CH ３ or CF ３ 2. The compound of claim 1,

6. R １ is, independently, CH ３ , H, L １ -CH ２ -C≡C, L １ -CH ３ , L １ -H, L １ -L ２ -CH ２ -C≡C, L １ -L ２ -CH ３ , L １ -L ２ -G, L １ -L ２ -H, L １ -L ２ -H ２ , L １ -L ２ -L ３ -G, L １ -L ２ -L ３ -H, L １ -L ２ -L ３ -L ４ -Q-L ５ -G, L １ -L ２ -L ３ -Q, L １ -L ２ -L ３ -Q-L ４ -G, L １ -L ２ -N ３ , L １ -L ２ -OH, L １ -L ２ -Q, L １ -L ２ -Q-L ３ -L ４ -G, L １ -OH, L １ -Q, L １ -Q-L ２ -L ３ -L ４ -G, NH ２ , O-CH ３ , OH, 【Chemical 276】 and R ２ is independently CH ３ , H, L １ -CH ２ -C≡C, L １ -G, L １ -H, L １ -L ２ -CH ２ -C≡C, L １ -L ２ -G, L １ -L ２ -L ３ -G, L １ -L ２ -L ３ -L ４ -G, L １ -L ２ -L ３ -Q, L １ -L ２ -L ３ -Q-L ４ -G, L １ -L ２ -N ３ 、L １ -L ２ -Q, L １ -L ２ -Q-G, L １ -L ２ -Q-L ３ -G, L １ -OH, L １ -Q, L １ -Q-L ２ -G, NH ２ 、O － or O-CH ３ and is R ３ But independently, CH ３ , C.H. ２ -CH ３ Or O － That is, The compound of claim 1.

7. The compound is 【Chemical 277】 2. The compound of claim 1, which is a small molecule having a formula selected from the group consisting of:

8. The compound is for positron emission tomography (PET) imaging and has the following formula: 【Chemical 278】 2. The compound of claim 1 having the formula:

9. The compound is 【Chemical 279】 【Chemistry 280】 2. The compound of claim 1, which is a theranostic compound having a formula selected from the group consisting of:

10. The compound has the following formula: 【Chemistry 281】 2. The compound of claim 1, which is a dual targeting theranostic compound having the formula:

11. The compound of claim 1 , wherein the compound is configured for PET imaging and therapeutic radioligand therapy.

12. 2. The compound of claim 1, wherein the disease-binding ligand G is conjugated to the compound by a process selected from the group consisting of coupling chemistry, peptide coupling chemistry, copper catalyzed azide-alkyne cycloaddition (CuAAC) and solid phase peptide synthesis (SPPS).

13. 3p-C-NETA is for treatment, １７７ configured to form a chelate with Lu; DOTA and DOTAGA are used for treatment: １７７ Lu or ２２５ configured to form a chelate with Ac, DOTA and DOTAGA for PET imaging ６８ G.A. ８９ Zr or ６４ configured to form a chelate with Cu; The compound according to claim 2.

14. Providing a fluorosilicon compound containing a heteroaromatic ring; conjugating a disease-binding ligand G to said fluorinated silicon compound to form a radiopharmaceutical compound; 1. A method of synthesizing said radiopharmaceutical compound comprising: the heteroaromatic ring is selected from the group consisting of pyridine, pyridine oxide, pyridinium, pyrazole, fused pyrazole derivatives, benzofuran, benzothiophene, indole, azaindole, imidazole and pyrimidine; The pyridine, pyridine oxide or pyridinium compound is Formula I below: 【Chemical Formula 282】 having The pyrazole compound has the following formula II: 【Chemistry 283】 having The fused pyrazole derivative compound has the following formula III: 【Chemical 284】 having The benzofuran, benzothiophene, indole, or azaindole compound has the following formula IV: 【Chemistry 285】 having The imidazole compound has the following formula V: 【Chemistry 286】 having The pyrimidine compound has the following formula VI: 【Chemistry 287】 having During the ceremony, Each F is independently F or １８ F or １９ F, Each A is independently H, CH ３、 CH ２ -CH ３、 CH ３ -CH ２ -CH(CH ３ ), CH(CH ３ ) ２ and C(CH ３ ) ３ and Each U is independently O-CH ３ , C.H. ３ , C.H. ２ CH ３ , H, I, Br, Cl, F, N(CH ３ ) ２ and C.H. ２ CH(NH ２ ) CO ２ H, Each X is independently O, S, or N; each Y is independently C or N; R １ or R ２ or R ３ is each independently CH ３ CH ２ -CH ３ H, L １ -CH ２ -C≡C, L １ -CH ３ L １ -G, L １ -H, L １ -L ２ -CH ２ -C≡C, L １ -L ２ -CH ３ L １ -L ２ -G, L １ -L ２ -H, L １ -L ２ -H ２ L １ -L ２ -L ３ -G, L １ -L ２ -L ３ -H, L １ -L ２ -L ３ -L ４ -G, L １ -L ２ -L ３ -L ４ -H, L １ -L ２ -L ３ -L ４ -Q-L ５ -G, L １ -L ２ -L ３ -Q, L １ -L ２ -L ３ -Q-L ４ -G, L １ -L ２ -N ３ L １ -L ２ -OH, L １ -L ２ -Q, L １ -L ２ -Q-G, L １ -L ２ -Q-L ３ -G、L １ -L ２ -Q-L ３ -L ４ -G、L １ -L ２ -Q-L ３ -L ４ -H、L １ -OH、L １ -Q、L １ -Q-L ２ -L ３ -L ４ -G、L １ -Q-L ２ -G、NH ２ 、O － 、O-CH ３ 、OH、 【Chemistry 288】 and L １ Or L ２ Or L ３ Or L ４ Or L ５ Each independently represents -(O-CH ２ -CH ２ ) ｐ -, -(CH ２ -CH ２ -O) ｐ -,-(Glu-His) ｐ -,-(His-Glu) ｐ -,-(Glu-Trp) ｐ -,-(Trp-Glu) ｐ --NH-CH ２ -C ６ H ４ -NH-(C=O)-CH ２ -O-CH ２ -(C=O)-, -(C=O)-CH ２ -O-CH ２ -(C=O)-NH-C ６ H ４ -CH ２ -NH-, -(C=O)-CH ２ -CH ２ -(C=O)-, -NH-C ５ H ９ N-CH ２ -(C=O)-, -(C=O)-CH ２ -NC ５ H ９ -NH-, -(Gly) ｐ --, --CH ２ -CH ２ -NH-, -NH-CH ２ -(C=O)-, -(Glu)-, -NH-CH ２ -CH ２ -, -(C=O)-, NH-CH ２ -CH ２ -(O-CH ２ -CH ２ ) ｐ -(C=O)-, -(C=O)-(CH ２ -CH ２ -O) ｐ -CH ２ -CH ２ -NH-, -NH-(C=O)-CH ２ -、-NH-(C=O)-NH-CH ２ -、-NH-(C=S)-NH-CH ２ -、-NH-(CH ２ -CH ２ -O) ｐ -CH ２ -(C=O)-、-(C=O)-CH ２ -(O-CH ２ -CH ２ ) ｐ -NH-,-Asp-,-NH-,-NH-(CH ２ -CH ２ -O) ｐ -CH ２ -CH ２ -(C=O)-、-(C=O)-CH ２ -CH ２ -(O-CH ２ -CH ２ ) ｐ -NH-、-CH ２ -(C=O)-、-(C=O)-CH ２ -、-O-(C=O)-、-(C=O)-O-、-CH ２ -O-、-NH-(C=O)-O-、-O-(C=O)-NH-、-(C=O)-CH ２ -(O-CH ２ -CH ２ ) ｐ -O-CH ２ -(C=O)-,-NH-(C=O)-NH-,-NH-(C=S)-NH-,-CH ２ -N(CH ３ )-CH ２ -、-N(CH ３ )-、-(C=O)-C ６ H ４ -(C=O)-、-C ６ H ４ -(C=O)-、-(C=O)-C ６ H ４ -、-O-CH ２ -(C=O)-、-(C=O)-CH ２ -O-、-CH ２ -C ２ N ３ -CH ２ -、-CH ２ -CH ２ -(C=O)-、-(C=O)-CH ２ -CH ２ -、-CH ２ -N ＋ (CH ３ ) ２ -CH ２ -、-CH ２ -N(CH ３ )-、-(C=O)-CH ２ -(O-CH ２ -CH ２ ) ｐ -、-(CH ２ -CH ２ -O) ｐ -CH ２ -CH ２ -NH-、または 【Chemical 289】 and p=0 to 12; each G is independently a somatostatin receptor type 2 (SSTR2)-binding ligand, a gastrin releasing peptide receptor (GRPR)-binding ligand, a prostate specific membrane antigen (PSMA)-binding ligand, a fibroblast activation protein (FAP)-binding ligand, or a C-X-C chemokine receptor type 4 (CXCR-4)-binding ligand; Each Q is a chelating agent; method.

15. Q is each independently selected from -DOTA, -DOTAGA, -Dap(DOTA), -Lys(DOTA), -3p-C-NETA, -bis-thiosemicarbazone, -EDTA, -CHX-A"-EDTA, -DTPA, -p-SCN-DPTA, -CHX-A"-DTPA, -p-SCN-Bz-Mx-DTPA, -NOTA, -TETA, -CB-TE2A, -p-SCN-NOTA(cN -OTA), -nNOTA, -NODAGA, -p-SCN-DOTA (cDOTA), -2-cTETA, -6-cTETA, -BAT, -Diamsa, -SarAr, -PCTA, -NODIA-Me, -TRAP, -pycup1A1B, -p-SCN-DTPA, -desferrioxamine B (DFO) mesylate, -desferrioxamine-p-SCN, -DFO-Star (DFO ＊ ), -L5, -Orn3hx-NCS, -Orn4hx-NCS, -p-SCN-Bn-HOPO, -2,3-HOPO-p-Bn-NCS, -YM103, -Tc(V)oxo, -Tc(V)nitride, -Tc(V)HYNIC, -Tc(I)-fac-tricarbonyl, -Tc(VII)trioxo, -3p-C-NETA-NCS, -3p-C-DEPA-NCS, -TCMC, -p-SCN-Bn-H ４ 15. The method of claim 14, wherein said nucleic acid is -octapa, -HEHA-NCS or -Macropa-NCS.

16. further comprising a step of chelating Q with M, wherein M is ４３ Sc, ４４ Sc, ４５ Sc, ４７ Sc, ５１ Cr, ５２ｍ Mn, ６８ Co, ５２ Fe, ５６ Ni, ５７ Ni, ６１ Cu, ６２ Cu, ６３ Cu, ６４ Cu, ６５ Cu, ６７ Cu, ６６ Ga, ６７ Ga, ６８ Ga, ６９ Ga, ７１ Ga, ｎａｔ Ga, ９０ Zr, ９１ Zr, ９２ Zr, ８９ Zr, ８６ Y, ９０ Y, ８９ Y, ９９ｍ Tc, ９７ Ru, １０５ Rh, １０９ Pd, １１１ Ag, １１０ｍ In, １１１ I, １１３ In, １３３ｍ In, １１４ｍ In, １１７ｍ Sn, １２１ Sn, １２７ Te, １４２ Pr, １４３ Pr, １４９ Pm, １５１ Pm, １４９ Tb, １５５ Tb, １５３ Sm, １５７ Gd, １６１ Tb, １６６ Ho, １６５ Dy, １６９ Er, １６９ Yb, １７５ Yb, １７２ Tm, １７６ Lu, １７７ Lu, １７７ｍ Lu, ｎａｔ Lu, １８６ Re, １８８ Re, １９１ Pt, １９７ Hg, １９８ Au, １９９ Au, ２１２ Pb, ２０３ Pb, ２０４ Pb, ２０６ Pb, ２０７ Pb, ２０８ Pb, ２１１ At, ２０９ Bi, ２１２ Bi, ２１３ Bi, ２２３ Ra, ２２５ A c, ２２７ Th, ２３２ a cation of a metal selected from the group consisting of Th, and １８ Cationic molecules containing F and １８ F[AlF] ２＋ The method of claim 14, wherein

17. A is C (CH ３ ) ３ The method of claim 14, wherein

18. G is the following: 【Chemistry 290】 【Chemical 291】 【Chemical 292】 having a formula selected from the group consisting of: Z is H, CH ３ or CF ３ That is, The method of claim 14.

19. R １ is independently CH ３ , H, L １ -CH ２ -C≡C, L １ -CH ３ , L １ -H, L １ -L ２ -CH ２ -C≡C, L １ -L ２ -CH ３ , L １ -L ２ -G, L １ -L ２ -H, L １ -L ２ -H ２ , L １ -L ２ -L ３ -G, L １ -L ２ -L ３ -H, L １ -L ２ -L ３ -L ４ -Q-L ５ -G, L １ -L ２ -L ３ -Q, L １ -L ２ -L ３ -Q-L ４ -G, L １ -L ２ -N ３ , L １ -L ２ -OH, L １ -L ２ -Q, L １ -L ２ -Q-L ３ -L ４ -G, L １ -OH, L １ -Q, L １ -Q-L ２ -L ３ -L ４ -G, NH ２ , O-CH ３ , OH, 【Chemical 293】 and R ２ is independently CH ３ , H, L １ -CH ２ -C≡C, L １ -G, L １ -H, L １ -L ２ -CH ２ -C≡C, L １ -L ２ -G, L １ -L ２ -L ３ -G, L １ -L ２ -L ３ -L ４ -G, L １ -L ２ -L ３ -Q, L １ -L ２ -L ３ -Q-L ４ -G, L １ -L ２ -N ３ , L １ -L ２ -Q, L １ -L ２ -Q-G, L １ -L ２ -Q-L ３ -G, L １ -OH, L １ -Q, L １ -Q-L ２ -G, NH ２ , O － or O-CH ３ and is R ３ But independently, CH ３ , C.H. ２ -CH ３ Or O － That is, The method of claim 14.

20. 4. The radiopharmaceutical compound comprising: 【Chemical Formula 294】 15. The method of claim 14, wherein the compound is a small molecule having a formula selected from the group consisting of:

21. The radiopharmaceutical compound is for positron emission tomography (PET) imaging and has the following formula: 【Chemistry 295】 15. The method of claim 14, comprising:

22. 4. The radiopharmaceutical compound comprising: 【Chemical 296】 【Chemical Formula 297】 【Chemical 298】 15. The method of claim 14, wherein the theranostic compound has a formula selected from the group consisting of:

23. The radiopharmaceutical compound has the following formula: 【Chemical 299】 【Chemistry 300】 The method of claim 14, wherein the compound is a dual targeting theranostic compound having the formula:

24. 15. The method of claim 14, wherein the radiopharmaceutical compound is configured for PET imaging and therapeutic radioligand therapy.

25. 15. The method of claim 14, wherein the conjugation is by a process selected from the group consisting of coupling chemistry, peptide coupling chemistry, copper catalyzed azide-alkyne cycloaddition (CuAAC) and solid phase peptide synthesis (SPPS).

26. For treatment, 3p-C-NETA and １７７ forming a chelate with Lu; For treatment, DOTA and DOTAGA １７７ Lu or ２２５ forming a chelate with Ac; and For PET imaging, DOTA and DOTAGA ６８ G.A. ８９ Zr and ６４ forming a chelate with one of the Cu The method of claim 15 further comprising:

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