Silicon fluoride heteroaromatic systems for therapeutic diagnostics and methods thereof

Abstract

Systems and methods for heteroaromatic silicon fluoride compounds as radiopharmaceuticals with therapeutic diagnostic performance are described. Therapeutically diagnostic heteroaromatic silicon fluoride compounds may be conjugated to various disease binding ligands and / or chelating agents for imaging and therapeutic use.

Description

Field of the Invention

[0001] The present invention generally relates to systems and methods for heteroaromatic fluorinated silicon acceptors. More specifically, the present invention relates to systems and methods for heteroaromatic fluorinated silicon acceptor systems having theranostic properties. Background of the Invention

[0003] Nuclear medicine is a field of radiology that uses radiation produced by the decay of medical radioisotopes, which are usually administered to patients. Nuclear medicine has different therapeutic and diagnostic branches that differ in the type of radiation produced by the decay of the medical radioisotopes.

[0004] 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 associated with various diseases at the molecular and cellular levels. These techniques rely on radioactively labeled compounds (called tracers or radiopharmaceuticals) that 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 effective in brain imaging applications.

[0005] In therapeutic nuclear medicine, radiopharmaceuticals target pathological tissues to deliver cytotoxic radiation at the cellular level. - -radiating nuclides are used to destroy malignant cells to which the radiopharmaceutical is attached. α-particles have higher energy and much greater mass. Actinium-225 is a commonly used α-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. It can improve the quality of life of many patients and shrink or stabilize tumors.

[0006] Theranostics is a combination of the terms therapeutics and diagnostics. Theranostics can be used to describe the combination of using one radiopharmaceutical to identify (diagnose) and a second radiopharmaceutical to deliver therapy to treat the primary tumor and any metastatic tumors.

[0007] Theranostic approaches represent the pairing of molecular imaging with therapeutic nuclear medicine. A “see it, treat it” approach allows the selection of patients suitable for therapeutic nuclear medicine with PET imaging. A pair of radiopharmaceuticals targeting the same disease is required to image and treat the condition, for example, a theranostic pair targeting somatostatin receptor type 2 (SSTR2) on neuroendocrine tumors (NETs). The octapeptide TATE is a somatostatin analog (SSA) with high affinity for SSTR2. It can be used 177 Lu-labeled [ 177 Lu]Lu-DOTA-TATE for therapeutic nuclear medicine. In terms of diagnosis, 68 Ga-labeled SSA was used for molecular imaging of NETs using PET / CT. 68 PET / CT imaging with Ga]Ga-DOTA-TATE can stage NETs with high accuracy and qualify patients for therapeutic nuclear medicine. Figure 1 Explained 68 Ga-DOTA-TATE (PET imaging agent) and 177 Structure of Lu-DOTA-TATE (therapeutic agent). Another example includes the use of PSMA PET to diagnose metastatic prostate cancer. A PSMA-targeted theranostic pair is used for PET 68 Ga-PSMA-617 and its use in treatment 177 Lu-PSMA-617. Figure 2 Explained 68 Precursor of Ga-PSMA-617 and 177 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 for therapeutic purposes. Glu-urea-based peptide mimetics are high-affinity PSMA binders.

[0008] Fluorine-18 is a common PET-radionuclide in clinical applications. The half-life of fluorine-18 (t 1 / 2 =109.8min,97%β + -decay) is long enough to allow radiopharmaceutical production and transport to off-site imaging facilities. The output of cyclotron-produced nuclides is scalable, and doses to hundreds of patients can be generated in a single production run. Its relatively low positron energy (maximum beta + Energy = 633 keV) allows for imaging with high spatial resolution and few artifacts.

[0009] Conventional radiotracers used in diagnostic PET imaging 18F incorporation uses nucleophilic or electrophilic substitution chemistry involving C- 18 F bond formation. Usually requires harsh reaction conditions, including high temperature, aprotic organic solvents, strong basic conditions during radiolabeling, and strong acidic conditions during the removal of protecting groups. 18 F incorporation can also involve complex and lengthy multi-step production procedures and the generation of radioactive and non-radioactive byproducts that require time-consuming and expensive purification processes such as semi-preparative high performance liquid chromatography.

[0010] Compared with conventional radiolabeling methods, the silicon fluoride-acceptor (SiFA) building block can rapidly form Si- 18 F bond, thereby producing a high radiochemical yield (RCY) and high molar activity (A m )produce 18 F-SiFA-conjugated PET tracer. Si- 18 The formation of the F bond can occur under mild reaction conditions (such as at room temperature). It may not be necessary to mask sensitive functional groups with protecting groups. In addition, the absence of byproducts allows for simple column-based purification, resulting in a total synthesis time of about 20 minutes. However, an inherent disadvantage of traditional phenyl-SiFA technology is its high lipophilicity. The high lipophilicity can be caused by the two tert-butyl substituents on the silicon and the phenyl core (which has a logP of about 2.13). The two tert-butyl substituents on the silicon are required to cleave the Si- 18 The F bond is sterically shielded to prevent its hydrolysis in vivo. (See, e.g., 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 the phenyl-SiFA portion.

[0011] Heteroaromatic SiFA (HetSiFA) technology uses a more hydrophilic heteroaromatic ring to replace the benzene ring of SiFA. (See, e.g., PCT Application No. WO 2020 / 220020A1 by JM Murphy et al., U.S. Patent No. 10800797B2 by CMWaldmann et al.; the disclosures of which are incorporated herein by reference in their entirety). HetSiFA is fast and reliable. 18 F-fluorination is simple and production can be scaled up, which increases the availability of the drug to imaging centers and patients. Mild reaction conditions allow labeling of sensitive substrates, including (but not limited to) peptides and peptidomimetics. Despite advances, existing SiFA systems have inherent disadvantages in therapeutic, diagnostic and / or theranostic applications.

[0012] Brief description of the invention

[0013] Many embodiments are directed to systems and methods for heteroaromatic fluorinated silicon acceptor systems. In several embodiments, systems and methods for heteroaromatic fluorinated silicon acceptor systems with theranostic properties are described. Certain embodiments are directed to systems and methods for heteroaromatic fluorinated silicon acceptor systems with theranostic capabilities that target various types of metastatic cancers, including but not limited to prostate cancer.

[0014] One embodiment of the present invention includes a compound comprising: a silicon fluoride acceptor; and a heteroaromatic ring; wherein the heteroaromatic ring is selected from the group consisting of: pyridine, pyridinium oxide, pyridinium, pyrazole, fused pyrazole derivatives, benzofuran, benzothiophene, indole, azaindole, imidazole, and pyrimidine;

[0015] Wherein the pyridine, pyridine oxide or pyridinium compound has the following formula I:

[0016]

[0017] The pyrazole compound has the following formula II:

[0018]

[0019] The fused pyrazole derivative compound has the following formula III:

[0020]

[0021] Wherein the benzofuran, benzothiophene, indole or azaindole compound has the following formula IV:

[0022]

[0023] The imidazole compound has the following formula V:

[0024]

[0025] The pyrimidine compound has the following formula VI:

[0026]

[0027] in:

[0028] Each F is independently: F or 18 F or 19 F;

[0029] each A is independently: H, CH3, CH2-CH3, CH3-CH2-CH(CH3), CH(CH3)2 and C(CH3)3;

[0030] Each U is independently: O-CH3, CH3, CH2CH3, H, I, Br, Cl, F, N(CH3)2, and CH2CH(NH2)CO2H;

[0031] Each X is independently: O, S and N;

[0032] Each Y is independently: C and N;

[0033] Each R 1 or R 2 or R 3 independently: CH3, CH2-CH3, H, L 1 -CH2-C≡C, L 1 -CH3, L 1 -G, L 1 -H, L 1 -L 2 -CH2-C≡C, L 1 -L 2 -CH3, L 1 -L 2 -G, L 1 -L 2 -H, L 1 -L 2 -H2, 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 -N3, L 1 -L 2 -OH, L 1 -L 2-Q, L 1 -L 2 -QG, 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, NH2, O - 、O-CH3、OH、

[0034] Each L 1 or L 2 or L 3 or L 4 or L 5 Independently: -(O-CH2-CH2) p -、-(CH2-CH2-O) p -、-(Glu-His) p -、-(His-Glu) p -、-(Glu-Trp) p -、-(Trp-Glu) p -, -NH-CH2-C6H4-NH-(C=O)-CH2-O-CH2-(C=O)-, -(C=O)-CH2-O-CH2-(C=O)-NH-C6H4-CH2 -NH-, -(C=O)-CH2-CH2-(C=O)-, -NH-C5H9N-CH2-(C=O)-, -(C=O)-CH2-NC5H9-NH-, -(Gly) p -, -CH2-CH2-NH-, -NH-CH2-(C=O)-, -(Glu)-, -NH-CH2-CH2-, -(C=O)-, NH-CH2-CH2-(O-CH2-CH2) p -(C=O)-, -(C=O)-(CH2-CH2-O) p-CH2-CH2-NH-, -NH-(C=O)-CH2-, -NH-(C=O)-NH-CH2-, -NH-(C=S)-NH-CH2-, -NH-(CH2-CH2-O) p -CH2-(C=O)-, -(C=O)-CH2-(O-CH2-CH2) p -NH-, -Asp-, -NH-, -NH-(CH2-CH2-O) p -CH2-CH2-(C=O)-, -(C=O)-CH2-CH2-(O-CH2-CH2) p -NH-, -CH2-(C=O)-, -(C=O)-CH2-, -O-(C=O)-, -(C=O)-O-, -CH2-O-, -NH-(C=O)-O-, -O-(C=O)-NH-, -(C=O)-CH2-(O-CH2-CH2) p -O-CH2-(C=O)-, -NH-(C=O)-NH-, -NH-(C=S)-NH-, -CH2-N(CH3)-CH2-, -N(CH3)-, -(C=O)-C6H4-(C=O)-, -C6H4-(C=O )-, -(C=O)-C6H4-, -O-CH2-(C=O)-, -(C=O)-CH2-O-, -CH2-C2N3-CH2-, -CH2-CH2-(C=O)-, -(C=O)-CH2-CH2-, -CH2-N + (CH3)2-CH2-, -CH2-N(CH3)-, -(C=O)-CH2-(O-CH2-CH2) p -、-(CH2-CH2-O) p -CH2-CH2-NH- or

[0035] p = 0 to 12;

[0036] each G is a disease binding ligand, wherein 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; and

[0037] Each Q is a chelating agent.

[0038] In a further embodiment, each Q is independently: -DOTA, -DOTAGA, -Dap(DOTA), -Lys(DOTA), -3p-C-NETA, -di-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, -deferoxamine B (DFO) mesylate, -deferoxamine-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-H4octapa, -HEHA-NCS, or -Macropa-NCS.

[0039] In another embodiment, Q is unchelated or optionally chelated with M, wherein M is a cation of a metal selected from: 43 Sc, 44 Sc, 45 Sc, 47 Sc, 51 Cr, 52m Mn, 68 Co. 52 Fe, 56 You, 57 You, 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 Such as 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 2. 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 and including 18 The cationic molecules of F and 18 F[AlF] 2+ .

[0040] In another embodiment, A is C(CH3)3.

[0041] In another further embodiment, G has a formula selected from:

[0042]

[0043]

[0044] wherein Z is H, CH3 or CF3.

[0045] In yet a further embodiment,

[0046] R 1 Independently: CH3, H, L 1 -CH2-C≡C, L 1 -CH3, L 1 -H, L 1 -L 2 -CH2-C≡C, L 1 -L 2 -CH3, L 1 -L 2 -G, L 1 -L 2 -H, L 1 -L 2 -H2, 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 -N3, L 1 -L 2 -OH, L 1 -L 2 -Q, L 1 -L 2 -QL 3 -L 4 -G, L1 -OH, L 1 -Q, L 1 -QL 2 -L 3 -L 4 -G, NH2, O-CH3, OH,

[0047] R 2 Independently: CH3, H, L 1 -CH2-C≡C, L 1 -G, L 1 -H, L 1 -L 2 -CH2-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 -N3, L 1 -L 2 -Q, L 1 -L 2 -QG, L 1 -L 2 -QL 3 -G, L 1 -OH, L 1 -Q, L 1 -QL 2 -G, NH2, O - or O-CH3; and

[0048] R 3 are independently: CH3, CH2-CH3 or O - .

[0049] In yet another further embodiment, the compound is a small molecule having a formula selected from:

[0050]

[0051] In another embodiment, the compound is for use in positron emission tomography (PET) imaging and has the formula:

[0052]

[0053] In another further embodiment, the compound is a theranostic compound having a formula selected from:

[0054]

[0055]

[0056] In yet another further embodiment, the compound is a dual targeting theranostic compound having the formula:

[0057]

[0058] In another embodiment, the compounds are configured for use in PET imaging and therapeutic radioligand therapy.

[0059] In another further embodiment, the disease binding ligand G is conjugated to the compound via a method selected from the group consisting of coupling chemistry, peptide coupling chemistry, copper-catalyzed azide-alkyne cycloaddition (CuAAC) and solid phase peptide synthesis (SPPS).

[0060] In yet another embodiment, 3p-C-NETA is constructed with 177 Lu chelation for therapeutic use; DOTA and DOTAGA are constructed to 177 Lu or 225 Ac chelation is used for treatment; and DOTA and DOTAGA are constructed to 68 Ga, 89 Zr or 64 Cu chelation for PET imaging.

[0061] Another embodiment includes a method for synthesizing a radiopharmaceutical compound, the method comprising: providing a fluorinated silicon compound comprising a heteroaromatic ring; and conjugating a disease binding ligand G to the fluorinated silicon compound to form the radiopharmaceutical compound; wherein the heteroaromatic ring is selected from the group consisting of: pyridine, pyridinium, pyridinium, pyrazole, fused pyrazole derivatives, benzofuran, benzothiophene, indole, azaindole, imidazole, and pyrimidine;

[0062] Wherein the pyridine, pyridine oxide or pyridinium compound has the following formula I:

[0063]

[0064] The pyrazole compound has the following formula II:

[0065]

[0066] The fused pyrazole derivative compound has the following formula III:

[0067]

[0068] Wherein the benzofuran, benzothiophene, indole or azaindole compound has the following formula IV:

[0069]

[0070] The imidazole compound has the following formula V:

[0071]

[0072] The pyrimidine compound has the following formula VI:

[0073]

[0074] in:

[0075] Each F is independently: F or 18 F or 19 F;

[0076] each A is independently: H, CH3, CH2-CH3, CH3-CH2-CH(CH3), CH(CH3)2 and C(CH3)3;

[0077] Each U is independently: O-CH3, CH3, CH2CH3, H, I, Br, Cl, F, N(CH3)2, and CH2CH(NH2)CO2H;

[0078] Each X is independently: O, S and N;

[0079] Each Y is independently: C and N;

[0080] Each R 1 or R 2 or R 3 independently: CH3, CH2-CH3, H, L 1 -CH2-C≡C, L 1 -CH3, L 1 -G, L 1 -H, L 1 -L 2 -CH2-C≡C, L 1 -L 2 -CH3, L 1 -L 2 -G, L 1 -L 2 -H, L1 -L 2 -H2, 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 -N3, 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, NH2, O - , O - CH3, OH,

[0081]

[0082] Each L 1 or L2 or L 3 or L 4 or L 5 independently is: -(O-CH2-CH2) p -,-(CH2-CH2-O) p -,-(Glu-His) p -,-(His-Glu) p -,-(Glu-Trp) p -,-(Trp-Glu) p -,-NH-CH2-C6H4-NH-(C=O)-CH2-O-CH2-(C=O)-,-(C=O)-CH2-O-CH2-(C=O)-NH-C6H4-CH2-NH-,-(C=O)-CH2-CH2-(C=O)-,-NH-C5H9N-CH2-(C=O)-,-(C=O)-CH2-NC5H9-NH-,-(Gly) p -,-CH2-CH2-NH-,-NH-CH2-(C=O)-,-(Glu)-,-NH-CH2-CH2-,-(C=O)-,NH-CH2-CH2-(O-CH2-CH2) p -(C=O)-,-(C=O)-(CH2-CH2-O) p -CH2-CH2-NH-,-NH-(C=O)-CH2-,-NH-(C=O)-NH-CH2-,-NH-(C=S)-NH-CH2-,-NH-(CH2-CH2-O) p -CH2-(C=O)-,-(C=O)-CH2-(O-CH2-CH2) p -NH-,-Asp-,-NH-,-NH-(CH2-CH2-O) p -CH2-CH2-(C=O)-,-(C=O)-CH2-CH2-(O-CH2-CH2) p -NH-,-CH2-(C=O)-,-(C=O)-CH2-,-O-(C=O)-,-(C=O)-O-,-CH2-O-,-NH-(C=O)-O-,-O-(C=O)-NH-,-(C=O)-CH2-(O-CH2-CH2) p-O-CH2-(C=O)-, -NH-(C=O)-NH-, -NH-(C=S)-NH-, -CH2-N(CH3)-CH2-, -N(CH3)-, -(C=O)-C6H4-(C=O)-, -C6H4-(C=O )-, -(C=O)-C6H4-, -O-CH2-(C=O)-, -(C=O)-CH2-O-, -CH2-C2N3-CH2-, -CH2-CH2-(C=O)-, -(C=O)-CH2-CH2-, -CH2-N + (CH3)2-CH2-, -CH2-N(CH3)-, -(C=O)-CH2-(O-CH2-CH2) p -、-(CH2-CH2-O) p -CH2-CH2-NH-, or

[0083] p = 0 to 12;

[0084] 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; and

[0085] Each Q is a chelating agent.

[0086] In yet another further embodiment, each Q is independently: -DOTA, -DOTAGA, -Dap(DOTA), -Lys(DOTA), -3p-C-NETA, -di-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, -deferoxamine B (DFO) mesylate, -deferoxamine-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-H4octapa, -HEHA-NCS, or -Macropa-NCS.

[0087] Another additional embodiment further comprises chelating Q with M, wherein M is a cation of a metal selected from: 43 Sc, 44 Sc, 45 Sc, 47 Sc, 51 Cr, 52m Mn, 68 Co. 52 Fe, 56 You, 57 You, 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 Such as 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 2. 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, and including 18 The cationic molecules of F and 18 F[AlF] 2+ .

[0088] In another embodiment, A is C(CH3)3.

[0089] In yet another embodiment, G has a formula selected from:

[0090]

[0091]

[0092] wherein Z is H, CH3 or CF3.

[0093] In yet another embodiment,

[0094] R 1 Independently: CH3, H, L 1 -CH2-C≡C, L 1 -CH3, L 1 -H, L 1 -L 2 -CH2-C≡C, L 1 -L 2 -CH3, L 1 -L 2 -G, L 1 -L 2 -H, L 1 -L 2 -H2, 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 -N3, L 1 -L 2 -OH, L 1 -L 2 -Q, L 1 -L 2 -QL 3 -L 4 -G, L 1 -OH, L1 -Q, L 1 -QL 2 -L 3 -L 4 -G, NH2, O-CH3, OH,

[0095] R 2 Independently: CH3, H, L 1 -CH2-C≡C, L 1 -G, L 1 -H, L 1 -L 2 -CH2-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 -N3, L 1 -L 2 -Q, L 1 -L 2 -QG, L 1 -L 2 -QL 3 -G, L 1 -OH, L 1 -Q, L 1 -QL 2 -G, NH2, O - or O-CH3; and

[0096] R 3 are independently: CH3, CH2-CH3 or O - .

[0097] In another further embodiment, the radiopharmaceutical compound is a small molecule having a formula selected from:

[0098]

[0099] In yet another embodiment, the radiopharmaceutical compound is for use in positron emission tomography (PET) imaging and has the formula:

[0100]

[0101] In yet another embodiment, the radiopharmaceutical compound is a theranostic compound having a formula selected from:

[0102]

[0103]

[0104] In yet a further embodiment, the radiopharmaceutical compound is a dual targeted theranostic compound having the formula:

[0105]

[0106] In yet a further embodiment, the radiopharmaceutical compound is configured for use in PET imaging and therapeutic radioligand therapy.

[0107] In yet a further embodiment, the conjugation is via a method selected from the group consisting of coupling chemistry, peptide coupling chemistry, copper-catalyzed azide-alkyne cycloaddition (CuAAC), and solid phase peptide synthesis (SPPS).

[0108] Yet another further embodiment further comprises mixing 3p-C-NETA with 177 Lu chelation is used for treatment; DOTA and DOTAGA are used with 177 Lu or 225 Ac chelation for treatment; and DOTA and DOTAGA with 68 Ga, 89 Zr and 64 Cu chelate is used for PET imaging.

[0109] Other embodiments and features are described in part in the following description, and in part will become apparent to those skilled in the art after reading the specification, or may be learned by practicing the present disclosure. The nature and advantages of the present disclosure may be further understood by reference to the remainder of the specification and the accompanying drawings, which form a part of the present disclosure. BRIEF DESCRIPTION OF THE DRAWINGS

[0111] This description will be more fully understood with reference to the following drawings, which are presented as exemplary embodiments of the invention and should not be construed as being a complete depiction of the scope of the invention, wherein:

[0112] Figure 1 Explain the prior art 68 Ga-DOTA-TATE and 177Structure of Lu-DOTA-TATE.

[0113] Figure 2 Explain the prior art 68 Ga-PSMA-617 and 177 Structure of Lu-PSMA-617.

[0114] Figure 3 An example HPLC chromatogram in a HetSiFA hydrolytic stability assay according to one embodiment of the present invention is illustrated.

[0115] Figure 4 The structure of pyridine-HetSiFA and its properties according to one embodiment of the present invention are explained.

[0116] Figure 5 The hydrolytic stability and radiochemical conversion (RCC) of pyridyl-HetSiFA according to one embodiment of the present invention are explained.

[0117] Figure 6 The hydrolytic stability and radiochemical conversion (RCC) of pyridyl-HetSiFA according to one embodiment of the present invention are explained.

[0118] Figure 7 The structure of N-modified pyridine-HetSiFA according to one embodiment of the present invention and its properties are explained.

[0119] Figure 8 The structure of pyrazole-HetSiFA and its properties according to one embodiment of the present invention are explained.

[0120] Fig. 9 The hydrolytic stability and radiochemical conversion (RCC) of pyrazole-HetSiFA according to one embodiment of the present invention are explained.

[0121] Fig.10 The structure of [6+5]-fused-HetSiFA according to one embodiment of the present invention and its properties are explained.

[0122] Fig.11 The structures and properties of fused-HetSiFA, furan-HetSiFA, and pyrrole-HetSiFA according to one embodiment of the present invention are explained.

[0123] Fig.12 The synthesis of a novel molecule comprising HetSiFA and a disease binding ligand according to one embodiment of the present invention is explained. 18 Schematic representation of F-labeled PET imaging tracers.

[0124] Fig.13A synthetic scheme for a pyrazole-HetSiFA building block for conjugation to a disease binding ligand on a resin according to one embodiment of the present invention is explained.

[0125] Fig.14 Explain that according to one embodiment of the present invention, the TATE conjugated 18 Structure of F-labeled HetSiFA, which is used for PET imaging of SSTR2 in cancer.

[0126] Fig.15 Explain that according to one embodiment of the present invention, JR11 is conjugated 18 Structure of F-labeled HetSiFA, which is used for PET imaging of SSTR2 in cancer.

[0127] Fig.16 A scheme for synthesizing a theranostic pair comprising a HetSiFA-chelator construct and a disease binding ligand according to one embodiment of the present invention is explained.

[0128] Fig.17 The structure of a HetSiFA-chelator construct capped with a biologically inactive moiety used in the assay according to one embodiment of the present invention is illustrated.

[0129] Fig.18 A synthetic scheme for the HetSiFA theranostic agent FTX-165, according to one embodiment of the present invention, is explained.

[0130] Fig.19 The formation of HetSiFA-chelator-ligand constructs of chemically identical PET diagnostic and RLT therapeutic agents according to one embodiment of the present invention is explained.

[0131] Fig. 20 According to one embodiment of the present invention, 18 Radiolabeling results of F-FTX-165.

[0132] Fig.21 Explained according to one embodiment of the present invention, in healthy mice 18 F- In vitro biodistribution data of FTX-165.

[0133] Fig. 22 Explain that according to one embodiment of the present invention, the radiolysis indicator 18 Radiolabeling results of F-FTX-164.

[0134] Fig.23 According to one embodiment of the present invention, 18 Radiolabeling results of F-FTX-181.

[0135] Fig.24 Explained according to one embodiment of the present invention, in healthy mice 18 F-In vitro biodistribution data of FTX-181.

[0136] Fig.25 Explained according to one embodiment of the present invention, in healthy mice 18 F-PET image of FTX-181.

[0137] Fig.26 The results of an HSA binding assay of HetSiFA compounds according to one embodiment of the present invention are explained.

[0138] Figures 27A-27N Various theranostic HetSiFA pairs according to one embodiment of the present invention are explained.

[0139] Fig.28 A dual targeting theranostic HetSiFA pair according to one embodiment of the present invention is explained.

[0140] Fig.29 A synthetic scheme of PPI-24069 / FTX-175 according to one embodiment of the present invention is explained.

[0141] Fig.30 A synthetic scheme of PPI-24073 / FTX-181 according to one embodiment of the present invention is explained.

[0142] Fig.31 A synthetic scheme of PPI-24082 / FTX-219 according to one embodiment of the present invention is explained. DETAILED DESCRIPTION OF THE INVENTION

[0144] In the description of the embodiments, reference may be made to the accompanying drawings which form a part of this article: and therein are shown by way of example specific embodiments in which the present invention may be put into practice. 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 technical terms, symbols and other scientific terms or special terms used herein are intended to have the meanings commonly understood by those skilled in the art to which the present invention belongs. In some cases, for clarity and / or for ease of reference, terms with commonly understood meanings are defined herein, and the inclusion of such definitions herein is not necessarily interpreted as representing considerable differences compared to the common understanding of the art. Many aspects of the techniques and procedures described or mentioned herein are fully understood and generally adopted by those skilled in the art. Exemplary embodiments of the present invention are provided below.

[0145] 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 the 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, preferred methods and materials are described.

[0146] As used herein, each of the following terms has the meaning associated with it in this section.

[0147] The articles "a" and "an" are used herein to refer to one or more than one (eg, at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

[0148] "About" and "approximately" are used to describe and explain minor variations. When used in conjunction with an event or circumstance, the term can represent a situation in which the event or circumstance occurs exactly, as well as a situation in which the event or circumstance occurs to close proximity. When used in conjunction with a numerical value, the term can represent a range of variation less than or equal to ±10% of the 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%.

[0149] In addition, amount, ratio and other numerical value may be presented in this article with range format sometimes.Should be understood that such range format is used for convenience and brevity, and should be flexibly understood to include the numerical value that is clearly indicated as range boundary, and include all individual numerical values ​​or subranges that are included in the range, as clearly indicating each numerical value and subrange.For example, the ratio in the range of about 1 to about 200 should be understood to include the boundary of about 1 and about 200 that are clearly listed, and 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, and the like.

[0150] The term "pharmaceutically acceptable" as used herein refers to materials such as carriers or diluents that do not abrogate the biological activity or properties of a compound and are relatively nontoxic, i.e., the material can be administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any component of a composition containing the material. For compositions suitable for administration to humans, the term "pharmaceutically acceptable" is intended to include, but is not limited to, those ingredients described in Remington: The Science and Practice of Pharmacy, Lippincott Williams & Wilkins, 21st edition (2006).

[0151] The wording "pharmaceutically acceptable salt" used herein means the salt of the compound administered prepared from a pharmaceutically acceptable non-toxic acid (including an inorganic acid, an organic acid, a solvate thereof, a hydrate or a clathrate). The example of such an inorganic acid is hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid and hexafluorophosphoric acid. Suitable organic acid can be selected from organic acids such as aliphatic, aromatic, carboxylic acid and sulfonic acids, and its example is 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, p-toluenesulfonic acid, glycolic acid, glucuronic acid, maleic acid, furoic acid, glutamic acid, benzoic acid, anthranilic acid, salicylic acid, phenylacetic acid, mandelic acid, pamoic acid (pamoic acid), methanesulfonic acid, ethanesulfonic acid, pantothenic acid, benzenesulfonic acid (benzenesulfonate), stearic acid, p-aminobenzenesulfonic acid, alginic acid, galacturonic acid etc. Additionally, pharmaceutically acceptable salts include, by way of non-limiting example, alkaline earth metal salts (eg, calcium or magnesium), alkali metal salts (eg, sodium-based or potassium), and ammonium salts.

[0152] As used herein, unless otherwise specified, the term "imaging agent", "imaging probe" or "imaging compound" refers to a molecule that can be detected by its emitted signal (such as positron emission, autofluorescence emission or optical properties). The detection method of the compound may include, but is 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 a combination thereof, depending on the intended use and the imaging methods available to the medical or researcher.

[0153] The term "biomolecule" as used herein refers to any molecule produced by a living organism and may be selected from proteins, peptides, polysaccharides, carbohydrates, lipids, and the like and fragments thereof.

[0154] Unless otherwise indicated, the terms "bioconjugate" and "conjugation" used herein refer to the chemical derivatization of a macromolecule with another molecular entity. 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, 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, coumarin, metal chelators or any other modifying groups. The terms bioconjugate and conjugation are used interchangeably throughout this specification.

[0155] As used herein, unless otherwise indicated, the term "alkyl" by itself or as part of another substituent refers to a radical having the specified number of carbon atoms (e.g., C 1-6 refers to a straight or branched hydrocarbon of 1 to 6 carbon atoms), and includes straight, branched or cyclic substituents. Examples include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, pentyl, neopentyl, hexyl and cyclopropylmethyl.

[0156] The term "substituted alkyl" as used herein refers to an alkyl as defined above, substituted by one, two or three substituents selected from the group consisting of halogen, -OH, alkoxy, -NH2, -N(CH3)2, -C(=O)OH, trifluoromethyl, -C≡N, -C(=O)O(C1-C4)alkyl, -C(=O)NH2, -SO2NH2 and -C(=NH)NH2. Examples of substituted alkyl include, but are not limited to, 2,2-difluoropropyl, 2-carboxycyclopentyl and 3-chloropropyl.

[0157] As used herein, unless otherwise indicated, the term "heteroalkyl" by itself or in combination with other terms means a stable straight or branched chain alkyl group consisting of the stated number of carbon atoms and 1 or 2 heteroatoms selected from O, N and S, and wherein the nitrogen and sulfur atoms may be optionally oxidized, and the nitrogen heteroatom may be optionally quaternized. The heteroatom 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, as well as attached to the farthest carbon atom in the heteroalkyl group.

[0158] As used herein, unless otherwise indicated, the term "alkoxy," employed alone or in combination with other terms, refers to an alkyl group as defined above having the specified number of carbon atoms, attached to the remainder of the molecule through an oxygen atom, for example, methoxy, ethoxy, 1-propoxy, 2-propoxy (isopropoxy) and higher homologs and isomers.

[0159] As used herein, unless otherwise stated, the terms "halo" or "halogen," by themselves or as part of another substituent, refer to a fluorine, chlorine, bromine, or iodine atom.

[0160] As used herein, the term "aromatic" refers to a carbocyclic or heterocyclic ring having one or more polyunsaturated rings and having aromatic characteristics, for example having (4n+2) delocalized π (pi) electrons, where n is an integer.

[0161] As used herein, unless otherwise indicated, the term "aryl", used alone or in combination with other terms, refers to a carbocyclic aromatic system containing one or more rings (usually one, two or three rings), wherein such rings may be attached together in a pendant manner, such as biphenyl, or may be fused, such as naphthalene. Examples of aryl groups include phenyl, anthracenyl and naphthyl.

[0162] The term "substituted" as used herein refers to that an atom or a group of multiple atoms has replaced the hydrogen connected as a substituent with another group. The term "substituted" further represents any level of substitution, i.e., mono-, di-, tri-, tetra- or penta-substitution, as long as such substitution is allowed. Substituents are independently selected, and substitution can be at any chemically accessible position. In one embodiment, the number of the substituents varies between 1 and 4. In another embodiment, the number of the substituents varies between 1 and 3. In yet another embodiment, the number of the substituents varies between 1 and 2.

[0163] As used herein, the term "optionally substituted" means that the group mentioned may be substituted or unsubstituted. In one embodiment, the group mentioned is optionally substituted with 0 substituents, for example, the group mentioned is unsubstituted. In another embodiment, the group mentioned is optionally substituted with one or more additional groups, which are individually and independently selected from the groups described herein.

[0164] Scope: 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 only for convenience and brevity and should not be interpreted as an immutable limitation on the scope of the invention. Therefore, the description of a range should be considered to have explicitly disclosed all possible subranges and each numerical value within the range. For example, a description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges, such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6, etc., and each number within the range, for example, 1, 2, 2.7, 3, 4, 5, 5.3 and 6. This applies regardless of the width of the range.

[0165] Systems and methods of heteroaromatic silicon fluoride acceptor (HetSiFA) systems with theranostic properties are described. Many embodiments include systems and methods of HetSiFA systems with theranostic capabilities to provide conjugates that bind to biological targets overexpressed in cancer. Theranostics have the combined capabilities of diagnostic PET imaging and therapeutic radioligand therapy (RLT). Theranostics according to several embodiments can have the same chemical structure and contain a heteroaromatic silicon fluoride acceptor system (for 18F incorporation for PET diagnostic agents) and chelators (for incorporation with radioactive metals for RLT). In many embodiments, the theranostic pairs can allow for diagnosis and treatment of patients with various types of metastatic cancer, including but not limited to metastatic prostate cancer.

[0166] In many embodiments, various HetSiFA compounds can be used for imaging. In several embodiments, the HetSiFA compounds can be used for PET imaging. The HetSiFA compounds can include heteroaryl rings substituted with various side chains, linkers, and disease targeting ligands for PET imaging.

[0167]

[0168] Where: F is F, 18 F or 19 F; each A is independently: H, methyl, ethyl, sec-butyl, isopropyl and tert-butyl.

[0169] In many embodiments, various HetSiFA compounds can be used in theranostics. In several embodiments, the HetSiFA compounds can include a single disease binding ligand that targets a receptor overexpressed on cancer cells. Single-target theranostic compounds can include heteroaryl rings substituted with various side chains, linkers, disease targeting ligands, and chelators for radiometallation.

[0170]

[0171] Where: F is F, 18 F or 19 F; each A is independently: H, methyl, ethyl, sec-butyl, isopropyl and tert-butyl.

[0172] In many embodiments, various HetSiFA compounds can be used in theranostics. In several embodiments, the HetSiFA compounds can include two disease binding ligands as dual-target theranostic compounds. The two disease binding ligands can target different overexpressed receptors on cancer cells. The dual-target theranostic compounds can include heteroaryl rings substituted with various side chains, linkers, disease targeting ligands, and chelators for radiometallation.

[0173]

[0174] Where: F is F, 18 F or 19 F; each A is independently: H, methyl, ethyl, sec-butyl, isopropyl and tert-butyl.

[0175] In many embodiments, the HetSiFA compound may include a heteroaryl ring, including but not limited to pyridine, pyridinium, pyrazole, fused pyrazole, benzofuran, benzothiophene, indole, azaindole, imidazole and pyrimidine. It can be easily understood that according to various embodiments of the present invention, any type of heteroaryl ring can be appropriately used according to the requirements of a specific application.

[0176] In certain embodiments, the HetSiFA compound may include a heteroaryl ring such as pyridine or pyridinium or a salt thereof:

[0177]

[0178] Or the HetSiFA compound may include a heteroaryl ring such as pyrazole or a salt thereof:

[0179]

[0180] Or the HetSiFA compound may include a heteroaryl ring such as a fused pyrazole derivative or a salt thereof:

[0181]

[0182] Or the HetSiFA compound may include a heteroaryl ring such as benzofuran, benzothiophene, indole, azaindole or a salt thereof:

[0183]

[0184] Or the HetSiFA compound may include a heteroaryl ring such as imidazole or a salt thereof:

[0185]

[0186] Or the HetSiFA compound may include a heteroaryl ring such as pyrimidine or a salt thereof:

[0187]

[0188] in:

[0189] F is independently: F or 18 F or 19 F;

[0190] A is independently: H, CH3, CH2-CH3, CH3-CH2-CH(CH3), CH(CH3)2 and C(CH3)3;

[0191] U is independently: O-CH3, CH3, CH2CH3, H, I, Br, Cl, F, N(CH3)2, and CH2CH(NH2)CO2H;

[0192] X is independently: O, S and N;

[0193] Y is independently: C and N;

[0194] R 1 or R 2 or R 3 independently: CH3, CH2-CH3, H, L 1 -CH2-C≡C, L 1 -CH3, L 1 -G, L 1 -H, L 1 -L 2 -CH2-C≡C, L 1 -L 2 -CH3, L 1 -L 2 -G, L 1 -L 2 -H, L 1 -L 2 -H2, 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 -N3, L 1 -L 2 -OH, L 1 -L 2 -Q, L 1 -L 2 -QG, L 1 -L 2 -QL 3 -G, L 1 -L2 -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, NH2, O - 、O-CH3、OH、 L 1 or L 2 or L 3 or L 4 or L 5 Independently: -(O-CH2-CH2) p -、-(CH2-CH2-O) p -、-(Glu-His) p -、-(His-Glu) p -、-(Glu-Trp) p -、-(Trp-Glu) p -, -NH-CH2-C6H4-NH-(C=O)-CH2-O-CH2-(C=O)-, -(C=O)-CH2-O-CH2-(C=O)-NH-C6H4-CH2 -NH-, -(C=O)-CH2-CH2-(C=O)-, -NH-C5H9N-CH2-(C=O)-, -(C=O)-CH2-NC5H9-NH-, -(Gly) p -, -CH2-CH2-NH-, -NH-CH2-(C=O)-, -(Glu)-, -NH-CH2-CH2-, -(C=O)-, NH-CH2-CH2-(O-CH2-CH2) p -(C=O)-, -(C=O)-(CH2-CH2-O) p -CH2-CH2-NH-, -NH-(C=O)-CH2-, -NH-(C=O)-NH-CH2-, -NH-(C=S)-NH-CH2-, -NH-(CH2-CH2-O) p -CH2-(C=O)-, -(C=O)-CH2-(O-CH2-CH2) p -NH-, -Asp-, -NH-, -NH-(CH2-CH2-O) p-CH2-CH2-(C=O)-, -(C=O)-CH2-CH2-(O-CH2-CH2) p -NH-, -CH2-(C=O)-, -(C=O)-CH2-, -O-(C=O)-, -(C=O)-O-, -CH2-O-, -NH-(C=O)-O-, -O-(C=O)-NH-, -(C=O)-CH2-(O-CH2-CH2) p -O-CH2-(C=O)-, -NH-(C=O)-NH-, -NH-(C=S)-NH-, -CH2-N(CH3)-CH2-, -N(CH3)-, -(C=O)-C6H4-(C=O)-, -C6H4-(C=O )-, -(C=O)-C6H4-, -O-CH2-(C=O)-, -(C=O)-CH2-O-, -CH2-C2N3-CH2-, -CH2-CH2-(C=O)-, -(C=O)-CH2-CH2-, -CH2-N + (CH3)2-CH2-, -CH2-N(CH3)-, -(C=O)-CH2-(O-CH2-CH2) p -、-(CH2-CH2-O) p -CH2-CH2-NH-,

[0195] p = 0 to 12;

[0196] G is a disease binding ligand, wherein each G is independently:

[0197] Somatostatin receptor type 2 (SSTR2) binds to ligand G 1

[0198]

[0199] SSTR2 binds to ligand G 2

[0200]

[0201] SSTR2 binds to ligand G 3

[0202]

[0203] SSTR2 binds to ligand G 4

[0204]

[0205] Gastrin-releasing peptide receptor (GRPR) binds to ligand G 5

[0206]

[0207] wherein Z is H, CH3 or CF3;

[0208] GRPR binds to ligand G 6

[0209]

[0210] wherein Z is H, CH3 or CF3;

[0211] Prostate-specific membrane antigen (PSMA) binding ligand G 7

[0212]

[0213] PSMA-binding ligand G 8

[0214]

[0215] PSMA-binding ligand G 9

[0216]

[0217] PSMA-binding ligand G 10

[0218]

[0219] PSMA-binding ligand G 11

[0220]

[0221] Fibroblast activation protein (FAP) binding ligand G 12

[0222]

[0223] FAP-binding ligand G 13

[0224]

[0225] FAP-binding ligand G 14

[0226]

[0227] FAP-binding ligand G 15

[0228]

[0229] CXC chemokine receptor type 4 (CXCR-4) binding ligand G 16

[0230]

[0231] CXCR-4 binding ligand G 17

[0232]

[0233] Q is a chelating agent, wherein each Q is independently:

[0234] -DOTA

[0235] -DOTAGA

[0236] -Dap(DOTA)

[0237] -Lys(DOTA)

[0238] -3p-C-NETA

[0239] -Di-thiocarbazone Wherein R may be methyl (H2ATSM), or R may be NH2 (H2ATSM / A),

[0240] -EDTA

[0241] -CHX-A"-EDTA

[0242] -DTPA

[0243] -p-SCN-DPTA

[0244] -CHX-A”-DTPA

[0245] -p-SCN-Bz-Mx-DTPA

[0246] -NOTA

[0247] -TETA

[0248] -CB-TE2A Wherein R may be (C=O)-OH (CB-TE2A), or R may be P(O)(OH)2 (CB-TE1A1P),

[0249] -p-SCN-NOTA(cNOTA)

[0250] -nNOTA

[0251] -NODAGA

[0252] -p-SCN-DOTA(cDOTA)

[0253] -2-cTETA

[0254] -6-cTETA

[0255] -BAT

[0256] -Diamsar

[0257] -SarAr

[0258] -PCTA

[0259] -NODIA-Me

[0260] -TRAP

[0261] -pycup1a1b Wherein R may be phenyl (pycup1A1B), or R may be (C=O)OH (pycup2A),

[0262] -p-SCN-DTPA

[0263] -Deferoxamine B (DFO) mesylate

[0264]

[0265] -Deferoxamine-p-SCN

[0266]

[0267] -DFO-Star(DFO*) -L5

[0268] -Orn3hx-NCS Where n = 1,

[0269] -Orn4hx-NCS Where n = 2,

[0270] -p-SCN-Bn-HOPO -2,3-HOPO-p-Bn-NCS

[0271]

[0272] -YM103 Where R is

[0273] -Tc(V)oxo

[0274] -Tc(V) Nitride

[0275] -Tc(V)HYNIC

[0276] -Tc(I)-fac-tricarbonyl

[0277] -Tc(VII) trioxo

[0278] -3p-C-NETA-NCS

[0279] -3p-C-DEPA-NCS

[0280] -TCMC

[0281] -p-SCN-Bn-H4octapa

[0282] -HEHA-NCS

[0283] -Macropa-NCS

[0284] In certain embodiments, Q may be unchelated. In several embodiments, Q may be optionally chelated with a metal cation M, wherein M is a cation of: 43 Sc, 44 Sc, 45 Sc, 47 Sc, 51 Cr, 52m Mn,68 Co、 52 Fe、 56 Aunt, 57 Aunt, 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 Through, 111 OF, 113 Through, 133m Through, 114m Through, 117m Sn、 121 Sn、 127 The、 142 Pr、 143 Pr、 149 Pm、 151 Pm、 149 Tb、 155 Tb、 153 Sm、 157 Gd、 161 Tb、 166 You、 165 Dy、 169 Er、 169 Yb、 175 Yb、 172 Tm、 176 Head, 177 Head, 177m Head, nat Head, 186 Re、 188 Re、 191 Pt、 197 Hg、 198 Shout, 199 Shout, 212 Pb、 203Pb, 204 Pb, 206 Pb, 207 Pb, 208 Pb, 211 At 209 Bi, 212 Bi, 213 Bi, 223 Ra, 225 Ac, 227 Th, 232 Th, and including 18 Cationic molecules such as F 18 F[AlF] 2+ The following non-limiting examples illustrate chelating agents that chelate metal cations. It can be easily understood that any of the above chelating agents can be chelated in a similar manner. The chelated Q can be:

[0285] DOTA with M Chelate:

[0286] DOTAGA chelated with M:

[0287] Dap(DOTA) chelated with M:

[0288] Lys(DOTA) chelated to M: and

[0289] 3p-C-NETA chelated with M:

[0290] In several embodiments, various small molecule HetSiFA compounds can be used to synthesize radiopharmaceuticals. During the synthesis process, different types of disease binding ligands and / or chelators can be attached to the small molecule HetSiFA compounds to achieve their respective applications. In certain embodiments, the small molecule HetSiFA compound can have the following formula:

[0291]

[0292] Various HetSiFA compounds can be used for PET imaging. Different types of disease binding ligands are conjugated to radioactively labeled HetSiFA compounds. In several embodiments, the HetSiFA compound for PET imaging can have the following formula:

[0293]

[0294] Various HetSiFA compounds are theranostic compounds. Different types of disease binding ligands are conjugated to radioactively labeled HetSiFA compounds. The theranostic compounds have the same chemical structure but differ in the nuclide. The theranostic compounds can be used for PET imaging and / or as therapeutic agents. In several embodiments, the theranostic HetSiFA compound can have the following formula:

[0295]

[0296]

[0297]

[0298] Various HetSiFA compounds are dual-targeted theranostic compounds. Two types of disease-binding ligands are conjugated to a radioactively labeled HetSiFA compound. The theranostic compounds can be used for PET imaging and / or as therapeutic agents. In several embodiments, the theranostic HetSiFA compound can have the following formula:

[0299]

[0300] 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, dynamic solubility, target binding affinity, and biodistribution in mice. In several embodiments, HetSiFAs containing heteroaromatic compounds (including, but not limited to, pyrazoles, pyridines, pyridine oxides, and azaindoles) exhibit better performance than phenyl-SiFAs in making radiopharmaceuticals. Various HetSiFAs containing heteroaromatic compounds (including, but not limited to, indoles, benzothiophenes, benzofurans, furans, and pyrroles) exhibit less favorable performance than pyrazoles, pyridines, pyridine oxides, and azaindoles.

[0301] HetSiFA, including but not limited to, pyrazole-HetSiFA, pyridine-HetSiFA, pyridine oxide-HetSiFA, and azaindole-HetSiFA, can be conjugated to a disease binding ligand. Examples of disease binding ligands include but are not limited to somatostatin receptor type 2 (SSTR2) binding ligands (such as G 1 , G 2 , G 3 and G 4 ), gastrin releasing peptide receptor (GRPR) binding ligands (such as G 5 and G 6 ), prostate-specific membrane antigen (PSMA) binding ligands (such as G7 , G 8 , G 9 , G 10 and G 11 ), fibroblast activation protein (FAP) binding ligands (such as G 12 , G 13 , G 14 and G 15 ) and CXC chemokine receptor type 4 (CXCR-4) binding ligands (such as G 16 and G 17 ) to form 18 Precursors of F-PET tracers. 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).

[0302] Prostate cancer cells may become PSMA-negative during the malignancy process in the stage of metastatic castration-resistant prostate cancer (mCRPC).GRPR is a member of the G-protein coupled receptor superfamily and is a part of the bombesin receptor family.GRPR can be a potential specific target for different malignancies because it is overexpressed in various malignant entities, including neuroblastoma, lung cancer, pancreatic cancer, gastric cancer, colorectal cancer, esophageal cancer, breast cancer and prostate cancer.This overexpression of GRPR and its fairly low expression in normal organs and healthy tissues make the receptor a promising diagnostic and therapeutic target for PET and RLT, respectively.In view of the expression patterns and GRPR overexpression of different PSMA and GRPR in the cell membrane of prostate cancer and prostate intraepithelial neoplasms compared with healthy prostate tissue and benign prostatic hyperplasia, the use of therapeutic diagnostic radiopharmaceuticals targeting GRPR can be applicable to patients who are unresponsive to PSMA therapeutic diagnosis and may be PSMA-negative.

[0303] In many embodiments, systems and methods of theranostic HetSiFA systems with dual targeting capabilities are described. The HetSiFA system can be conjugated to two different disease binding ligands to target receptors overexpressed on cancer cells. The dual targeting capability can improve accuracy in imaging and / or treatment. In certain embodiments, the HetSiFA system can be conjugated to dual disease binding ligands for the receptors PSMA and GRPR for imaging and treatment of metastatic prostate cancer. In certain embodiments, the HetSiFA system can be conjugated to dual disease binding ligands for the receptors GRPR and SSTR2 for imaging and treatment of metastatic breast or lung cancer.

[0304] According to certain embodiments, various HetSiFA compounds can be conjugated to small molecules (or so-called caps) that have no biological function. The resulting compounds can be used in radiolabeling experiments and / or other assays.

[0305] HetSiFA combined with metal chelators can be made into HetSiFA for theranostic use. Many embodiments provide various HetSiFA compounds that can be conjugated with chelators, including but not limited to DOTA, DOTAGA, Dap(DOTA), Lys(DOTA), 3p-C-NETA, AAZTA, di-thiosemicarbazone, H2ATSM, H2ATSM / 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, N ODIA-Me, TRAP, pycup1A1B, pycup2A, p-SCN-DTPA, deferoxamine, deferoxamine B, deferoxamine B (DFO) mesylate, deferoxamine-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-H4octapa, HEHA-NCS, Macropa-NCS.

[0306] The chelating agent can increase 18 According to certain embodiments, the combination of HetSiFA and metal chelators can be used in non-therapeutic diagnostic applications. 18 In F-PET imaging radiopharmaceuticals. Chelating agents can be added to increase the overall polarity of the HetSiFA moiety. In certain embodiments, the chelating agent can remain free without any metal ions attached. In several embodiments, the chelating agent can chelate with non-radioactive metals, including (but not limited to) nat Ga and nat Lu.

[0307] In many embodiments, the chelating agent can chelate with a metal cation. Each chelating agent can chelate with a cation selected from the following: 43 Sc, 44 Sc, 45 Sc, 47 Sc, 51 Cr, 52m Mn, 68 Co. 52 Fe, 56 You, 57 You, 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 Such as 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 2. 169 Yb, 175 Yb, 172 Tm, 176 Lu, 177 Lu, 177m Lu, 186 Re, 188Re, 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, and including 18 Cationic molecules such as F 18 F[AlF] 2+ .

[0308] In many embodiments, 3p-C-NETA chelators can be labeled for therapeutic use with radionuclides including, but not limited to, 177 Lu. 3p-C-NETA can be used efficiently 177 Lu labeling to form in about 5 minutes at room temperature 177 Lu-3p-C-NETA complex. In many embodiments, DOTA and DOTAGA chelators can be labeled with radionuclides for PET imaging applications, including but not limited to 68 Ga, 89 Zr or 64 Cu. In several embodiments, DOTA and DOTAGA chelators may be labeled with nuclides for therapeutic use, including but not limited to 177 Lu or 225 Ac. DOTA- and DOTAGA- 177 Lu-labeling can occur at about 95°C for about 15-45 minutes.

[0309] In many embodiments, amino acid spacers can be added to the HetSiFA tracer. In certain embodiments, amino acid spacers 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 enhance the affinity of the HetSiFA tracer for the target receptor and obtain better in vivo imaging performance.

[0310] In many embodiments, the HetSiFA-chelator construct can be conjugated to a disease binding ligand to form a precursor for theranostic applications. According to certain embodiments, the HetSiFA-derived theranostic pairs can be identical twins with true "see it, treat it" capabilities. The diagnostic and therapeutic pairs have the same chemical composition, but different nuclides.

[0311] HetSiFA Compound Properties

[0312] Many embodiments provide therapeutic diagnostic 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, dynamic solubility, target binding affinity, and biodistribution properties in mice.

[0313] In many embodiments, pyrazole-HetSiFA compounds have desired radiolabeling properties, dynamic solubility, chemical versatility, hydrophilicity, and in vivo stability. Pyridine-HetSiFA according to certain embodiments have desired hydrophilicity and chemical versatility. In certain embodiments, azaindole-HetSiFA has desired radiolabeling properties, hydrolytic stability, and chemical versatility. Each property and the characterization of each property are briefly described below.

[0314] a) Hydrophilicity. Hydrophilicity is related to the strength of solubility or absorption in aqueous solutions. It 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 need there is to mask the lipophilicity in the radiopharmaceutical by introducing cumbersome and lengthy linkers. The hydrophilicity of the HetSiFA can be assessed by calculating and / or measuring the octanol / water partition coefficient, logP. LogD measures the lipophilicity of an ionizable compound, where the partition is a function of pH. Reverse phase HPLC retention time t R It can be used to qualitatively compare the polarity of HetSiFA.

[0315] b) Hydrolytic stability. 18 The F bond can be easily hydrolyzed in aqueous media, leading to the formation of silanols. The molecular design of HetSiFA can affect the Si- 18The hydrolytic stability of the F bond. The hydrolytic stability of the synthesized HetSiFA can be checked in a carbonate buffer (0.1M aqueous solution, 0.05M mixture) at pH 10. The HetSiFA substrate (100 μM, in 1:1 MeCN / pH 10 carbonate buffer) was aged at room temperature (25°C). At different time points, the substrate was quantified by HPLC UV monitoring. HetSiFA was dissolved in 100 μM acetonitrile-aqueous buffer (pH 7.4 or 10) 1:1 mixture. Hydrolysis was monitored by HPLC (about 7 time points). The hydrolytic stability can be referred to as pH 10 stability and is reported as the half-life (t 1 / 2(pH10) ). Figure 3 The HPLC chromatograms of HetSiFA and hydrolyzed HetSiFA are explained according to one embodiment. Typical HPLC conditions: Phenomenex Prodigy ODS-3 column (250×4.6 mm, 10 μm), mobile phase: MeCN / H2O (0.1% HCO2H), gradient, 20:80 to 50:50 (15 min), hold (5 min), 0.8 mL / min. T=25° C. In addition, the stability of the compound can be evaluated in rat and human plasma and in microsomes.

[0316] c) Radiolabeling. In order for HetSiFA-based PET tracers to be clinically useful, they need to be radiolabeled with a high radiochemical yield (RCY). Low amounts of radioactivity can be used to assess the radiolabeling properties of synthetic HetSiFA. Radioactive thin layer chromatography (radio-TLC) is used to measure 18 F-fluoride incorporation or radiochemical conversion (RCC).

[0317] d) Chemical versatility. The presence of aromatic heterocycles allows HetSiFA to have different ring sizes, heteroatom cores, and substitution patterns. Modification of the HetSiFA core allows fine-tuning of steric and electronic properties as well as the addition of linkers and other functional groups.

[0318] E) Human serum albumin and plasma protein binding. Binding to plasma proteins such as human serum albumin (HSA) can affect the blood circulation time of radiopharmaceuticals and affect their ability to bind to biological targets. Using Chiralpak HSA columns, the HSA binding performance of HetSiFA can be evaluated by HPLC methods. In order to calibrate the HSA column, nine reference substances (which showed a 13% to 99% HSA binding range) were measured and a standard curve was established. The reference substances were p-benzyl alcohol (lit.HSA%=13.15), aniline (lit.HSA%=14.06), phenol (lit.HSA%=20.69), benzoic acid (lit.HSA%=34.27), carbamazepine (lit.HSA%=75.00), p-nitrophenol (lit.HSA%=77.65), estradiol (lit.HSA%=64.81), probenecid (95.00) and glibenclamide (lit.HSA%=99.00). The HSA % binding of the compounds was deduced from the standard curve. The plasma protein binding properties of HetSiFA can be assessed using mouse and human plasma proteins.

[0319] f) Dynamic solubility. Solubility is an important parameter affecting pharmacokinetic behavior. Dynamic solubility can be assessed in phosphate buffered saline (PBS) at pH 7.4.

[0320] 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 an iodine-125 labeled ligand in a dose-dependent manner.

[0321] h) Biodistribution in mice. In vitro biodistribution studies in mice reveal the distribution of the injected tracer in certain organs after a predetermined time post-injection (pi). In a typical in vitro biodistribution experiment, four healthy mice were injected with 3.7-10 MBq of 18 F-labeled HetSiFA tracer. One mouse was imaged with PET 10-90 minutes after injection and then euthanized. Three mice were imaged with PET 70-90 minutes after injection and then euthanized. Organs were weighed and activity was measured in a gamma counter.

[0322] Used for 18 F radiolabeled HetSiFA compound

[0323] Many embodiments provide for 18F radiolabeled HetSiFA arrays. In several embodiments, HetSiFA containing heteroaromatic compounds including, but not limited to, pyridine, pyridinium, pyridinium oxide, pyrazole, fused pyrazole, imidazole, pyrimidine, and azaindole exhibit better performance for preparing radiopharmaceuticals than phenyl-SiFA. Certain embodiments show that HetSiFA containing heteroaromatic compounds including, but not limited to, indole, benzothiophene, benzofuran, furan, and pyrrole exhibit poorer radiolabeling performance than phenyl-SiFA.

[0324] Figure 4 The structure of the pyridine-HetSiFA compound according to one embodiment of the present invention is illustrated. The hydrolytic stability at pH 10 is reported as the half-life of the Si-F bond at pH 10 (t 1 / 2(pH10) ). Reverse phase HPLC retention time t R It can be used to qualitatively compare the polarity of HetSiFA. Pyridyl-HetSiFA has a stronger polarity than phenyl-SiFA, as evidenced by the shorter t R This is consistent with the logP of the aromatic core (logP 吡啶 =0.65; logP 苯 =2.13). By 18 F-Yes- 19 F isotope exchange (SiFEx), 18 The percentage of F incorporation can be reported as percent radiochemical conversion (RCC).

[0325] Many embodiments show that the substitution effect can increase the stability of the Si-F bond. The methoxy group in the silicon ortho position will increase the stability of the Si-F. 3-(di-tert-butylfluorosilyl)-4-methoxypyridine has a slightly lower hydrolytic stability than phenyl-SiFA. 5-(di-tert-butylfluorosilyl)-6-methoxypyridine has a higher hydrolytic stability than phenyl-SiFA. Figure 5 The hydrolytic stability and radiochemical conversion (RCC) of pyridyl-HetSiFA according to one embodiment are explained.

[0326] Figure 6 The hydrolytic stability and radiochemical conversion (RCC) of pyridyl-HetSiFA according to one embodiment are explained. Figure 6 It is shown that the substituents at the para-position of silicon affect the stability of Si-F. Pyridine-HetSiFA is efficiently used 18 The radiochemical conversion (RCC) is comparable to that of phenyl-SiFA, with the RCC typically exceeding 80%.

[0327] Pyridine-HetSiFAs are chemically versatile and allow for extensive regioselective modification of the pyridine core, also by substitution on oxygen and nitrogen according to certain embodiments. Side chains with functional groups can be added to provide attachment points for disease binding ligands.

[0328] In many embodiments, the pyridine-HetSiFA is converted to the corresponding N-modified derivative to increase its polarity. Figure 7 The structure of a pyridyl N-modified HetSiFA compound according to one embodiment is explained. In many embodiments, the N-modified pyridine-HetSiFA provides a point of attachment at the nitrogen. Pyridine-oxides and pyridinium HetSiFA have stronger polarity than their pyridine counterparts. They are highly efficient for radiolabeling, but tend to decompose in solution over time.

[0329] Many embodiments provide pyrazole-HetSiFA compounds with better radiolabeling performance, dynamic solubility, and hydrophilicity. Compared with phenyl-SiFA, pyrazole-HetSiFA compounds are smaller and more polar (logP 吡唑 =0.26; logP 苯 =2.13). Figure 8 The structure of the pyrazole-HetSiFA compound according to one embodiment of the present invention is explained.

[0330] Up to three side chains can be attached to pyrazole-HetSiFA, thereby obtaining a wide variety of different molecules. Pyrazole-HetSiFA offers good chemical versatility.

[0331] The hydrolytic stability of pyrazole-HetSiFA evaluated in the pH 10 stability assay was relatively low. However, a pH 10 environment may not be reached in a physiological environment. Fig. 9 The hydrolytic stability and radiochemical conversion (RCC) of pyrazole-HetSiFA were explained. Fig. 9 It was shown that the substituents of pyrazole-HetSiFA can affect the hydrolytic stability.

[0332] Many embodiments provide [6+5]-fused-HetSiFA compounds with advantageous radiolabeling properties, hydrolytic stability, dynamic solubility, and hydrophilicity. Fig.10 The structure of a [6+5]-fused-HetSiFA compound according to one embodiment of the present invention is explained.

[0333] Several embodiments demonstrate that certain [6+5]-fused-HetSiFAs are efficiently radiolabeled, hydrolytically stable, and chemically versatile. [6+5]-fused-HetSiFAs are generally larger than pyrazole- and pyridine-HetSiFAs, but some are more polar than phenyl-SiFAs.

[0334] Many [6+5]-fused-HetSiFAs have an azaindole core. Azaindole-HetSiFAs according to certain embodiments can be well radiolabeled and exhibit high hydrolytic stability, depending on how the azaindole core is modified.

[0335] Certain embodiments show that the nitrogen of the pyridine moiety in the azaindole can be located at the 7-, 6-, 5-, or 4-position.Azaindole-HetSiFA offers high chemical versatility.

[0336] In certain embodiments, the azaindole is converted to its N-oxide or N-substituted form. Such modifications increase the polarity of the core. They are often efficiently radiolabeled at the expense of hydrolytic stability. Due to its large size and relatively low hydrophilicity, the azaindole has a small preference for the HetSiFA core as a radiopharmaceutical development.

[0337] Many embodiments show that indoles, benzothiophenes, and benzofurans have lower polarity than phenyl-SiFAs, and their chemical versatility may be lower. Certain furan- and pyrrole-HetSiFAs lack chemical versatility and have high lipophilicity. Certain furan-HetSiFAs radiolabel efficiently, but the stability of the Si-F bond is low. Certain pyrrole-HetSiFAs are less efficient in radiolabeling. 18 F-labeled. These compounds may not be ideal for HetSiFA radiopharmaceutical development.

[0338] Fig.11 The structures and properties of fused-HetSiFA, furan-HetSiFA, and pyrrole-HetSiFA according to one embodiment of the present invention are explained.

[0339] HetSiFA constructs for PET imaging

[0340] HetSiFA with different physicochemical and labeling properties can be conjugated with disease-targeting ligands to generate therapeutic targets. 18 The F-labeled precursor was used for PET imaging. Fig.12A schematic diagram of the synthesis of HetSiFA PET tracers according to one embodiment is explained. The disease targeting ligand can be conjugated through the N-terminus of the peptide on the resin. Any type of disease targeting ligand that can target cancer cells can be implemented, such as (but not limited to) peptides or peptide mimetics. 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 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 for conjugation can vary in physicochemical and labeling characteristics and can be screened for their radiolabeling, hydrolytic stability, binding affinity, and other properties. The conjugation can then be performed with 18 F HetSiFA-ligand constructs were radiolabeled for PET imaging, yielding doses for up to several hundred patients.

[0341] Fig.13 Shown is a synthetic scheme for a pyrazole-HetSiFA building block that can be conjugated to a disease binding ligand according to one embodiment of the present invention.

[0342] Fig.14 The structure of HetSiFA conjugated to TATE for PET imaging of SSTR2 according to one embodiment of the present invention is illustrated. Fig.15 HetSiFA conjugated to JR11 for PET imaging of SSTR2 according to one embodiment of the present invention is explained.

[0343] HetSiFA constructs for theranostics

[0344] For theranostic applications, HetSiFA can be combined with chelators for (radio)metal complexation. Fig.16A schematic diagram of the conjugation of a HetSiFA-chelator construct with a disease targeting ligand according to one embodiment is explained. The HetSiFA-chelator construct can be conjugated with a disease targeting ligand to generate a precursor for PET imaging and RLT as a theranostic pair. The disease targeting ligand can be conjugated through the N-terminus of a peptide on a resin. Any type of disease targeting ligand that can target cancer cells can be implemented, such as (but not limited to) a peptide or a peptide mimetic. Examples of targets for disease binding ligands include (but are not limited to): GRPR, PSMA, SSTR2, FAP, and CXCR4. HetSiFA with various aromatic cores including (but not limited to) pyrazole, pyridine, pyridinium, azaindole, imidazole, and pyrimidine can be applied. The HetSiFA-chelator construct can differ in terms of the aromatic core, polar linker, and chelator. The HetSiFA-chelator construct can affect the pharmacological properties of the HetSiFA-chelator-ligand construct. Candidates for conjugation can vary in physicochemical and labeling characteristics and can be screened for their radiolabeling, hydrolytic stability, binding affinity, and other properties. 18 F (for PET imaging) or 177 Lu / 225 Ac (for RLT) is used to label the conjugated candidate. In addition, the chelator can be labeled with other PET isotopes, including but not limited to: 68 Ga, 64 Cu or 89 Zr.

[0345] Historically, the development of theranostic pairs has required separate and lengthy development processes for both the imaging and therapeutic partners. Only one precursor is needed to make certain 68 Ga PET / 177 The fact that Lu is a therapeutic diagnostic pair may have contributed to their popularity. 18 F / 177 Lu pairs may need to be more readily available to increase 18 Use of F in theranostics. 18 F Substitution 68 Ga can improve patient care (through higher resolution imaging) and increase the availability of radiopharmaceuticals (through expansion). HetSiFA-chelator-derived precursors allow labeling with nuclides including but not limited to 18 F. 177 Lu or 225 Ac. If necessary, it may also be used 68 Ga or 64 Cu labeling for PET imaging.

[0346] In certain embodiments, HetSiFA combined with a metal chelator can be made into a theranostic HetSiFA. According to several embodiments, the compound of HetSiFA and a metal chelator can also be used as a non-therapeutic diagnostic 18 F-PET imaging radiopharmaceuticals. In such embodiments, a chelating agent may be added to reduce the overall polarity of the HetSiFA moiety. The chelating agent may be left empty, or may chelate a non-radioactive metal.

[0347] Chelators that can be conjugated to the 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 labeled with nuclides for use in PET ( 68 Ga or 64 Cu) or treatment ( 177 Lu or 225 Ac). 3p-C-NETA can also be conjugated to HetSiFA. Examples of chelating agents 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-H4octapa, HEHA-NCS, and Macropa-NCS.

[0348] The cations that can be chelated by the chelating group are 43 Sc, 44 Sc, 45 Sc, 47 Sc, 51 Cr, 52m Mn, 68 Co. 52 Fe, 56 You, 57 You,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 Through, 111 OF, 113 Through, 133m Through, 114m Through, 117m Sn、 121 Sn、 127 The、 142 Pr、 143 Pr、 149 Pm、 151 Pm、 149 Tb、 155 Tb、 153 Sm、 157 Gd、 161 Tb、 166 You、 165 Dy、 169 Er、 169 Yb、 175 Yb、 172 Tm、 176 Head, 177 Head, 177m Head, 186 Re、 188 Re、 191 Pt、 197 Hg、 198 Shout, 199 Shout, 212 Pb、 203 Pb、 204 Pb、 206 Pb、 207 Pb、 208 Pb、 211 And、 209Bi, 212 Bi, 213 Bi, 223 Ra, 225 Ac, 227 Th, 232 Th cation, or containing 18 Cationic molecules such as F 18 F[AlF] 2+ .

[0349] Fig.17 The structure of a biologically nonfunctional HetSiFA theranostic compound for use in a radiolabeled assay according to one embodiment of the present invention is illustrated.

[0350] Fig.18 A synthetic scheme of HetSiFA for theranostic targeting SSTR2 according to one embodiment of the present invention is explained.

[0351] Fig.19 The invention explains an SSTR2-ligand conjugated to a HetSiFA-chelator construct to form a HetSiFA-theranostic targeting SSTR2 according to one embodiment of the invention. nat Lu, the compound can be used 18 F labeling for PET diagnosis ( 18 F-Pyrazole-HetSiFA- 176 Lu-DOTAGA-TATE( 18 F-FTX-165)). When the chelating agent is empty, the compound can be used 177 Lu labeling for RLT ( 19 F-Pyrazole-HetSiFA- 177 Lu-DOTAGA-TATE( 177 Lu-FTX-165)). HetSiFA-derived theranostic pairs according to certain embodiments may be identical twins with true "see it, treat it" capabilities. The difference between the diagnostic and therapeutic pairs is in the nuclide, not the chemical composition. Fig.19 show, 18 F PET diagnostic agents and 177 Lu therapeutic agents differ only in their radiolabeling. Other theranostic pairs, such as 68 Ga-DOTA-TATE and 177 Lu-DOTA-TATE( Figure 1 ), are not chemically identical, and differ in the radiometal. Replacement of the radiometal can affect biodistribution, target affinity, metabolic stability, and other properties.

[0352] Fig. 20 Explains an embodiment of 18 F-labeled pyrazole-HetSiFA compounds 18 F - FTX-165. Fig. 20 Shows the compound 18 Radio-HPLC and radio-TLC chromatograms of F-pyrazole-HetSiFA-Lu-DOTAGA-TATE. RCC (low activity) equals about 80% (rTLC, 5 min). RCY (medium activity) equals about 54% (isolated). RCY (high activity) equals about 47% (isolated). Maximum isolated activity equals about 23.9 GBq (645 mCi). A m Greater than about 159 GBq / μmol (4.3 Ci / μmol).

[0353] Fig.21 Explains an embodiment of 18 F-pyrazole-HetSiFA-Lu-DOTAGA-TATE( 18 The in vitro biodistribution data of F-FTX-165) in healthy mice. The chemical structure of the compound is shown in Fig. 20 In vitro biodistribution data were obtained in 3 Balb / c female mice. Minimal bone uptake was observed, indicating that Si- 18 Sufficient stability of F key in the body.

[0354] Fig. 22 Explains an embodiment of 18 F-labeled pyridine-HetSiFA compound 18 F-FTX-164. Fig. 22 Shows the compound 18 Radio-HPLC and radio-TLC chromatograms of F-pyridine-HetSiFA-Lu-DOTAGA-TATE. When radiolabeled with a starting activity of about 77 GBq, the compound decomposed. RCC (low activity) equals about 65%. RCY (medium activity) equals about 15%. RCY (high activity) is less than about 1%. Radiolysis may have occurred.

[0355] It may be necessary to counteract the lipophilicity of HetSiFA in the radiopharmaceutical. Fig.23 Explains an embodiment of 18 F-labeled pyrazole-HetSiFA compounds. Fig.23 The compound Lu-DOTAGA- 18 F-Pyrazole-HetSiFA-PEG 12 -TATE( 18Radio-HPLC and radio-TLC chromatograms of F-FTX-181. Polyethylene glycol (PEG) chains were added to increase solubility and hydrophilicity. High activity yields of up to 41 GBq can be isolated. 18 F-labeled compound. RCC (low activity) equals about 75% (rTLC, 5 min). RCY (medium activity) equals about 31% (isolated). RCY (high activity) equals about 51% (isolated). Maximum isolated activity equals about 41 GBq (1.1 Ci). A m Greater than about 273 GBq / μmol (7.33 Ci / μmol).

[0356] Fig.24 Explains Lu-DOTAGA- 18 F-Pyrazole-HetSiFA-PEG 12 - In vitro biodistribution data of TATE in healthy mice. 18 The chemical structure of F-FTX-181 is as follows Fig.23 In vitro biodistribution data were obtained in 3 female Balb / c mice. 18 Compared with F-FTX-165, minimal bone uptake was observed, indicating that Si- 18 F bonds are sufficiently stable in vivo. This suggests that, in addition to Si- 18 Factors other than the hydrolytic stability of the F bond can also affect the Si- 18 Stability of F bonds in vivo. Enzymatic metabolism in the liver can promote defluorination of lipophilic HetSiFA, even those that are stable to hydrolysis. (See, e.g., 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). Favoring renal elimination of HetSiFA radiopharmaceuticals may help reduce hepatic defluorination. 18 Accumulation of F-FTX-181 in the liver was low, and it was cleared from non-target organs other than the gallbladder. 18 F-FTX-181 showed a promising biodistribution that warrants further development.

[0357] Fig.25 Explains the healthy mice 70-90 minutes after injection 18 F - Maximum intensity PET image of FTX-181.

[0358] (Het)SiFA are known to bind plasma proteins. Binding to plasma proteins can affect the blood circulation time of the radiopharmaceutical and affect its ability to bind to biological targets. HetSiFA can change the plasma protein binding properties in two ways: 1) The wide variety of heterocycles in chemical space enables the search for candidates with the desired plasma protein binding properties; 2) The HetSiFA portion that binds to plasma proteins can be placed in different parts of the radiopharmaceutical. HetSiFA can protrude from the radiopharmaceutical to make it more accessible to plasma proteins, or be "sandwiched" by other parts of the molecule to make it less accessible. The phenyl group in phenyl-SiFA has not been chemically modified to affect its plasma protein binding. Phenyl-SiFA is usually connected to the radiopharmaceutical through a side chain extending from the para position relative to the silicon substituent. Therefore, all phenyl-SiFAs extend outside the molecular framework, which makes "sandwich" constructions impossible.

[0359] Fig.26 The results of human serum albumin (HSA) binding assays of HetSiFA compounds according to one embodiment are explained. A standard curve can be first established using a reference compound (see, e.g., 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 HSA binding assay results include four HetSiFA therapeutic diagnostic compounds FTX-164, FTX-165, FTX-168 and FTX-181 (structures such as Fig.26 As shown in ) and two therapeutic agents Lutathera and Lu-NeoB. Fig.26 As shown in , the four HetSiFA compounds have a HSA% range from about 84% to about 98%. The experimental conditions for the HSA binding assay include: column: Chiralpak HSA (100×2.1 mm, 5 μm, catalog number HSA5LM-C0004), flow rate: 0.3 mL / min. Mobile phase: A-NH4OAc buffer (50 mM, pH=7), freshly prepared every day; 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 at a concentration of 0.5 mg / mL in i-PrOH / NH4OAc (50 mM) at pH=7, 50:50. For each sample, all measurements of retention time were performed in triplicate.

[0360] Exemplary embodiments

[0361] The following examples are put forward to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the 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 experiments below 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 errors and deviations should be accounted for.

[0362] Example 1: HetSiFA Compound

[0363] In certain embodiments, HetSiFA compounds may include pyridine rings with various side chains, linkers, and / or chelators. Examples of HetSiFA compounds may include: di(tert-butyl)(fluoro)(2-pyridyl)silane having the following structure:

[0364]

[0365] Di(tert-butyl)(fluoro)(2-methoxy-3-pyridyl)silane having the following structure:

[0366]

[0367] Di(tert-butyl)(fluoro)(4-pyridyl)silane having the following structure:

[0368]

[0369] Di(tert-butyl)(fluoro)(2-methoxy-4-pyridyl)silane having the following structure:

[0370]

[0371] Di(tert-butyl)(fluoro)(6-methoxy-3-pyridyl)silane having the following structure:

[0372]

[0373] Di(tert-butyl)(fluoro)(3-methoxy-4-pyridyl)silane having the following structure:

[0374]

[0375] Di(tert-butyl)(fluoro)(3-methoxy-2-pyridyl)silane having the following structure:

[0376]

[0377] Di(tert-butyl)(fluoro)(4-methoxy-3-pyridyl)silane having the following structure:

[0378]

[0379] Di(tert-butyl)(fluoro)(3-pyridyl)silane having the following structure:

[0380]

[0381] [2-({N-5-[di(tert-butyl)(fluoro)silyl]-4-methoxy-2-pyridylcarbamoyl}methoxy)ethoxy]acetic acid having the following structure:

[0382]

[0383] Tert-butyl {[(3-{5-[di(tert-butyl)(fluoro)silyl]-4-methoxy-2-pyridyl}ureido)methyl]carbonylamino}acetate having the following structure:

[0384]

[0385] N-methyl{5-[di(tert-butyl)(fluoro)silyl]-4-methoxy-2-pyridyl}amine having the following structure:

[0386]

[0387] 5-[Di(tert-butyl)(fluoro)silyl]-2-pyridylamine having the following structure:

[0388]

[0389] 5-[di(tert-butyl)(fluoro)silyl]-2-{[(2-carboxymethoxyethoxy)methyl]carbonylamino}-4-methoxy-1-pyridinium-1-oxide (olate) having the following structure:

[0390]

[0391] 5-[di(tert-butyl)(fluoro)silyl]-2-({[2-(tert-butoxycarbonylmethoxy)ethoxy]methyl}carbonylamino)-4-methoxy-1-pyridinium-1-oxide having the following structure:

[0392]

[0393] Di(tert-butyl)(fluoro)(4-methoxy-6-methyl-3-pyridyl)silane having the following structure:

[0394]

[0395] Di(tert-butyl)[6-(dimethoxymethyl)-3-pyridyl](fluoro)silane having the following structure:

[0396]

[0397] 5-[Di(tert-butyl)(fluoro)silyl]-2-pyridinol having the following structure:

[0398]

[0399] Tert-butyl [2-({N-5-[di(tert-butyl)(fluoro)silyl]-2-pyridylcarbamoyl}methoxy)ethoxy]acetate having the following structure:

[0400]

[0401] 3-[Di(tert-butyl)(fluoro)silyl]-1-methyl-1-pyridinium having the following structure:

[0402]

[0403] 4-[Di(tert-butyl)(fluoro)silyl]-1-methyl-1-pyridinium having the following structure:

[0404]

[0405] 5-[Di(tert-butyl)(fluoro)silyl]-4-methoxy-2-pyridylamine having the following structure:

[0406]

[0407] 5-[Di(tert-butyl)(fluoro)silyl]-2-({[2-(tert-butoxycarbonylmethoxy)ethoxy]methyl}carbonylamino)-1-pyridinium-1-oxide having the following structure:

[0408]

[0409] [2-({N-5-[di(tert-butyl)(fluoro)silyl]-2-pyridylcarbamoyl}methoxy)ethoxy]acetic acid having the following structure:

[0410]

[0411] {5-[di(tert-butyl)(fluoro)silyl]-4-methoxy-2-pyridyl}-N-methylamino-formic acid tert-butyl ester having the following structure:

[0412]

[0413] N-{5-[di(tert-butyl)(fluoro)silyl]-4-methoxy-2-pyridyl}acetamide having the following structure:

[0414]

[0415] (3-{5-[di(tert-butyl)(fluoro)silyl]-4-methoxy-2-pyridyl}thioureido)acetic acid having the following structure:

[0416]

[0417] [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:

[0418]

[0419] ((5-(di-tert-butylfluorosilyl)-4-methoxypyridin-2-yl)carbamoyl)glycine having the following structure:

[0420]

[0421] Tert-butyl 4-[N-(S)-1,2-di{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]butanoate having the following structure:

[0422]

[0423] (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]butanoylamino}propanoic acid having the following structure:

[0424]

[0425] (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:

[0426]

[0427] (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]propanoic acid having the following structure:

[0428]

[0429] {5-[di(tert-butyl)(fluoro)silyl]-2-pyridyl}-N-methylamino-formic acid tert-butyl ester having the following structure:

[0430]

[0431] N-(3-pyridyl)methyl 3-(3-{5-[di(tert-butyl)(fluoro)silyl]-4-methoxy-2-pyridyl}ureido)propanamide having the following structure:

[0432]

[0433] {N-5-[di(tert-butyl)(fluoro)silyl]-4-methoxy-2-pyridylcarbamoyl}(trimethylammonio)methane iodide having the following structure:

[0434]

[0435] N-{5-[di(tert-butyl)(fluoro)silyl]-4-methoxy-2-pyridyl}(dimethylamino)acetamide having the following structure:

[0436]

[0437] 3-{N-2-[2-({N-5-[di(tert-butyl)(fluoro)silyl]-4-methoxy-2-pyridylcarbamoyl}methoxy)ethoxy]ethylcarbamoyl}-3-({[4,7,10-tris(tert-butyloxycarbonylmethyl)-1,4,7,10-tetraaza-1-cyclododecyl]methyl}carbonylamino)propanoic acid having the following structure:

[0438]

[0439] 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-butyloxycarbonylmethyl)-1,4,7,10-tetraaza-1-cyclododecyl]methyl}carbonylamino)propanoate having the following structure:

[0440]

[0441] N-{5-[di(tert-butyl)(fluoro)silyl]-4-methoxy-2-pyridyl}[2-(2-azidoethoxy)ethoxy]acetamide having the following structure:

[0442]

[0443] 3-(3-{5-[di(tert-butyl)(fluoro)silyl]-4-methoxy-2-pyridyl}ureido)propanoic acid having the following structure:

[0444]

[0445] 2-Amino-5-[di(tert-butyl)(fluoro)silyl]-4-methoxy-1-pyridinium-1-oxide having the following structure:

[0446]

[0447] 3-[Di(tert-butyl)(fluoro)silyl]-2-methoxy-1-pyridinium-1-oxide having the following structure:

[0448]

[0449] 5-[Di(tert-butyl)(fluoro)silyl]-2-(tert-butoxycarbonylamino)-4-methoxy-1-pyridinium-1-oxide having the following structure:

[0450]

[0451] 5-[Di(tert-butyl)(fluoro)silyl]-4-methoxy-2-(2-propynylamino)-1-pyridinium-1-oxide having the following structure:

[0452]

[0453] 2-(N-tert-Butyloxycarbonyl-N-2-propynylamino)-5-[di(tert-butyl)(fluoro)silyl]-4-methoxy-1-pyridinium-1-oxide having the following structure:

[0454]

[0455] {5-[di(tert-butyl)(fluoro)silyl]-4-methoxy-2-pyridyl}-N-2-propynylamino-formic acid tert-butyl ester having the following structure:

[0456]

[0457] 4-[Di(tert-butyl)(fluoro)silyl]-3-methoxy-1-pyridinium-1-oxide having the following structure:

[0458]

[0459] 3-[Di(tert-butyl)(fluoro)silyl]-4-methoxy-1-pyridinium-1-oxide having the following structure:

[0460]

[0461] 5-[Di(tert-butyl)(fluoro)silyl]-2-methoxy-1-pyridinium-1-oxide having the following structure:

[0462]

[0463] 4-[Di(tert-butyl)(fluoro)silyl]-1-(tert-butoxycarbonylmethyl)-3-methoxy-1-pyridinium having the following structure:

[0464]

[0465] Tert-butyl {3-[di(tert-butyl)(fluoro)silyl]-4-oxo-1-pyridyl}acetate having the following structure:

[0466]

[0467] 3-[Di(tert-butyl)(fluoro)silyl]-1-(tert-butoxycarbonylmethyl)-4-methoxy-1-pyridinium bromide having the following structure:

[0468]

[0469] N-(3-pyridyl)methyl(3-{5-[di(tert-butyl)(fluoro)silyl]-4-methoxy-2-pyridyl}ureido)acetamide having the following structure:

[0470]

[0471] 5-[Di(tert-butyl)(fluoro)silyl]-2-pyridinylamino-formic acid tert-butyl ester having the following structure:

[0472]

[0473] 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:

[0474]

[0475] N-(3-pyridyl)methyl(3-{5-[di(tert-butyl)(fluoro)silyl]-4-methoxy-2-pyridyl}thioureido)acetamide having the following structure:

[0476]

[0477] Tert-butyl 3-(3-{5-[di(tert-butyl)(fluoro)silyl]-4-methoxy-2-pyridyl}ureido)propanoate having the following structure:

[0478]

[0479] Tert-butyl (3-{5-[di(tert-butyl)(fluoro)silyl]-4-methoxy-2-pyridyl}thioureido)acetate having the following structure:

[0480]

[0481] N-(3-pyridyl)methyl{5-[di(tert-butyl)(fluoro)silyl]-4-methoxy-2-pyridylamino}acetamide having the following structure:

[0482]

[0483] {5-[di(tert-butyl)(fluoro)silyl]-4-methoxy-2-pyridylamino}acetic acid having the following structure:

[0484]

[0485] Tert-butyl-5-[fluorobis(isopropyl)silyl]-4-methoxy-2-pyridylcarbamoyl having the following structure:

[0486]

[0487] N-2-propynyl{5-[di(tert-butyl)(fluoro)silyl]-4-methoxy-2-pyridyl}amine having the following structure:

[0488]

[0489] Tert-butyl (3-{5-[di(tert-butyl)(fluoro)silyl]-4-methoxy-2-pyridyl}ureido)acetate having the following structure:

[0490]

[0491] N-Benzyl{5-[di(tert-butyl)(fluoro)silyl]-4-methoxy-2-pyridylamino}acetamide having the following structure:

[0492]

[0493] N-{5-[di(tert-butyl)(fluoro)silyl]-4-methoxy-2-pyridyl}-N-butylsuccinamide having the following structure:

[0494]

[0495] N-Benzyl-N-{5-[di(tert-butyl)(fluoro)silyl]-4-methoxy-2-pyridyl}succinamide having the following structure:

[0496]

[0497] Tert-butyl 3-{N-5-[di(tert-butyl)(fluoro)silyl]-4-methoxy-2-pyridylcarbamoyl}propanoate having the following structure:

[0498]

[0499] 5-[Di(tert-butyl)(fluoro)silyl]-4-methoxy-2-pyridinylamino-formic acid tert-butyl ester having the following structure:

[0500]

[0501] In certain embodiments, HetSiFA compounds may include pyrazole rings with various side chains, linkers, and / or chelators. Examples of HetSiFA compounds may include: di(tert-butyl)(fluoro)(1-methyl-5-pyrazolyl)silane having the following structure:

[0502]

[0503] Di(tert-butyl)(fluoro)(5-pyrazolyl)silane having the following structure:

[0504]

[0505] Di(tert-butyl)(fluoro){1-[(2-methoxyethoxy)methyl]-5-pyrazolyl}silane having the following structure:

[0506]

[0507] Di(tert-butyl)(fluoro){1-[(2-methoxyethoxy)methyl]-4-methyl-5-pyrazolyl}silane having the following structure:

[0508]

[0509] {5-[di(tert-butyl)(fluoro)silyl]-1-methyl-3-pyrazolylamino}acetic acid having the following structure:

[0510]

[0511] N-(3-pyridyl)methyl{5-[di(tert-butyl)(fluoro)silyl]-1-methyl-3-pyrazolylamino}acetamide having the following structure:

[0512]

[0513] {5-[di(tert-butyl)(fluoro)silyl]-1-{2-[2-(tert-butoxycarbonylamino)ethoxy]ethyl}-3-pyrazolylamino}acetic acid having the following structure:

[0514]

[0515] 3-[Di(tert-butyl)(fluoro)silyl]-5-(carboxymethyl)-2,5-dimethyl-4,5,6,7-tetrahydro-2H-1,2,5-triazaindene-5-ium carboxylate having the following structure:

[0516]

[0517] N-(3-pyridyl)methyl{3-[di(tert-butyl)(fluoro)silyl]-2-methyl-4,5,6,7-tetrahydro-2H-1,2,5-triazaindan-5-yl}acetamide having the following structure:

[0518]

[0519] {3-[Di(tert-butyl)(fluoro)silyl]-2-methyl-4,5,6,7-tetrahydro-2H-1,2,5-triazaindan-5-yl}acetic acid having the following structure:

[0520]

[0521] [({5-[di(tert-butyl)(fluoro)silyl]-1-methyl-3-pyrazolylamino}methyl)carbonylamino]acetic acid having the following structure:

[0522]

[0523] 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:

[0524]

[0525] 3-[Fluorobis(isopropyl)silyl]-2-methyl-4,5,6,7-tetrahydro-2H-1,2,4-triazaindene-4-carboxylic acid tert-butyl ester having the following structure:

[0526]

[0527] 5-[Di(tert-butyl)(fluoro)silyl]-3-(tert-butoxycarbonylamino)-1-methylpyrazole having the following structure:

[0528]

[0529] ({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:

[0530]

[0531] 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-lutetriatricyclo[9.6.3.2 5,14 ]docosan-8-yl)acetamide:

[0532]

[0533] 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]butanoic acid having the following structure:

[0534]

[0535] 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-gallatricyclo[9.6.3.2 5,14 ]docosan-8-yl)butanoic acid:

[0536]

[0537] N-(3-pyridyl)methyl[({5-[di(tert-butyl)(fluoro)silyl]-1-methyl-3-pyrazolylamino}methyl)carbonylamino]acetamide having the following structure:

[0538]

[0539] [({5-[di(tert-butyl)(fluoro)silyl]-1-{2-[2-({(3,16,19-trioxo-2,17,18-trioxa-5,8,11,14-tetraaza-1-gallatricyclo[9.6.3.2 5,14 ]docosan-8-yl)methyl}carbonylamino)ethoxy]ethyl}-3-pyrazolylamino}methyl)carbonylamino]acetic acid methyl ester:

[0540]

[0541] Methyl ({[({5-[di(tert-butyl)(fluoro)silyl]-1-methyl-3-pyrazolylamino}methyl)carbonylamino]methyl}carbonylamino)acetate having the following structure:

[0542]

[0543] 1-{5-[di(tert-butyl)(fluoro)silyl]-1-methyl-3-pyrazolyl}-2,5-piperazinedione having the following structure:

[0544]

[0545] (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:

[0546]

[0547] [({5-[di(tert-butyl)(fluoro)silyl]-1-{2-[2-({[4,7,10-tris(tert-butyloxycarbonylmethyl)-1,4,7,10-tetraaza-1-cyclododecyl]methyl}carbonylamino)ethoxy]ethyl}-3-pyrazolylamino}methyl)carbonylamino]acetic acid methyl ester having the following structure:

[0548]

[0549] 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-gallatricyclo[9.6.3.2 5,14 ]docosan-8-yl)acetamide:

[0550]

[0551] (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:

[0552]

[0553] 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:

[0554]

[0555] 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:

[0556]

[0557] {5-[di(tert-butyl)(fluoro)silyl]-1-{2-[2-({[4,7,10-tris(tert-butyloxycarbonylmethyl)-1,4,7,10-tetraaza-1-cyclododecyl]methyl}carbonylamino)ethoxy]ethyl}-3-pyrazolylamino}acetic acid having the following structure:

[0558]

[0559] In certain embodiments, HetSiFA compounds may include azaindole rings with various side chains, linkers, and / or chelators. Examples of HetSiFA compounds may include: {2-[di(tert-butyl)(fluoro)silyl]-1-methyl-1H-1,7-diazaindan-5-yloxy}acetic acid having the following structure:

[0560]

[0561] {{2-[Di(tert-butyl)(fluoro)silyl]-1-methyl-1H-1,7-diazaindan-6-ylamino}acetic acid having the following structure:

[0562]

[0563] Di(tert-butyl)(fluoro)(1-{1-[(p-methoxyphenyl)methyl]-3-azetidinyl}-1H-1,7-diazaindan-2-yl)silane having the following structure:

[0564]

[0565] 2-[Di(tert-butyl)(fluoro)silyl]-1-methyl-1H-1,7-diazaindan-7-ium-7-oxide having the following structure:

[0566]

[0567] 2-[Di(tert-butyl)(fluoro)silyl]-1-methyl-1H-1,4-diazaindan-4-ium-4-oxide having the following structure:

[0568]

[0569] N-(3-pyridyl)methyl{2-[di(tert-butyl)(fluoro)silyl]-1-methyl-1H-1,7-diazaindan-5-yloxy}acetamide having the following structure:

[0570]

[0571] 2-[Di(tert-butyl)(fluoro)silyl]-1,4-dimethyl-1H-1,4-diazaindan-4-ium having the following structure:

[0572]

[0573] Di(tert-butyl)(fluoro)(6-methoxy-1-methyl-1H-1,7-diazaindan-2-yl)silane having the following structure:

[0574]

[0575] Tert-butyl {2-[di(tert-butyl)(fluoro)silyl]-1-methyl-1H-1,7-diazaindan-5-yloxy}acetate having the following structure:

[0576]

[0577] 2-[Di(tert-butyl)(fluoro)silyl]-1-methyl-1H-1,7-diazaindan-5-ol having the following structure:

[0578]

[0579] Tert-butyl 3-{2-[di(tert-butyl)(fluoro)silyl]-1H-1,7-diazaindan-1-yl}-1-azetidinecarboxylate having the following structure:

[0580]

[0581] N-methyl{2-[di(tert-butyl)(fluoro)silyl]-1-methyl-1H-1,4-diazaindan-5-yl}amine having the following structure:

[0582]

[0583] {2-[Di(tert-butyl)(fluoro)silyl]-1-methyl-1H-1,4-diazaindan-6-yl}-N-methylamino-formic acid tert-butyl ester having the following structure:

[0584]

[0585] {2-[Di(tert-butyl)(fluoro)silyl]-1-methyl-1H-1,4-diazaindan-5-yl}-N-methylamino-formic acid tert-butyl ester having the following structure:

[0586]

[0587] N-methyl{2-[di(tert-butyl)(fluoro)silyl]-1-methyl-1H-1,4-diazaindan-6-yl}amine having the following structure:

[0588]

[0589] Di(tert-butyl)(fluoro)[1-(2-methoxyethyl)-1H-1,4-diazaindan-2-yl]silane having the following structure:

[0590]

[0591] Di(tert-butyl)(fluoro)(5-methoxy-1-methyl-1H-1,7-diazaindan-2-yl)silane having the following structure:

[0592]

[0593] Example 2: HetSiFA compounds for therapeutic diagnosis

[0594] Figures 27A-27N A theranostic HetSiFA pair according to one embodiment of the present invention is explained. Fig.27A The structures of the GRPR-targeting HetSiFA theranostic agents FTX-216 and FTX-219 are shown. Fig.27B The structure of the pyridine-HetSiFA-DOTA-TATE theranostic pair is shown. Fig.27C The structure of the pyrazole-HetSiFA-DOTAGA-TATE theranostic pair is shown. Fig.27D The structure of the pyridine-HetSiFA-DOTAGA-TATE theranostic pair is shown. Fig.27E Pyrazole-HetSiFA-DOTAGA-(HE) i - Structure of TATE (i=1-3) theranostic pairs. Fig.27F Pyridine-HetSiFA-DOTAGA-(HE) i - Structure of TATE (i=1-3) theranostic pairs. Figure 27G Pyrazole-HetSiFA-DOTAGA-(HE) i - Structure of PSMA (i=0-3) theranostic pairs. Fig.27H Pyridine-HetSiFA-DOTAGA-(HE) i - Structure of PSMA (i=0-3) theranostic pairs. Fig.27I Pyrazole-HetSiFA-DOTAGA-(HE) i - Structure of P-PSMA (i=0-3) theranostic pairs. Fig.27JPyridine-HetSiFA-DOTAGA-(HE) i - Structure of P-PSMA (i=0-3) theranostic pairs. Figure 27K Pyrazole-HetSiFA-DOTAGA-(HE) i - Structure of GRPR (i=0-3) theranostic pairs. Figure 27L Pyridine-HetSiFA-DOTAGA-(HE) i - Structure of GRPR (i=0-3) theranostic pairs. Fig.27M Pyrazole-HetSiFA-DOTAGA-(HE) i - Structure of FAP (i=0-3) theranostic pairs. Fig.27N Pyridine-HetSiFA-DOTAGA-(HE) i - Structure of FAP (i=0-3) theranostic pairs.

[0595] Fig.28 A dual targeting theranostic HetSiFA pair according to one embodiment of the present invention is explained.

[0596] Example 3: HetSiFA Compounds 18 F-Radiolabeling Procedure

[0597] Although the following describes the general 18 F-radiolabeling procedure, but it will be readily appreciated that any radiolabeling procedure may be used to radiofluorinate the HetSiFA precursor molecule, such as one that relies on [ 18 F] azeotropic drying of fluoride. Before the start of the synthesis, the reaction vessel was charged with a solution of HetSiFA precursor (150 nmol) in anhydrous dimethyl sulfoxide (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 was captured in a QMA column (Sep-PakAccell Plus QMACarbonate Plus Light column, 46 mg, 40 μm, Waters) and pre-treated with 10 mL of ultrapure water. The column was dried by a nitrogen stream, rinsed with MeCN (10 mL), and dried again by a nitrogen stream. OH - -Cryptate in anhydrous MeCN (elution mixture) The active material was eluted from the QMA column into a pre-packed reactor. OH --Cryptate compounds, 222 (343 mg, 910 μmol, 1.1 eq., Sigma-Aldrich) and 1 M KOH (830 μL, 830 μmol, 1.0 eq., 99.99% semiconductor grade, Sigma Aldrich) were dissolved in water (10 mL) and aliquoted into Eppendorf vials (1 mL or 1.5 mL per vial). The contents of each vial were lyophilized to obtain a single dose of OH - The lower content vial will contain 91 μmol K222 and 83 μmol KOH and is typically used in manual radiolabeling experiments where fluid loss is minimal. The higher content vial will contain 137 μmol K222 and 125 μmol KOH and is typically used in automated radiolabeling experiments where fluid loss in the transfer lines is expected. OH - -Cryptates must be dissolved in anhydrous MeCN immediately before the synthesis begins, as they decompose in MeCN at room temperature. The reaction was kept at room temperature for 10 minutes. Formulation buffer (10 mL of phosphate buffered saline (PBS) pH 7.4, containing 0.5% (w / v) sodium ascorbate) was added to the reactor, and the resulting mixture was transferred through an HLB column (Oasis HLB column Plus Short, 225 mg adsorbent, 60 μm particle size, Waters) pretreated with 10 mL of water to a waste container. The reactor was rinsed with additional formulation buffer (10 mL), and all contents were transferred through the HLB column to the waste. The HLB column was washed with formulation buffer (10 mL) to the waste. The product was eluted from the column 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 was diluted with formulation buffer (20 mL). (See, e.g., Wurzer et al. EJNMM I radiopharm. chem. 6, 4 2021; the disclosure of which is incorporated herein by reference).

[0598] Example 4: Synthesis of HetSiFA compounds

[0599] The synthesis process of the pyrazole-HetSiFA compound is described in detail below. It can be easily understood that various HetSiFA compounds can be synthesized through similar processes.

[0600] Unless otherwise noted, otherwise use the commercially available reactants / reagents purchased from suppliers such as Sigma-Aldrich, TCI, Combi-Blocks, AK Scientific, Gelest, Ambeed, Macrocyclics, Chempep or AAPPTec without further purification. Unless otherwise mentioned, all reactions were carried out in air-dried (unless specified flame drying) reaction tubes / flasks at room temperature and under nitrogen / argon positive pressure. The Waters HPLC system equipped with diode array detector and ESI-MS detector was used to monitor the reaction. React in commercially available reagent grade solvents without further purification or drying solvent, unless mentioned in the program. If necessary, crude product was processed before purification.

[0601] Use under standard conditions Isolera one efficient and rapid purification system is used for reverse phase HPLC purification. A linear gradient of acetonitrile / water (10mM AmF or AmBic in deionized water) is used for elution. The solvent system is customized according to the polarity and stability of the compound, the flow rate used in the purification or the flow rate recommended by the manufacturer, and varies according to the size of the C18 column used. Compounds are collected by ultraviolet light or waters Mass Detector, ESI positive mode. The fractions containing the desired compound are combined, concentrated (rotary evaporator) to remove excess CH3CN, and the resulting aqueous solution is lyophilized to provide the desired material.

[0602] Nuclear magnetic resonance (NMR) spectra were recorded on a JEOL 400 MHz spectrometer. 1 H) was used as a chemical shift reference standard. The following solvents were used: CDCl3, methanol-d4, DMSO-d6, acetone-d6 and CD3CN. 1 H-NMR data: Chemical shifts (multiplicity, coupling constants, integration) are expressed in ppm downfield from tetramethylsilane. The following abbreviations are used in reporting NMR data: s, singlet; d, doublet; t, triplet; q, quartet; p, quintet; h, sextet; dd, double of doublets; ddd, double of doublets of doublets; dddd, double of doublets of doublets; dt, double of triplets; dtd, double of triplets of doublets; ddt, double of doublets of triplet; dq, double of quartets; dp, double of quintets; td, triple of doublets; qd, quintet of doublets; m, multiplet. The following abbreviations are used in reporting NMR data: br, broad; app, apparent, to describe certain singlets or certain multiplets where appropriate. First-order coupling constants are reported using Hz as the unit of frequency and are measured using the distance from the center of one peak to the center of another peak.

[0603] Unless otherwise stated, normal phase flash column chromatography purification on silica gel was performed under standard conditions using, but not limited to, any of the following instruments and auxiliary materials: SNAP column KP-Sil column 10g, 25g, 50g, 100g or 340g SP1 or SP2 purification system, and with Silica Rf normal phase column 12g, 24g, 40g, 80g, 120g, 220g or 330g Rf Teledyne Isco purification system. If the crude material is purified by vacuum-liquid chromatography (amplification procedure), industrial grade Supelco (Sigma Aldrich) silica gel is used as the stationary phase and adjusted with a large amount of hexanes before use. The solvent system is customized 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 provide the desired substance (mainly used for normal phase purification), or lyophilized after the fractions are concentrated under reduced pressure (mainly used for reverse phase purification to remove CH3CN), or the residue separated by normal phase (after reduced pressure evaporation) is suspended in CH3CN (drops) / water mixture, and then lyophilized, with the better physical appearance that is considered to be more suitable for producing the desired compound. The LCMS method is described as follows.

[0604] LCMS (Method 8B): Column: Waters Acquity UPLC CSH C18, 1.8 μm, 2.1 x 30 mm at 40°C; Gradient: 5% to 100% B in 5.2 minutes; Hold 100% B for 1.8 minutes; Run time = 7.0 min; Flow rate = 0.9 mL / min; Eluent: A = Milli-Q H2O + 10 mM ammonium formate pH = 3.8 (Am.F); Eluent B: Acetonitrile (no additives).

[0605] LCMS (Method 10A): Column: Waters Acquity UPLC CSH C18, 1.8 μm, 2.1 x 30 mm at 40°C; Gradient: 5% to 100% B in 2.0 minutes; Hold 100% B for 0.7 minutes; Run time = 2.7 minutes; Flow rate = 0.9 mL / min; Eluent: A = Milli-Q H2O + 10 mM ammonium formate pH = 3.8 (Am.F); Eluent B: Acetonitrile (no additives).

[0606] Synthesis of 1-(2-(2-azidoethoxy)ethyl)-3-nitro-1H-pyrazole (5a) and 1-(2-(2-azidoethoxy)ethyl)-5-nitro-1H-pyrazole (5b).

[0607]

[0608] To a flame-dried round-bottom flask was added 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 a 60% sodium hydride dispersion in mineral oil (797 mg, 19.9 mmol) was added portionwise. 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 warmed to room temperature.

[0609] After stirring at room temperature for 2 hours, the reactant was cooled to 0 ° C and slowly quenched with saturated aqueous ammonium chloride solution and the mixture was extracted with ethyl acetate. The aqueous phase was extracted with ethyl acetate for another 2 times. The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to provide a crude alkylated product. DMF (20.0mL) and sodium azide (2.38g, 36.4mmol) were added to the crude material obtained from the first step. The resulting mixture was heated to 80 ° C. After stirring at 80 ° C for 2 hours, the mixture was cooled to room temperature, and then poured into water and extracted with ethyl acetate. The water layer was extracted with ethyl acetate for another 3 times, and the combined organic layer was washed with saturated aqueous ammonium chloride solution, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude oil was purified by normal phase chromatography using a 25g SiO2 column and eluted with an ethyl acetate / hexane gradient. The product was eluted at 35% ethyl acetate and concentrated to provide 1-(2-(2-azidoethoxy)ethyl)-3-nitro-1H-pyrazole (5a, 2.11 g, 54%) as a clear liquid. 1 H-NMR (400MHz, CDCl3) δ7.56 (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):C7H 10 N6O3Na + [M+H] + Calculated value: 249.1, measured value: 249.2. Rt = 0.80 min.

[0610] Scale up. A flame-dried 3-necked round-bottom flask equipped with a mechanical stirrer, condenser and temperature probe was added with 4-methylbenzenesulfonic acid 2-(2-azidoethoxy)ethyl ester (3, 63.9 g, 224 mmol) (Delmas, AF et al., Angew. Chem. Int. ed., 2012, 51, 11320-11324) in DMF (290 mL), and then 3-nitro-1H-pyrazole (4, 26.6 g, 231 mmol) and potassium carbonate (63.2 g, 448 mmol) were added at room temperature. The resulting suspension was stirred and heated (externally) at 60 ° C for 90 min, maintaining an internal temperature (about 55 ° C).

[0611] Reaction mixture is cooled to room temperature, and mixture is diluted with ethyl acetate (400mL).This diluent is washed 3 times with water (150mL x 3) and distributed.The water layer ethyl acetate (400mL x 3) that merges is extracted, then the organic layer salt water pre-drying that merges, through Na SO Drying, filter and under reduced pressure concentrate to provide 60.4g rough light yellow liquid (rr is about 8:1, is conducive to the regioisomer of required N-alkylation).Rough liquid is used about 1.4kg SiO (using vacuum-liquid chromatography device) post by normal phase chromatography purification, and with required regioisomer 1-(2-(2-azidoethoxy)ethyl)-3-nitro-1H-pyrazoles (5a) ethyl acetate / hexanes gradient wash-out. The desired regioisomer eluted in a solution of approximately 50% ethyl acetate / hexanes to provide the desired pure regioisomer as a clear colorless liquid (11.5 g, 23%), and another fraction contained both regioisomers in a major:minor regioisomer ratio of approximately 85:15 (36.6 g, 72% combined). Note: We found that in a separate parallel reaction, the undesired regioisomer did not react in the subsequent reaction step (silylation) and could be better separated at the silylation stage; however, if desired, the impure fraction could be purified again using the same gradient to provide more of the desired regioisomer 1-(2-(2-azidoethoxy)ethyl)-3-nitro-1H-pyrazole (5a). The characterization of the pure 1-(2-(2-azidoethoxy)ethyl)-3-nitro-1H-pyrazole (5a) obtained here was consistent with a previous batch (small scale, see above).

[0612] Synthesis of 1-(2-(2-azidoethoxy)ethyl)-5-(di-tert-butylsilyl)-3-nitro-1H-pyrazole (6).

[0613]

[0614] Diisopropylamine (1.37 mL, 9.75 mmol) and THF (15.0 mL) were added to a flame-dried round-bottom flask. The solution was cooled to 0°C and n-butyllithium (2.5 M in hexanes, 3.57 mL, 8.93 mmol) was slowly added. The solution was stirred at 0°C for 30 minutes, then 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 hour, then di-tert-butylchlorosilane (1.67 mL, 8.18 mmol) was added at the same temperature. The cold bath was removed and the mixture was allowed to gradually warm to room temperature. After stirring for 21 hours, the mixture was cooled to 0°C and quenched with saturated ammonium chloride. It was extracted with ethyl acetate, washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude oil was purified by normal phase chromatography using a 25 g SiO column and eluted with an ethyl acetate / hexanes gradient. The product eluted in 15% ethyl acetate, which was then concentrated to provide 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, CDCl3) δ7.03 (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 N6O3Si + [M+H] + Calculated value: 369.2, measured value: 369.3. Rt = 1.73 min.

[0615] Scale up. 1-(2-(2-azidoethoxy)ethyl)-3-nitro-1H-pyrazole (5a, 14.3 g, 56.9 mmol) in THF (330 mL) was added to a flame-dried round-bottom flask equipped with a stirring rod. The solution was cooled to -78 ° C and diisopropylamine lithium (57.5 mL, 57.5 mmol) was slowly added over 40 minutes. The resulting mixture was stirred at -78 ° C for 1 hour, and then di-tert-butylchlorosilane (14.2 mL, 68.3 mmol) was added dropwise over 30 minutes at the same temperature. The reaction mixture was allowed to reach room temperature during the overnight (16 h) reaction by removing the cooling bath.

[0616] The mixture was cooled to 0 ° C and quenched with saturated ammonium chloride. It was extracted with ethyl acetate, pre-dried with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude oil was purified by normal phase chromatography using SiO2 column (vacuum-liquid chromatography device) and eluted with ethyl acetate / hexanes gradient (10-55%). The desired product was eluted in about 45% ethyl acetate, and the fraction containing the desired compound was concentrated under reduced pressure (the solution was immersed in a water bath of about 75 ° C) until the constant weight of the oil was observed, and the desired compound finally solidified after standing at room temperature. Finally, the desired compound was resuspended in an ACN / water mixture and lyophilized to provide 1-(2-(2-azidoethoxy)ethyl)-5-(di-tert-butylsilyl)-3-nitro-1H-pyrazole (6, 7.60g, 34%) as a yellow powder. The characterization of the desired compound obtained here is consistent with the previous batch (small scale, see above).

[0617] Synthesis of tert-butyl (2-(2-(5-(di-tert-butylsilyl)-3-nitro-1H-pyrazol-1-yl)ethoxy)ethyl)carbamate (7).

[0618]

[0619] 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 solution 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 slowly added. The reaction was stirred at room temperature for an additional 30 minutes, 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. (Warning: Vigorous bubbling was observed after the addition of trimethylphosphine. The reaction was exothermic after the addition of water). After the resulting mixture was stirred at room temperature for 30 minutes, the mixture was extracted with ethyl acetate, washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude oil was purified by normal phase chromatography using a 25 g SiO column and eluted with an ethyl acetate / hexanes gradient. The product eluted in 15% ethyl acetate, which was then concentrated to provide 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. 1H-NMR(400MHz,CDCl3)δ7.03(s,1H),4.69(br s,1H),4.49(t,J=5.7Hz,2H),4.11(s,1H),3.91(t,J=5.7Hz,2H),3.47(t,J=5.2Hz,2H),3.22(dd,J=10.1,5.0Hz,2H),1.41(s,9H),1.06(s,18H). LCMS (Method 10A):C 20 H 39 N4O5Si + [M+H] + Calculated value: 443.3, measured value: 443.4. Rt = 1.75 min.

[0620] Scale up. To 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) was added dropwise a solution of trimethylphosphine (1 M, 110 mL, 110 mmol) in THF at 0°C in a round bottom flask equipped with a stir bar. After the addition was complete, the reaction mixture was stirred at 0°C for an additional approximately 5 minutes or until bubbling ceased, and then stirred at room temperature for 1 hour. The reaction mixture was cooled to 0°C, H2O (83.5 mL) was slowly introduced into the reaction mixture, and then stirred at room temperature for an additional 30 minutes before starting the next step. 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, and the organic layer was washed thoroughly with water and then pre-dried with brine, dried over Na2SO4, filtered and concentrated under reduced pressure until constant weight, and then dried under high vacuum overnight to provide 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) which was considered pure enough for the next stage. The oil was used in the next step without purification. The LCMS characterization of the desired compound obtained here was consistent with the previous batch (small scale, see above).

[0621] Synthesis of tert-butyl (2-(2-(3-amino-5-(di-tert-butylsilyl)-1H-pyrazol-1-yl)ethoxy)ethyl)carbamate (8).

[0622]

[0623] 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 wet activated carbon, 48.2 mg, 45.3 μmol). The mixture was flushed with nitrogen before a hydrogen balloon was connected. The reaction mixture was stirred at room temperature under a hydrogen atmosphere. After stirring at room temperature for 19 hours, the reaction mixture was filtered through a celite pad and the filter cake was rinsed with methanol an additional 3 times. The filtrate was concentrated to provide 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 N4O3Si + [M+H] + Calculated value: 413.4, measured value: 413.6. Rt = 1.54 min.

[0624] Scale up. To a round-bottom flask equipped with a stirring bar, 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) was added. Using a good balloon (1 atmosphere), the solution was bubbled with nitrogen for 30 min, and then palladium (10% on activated carbon, 849 mg, 798 μmol) was added to the reaction mixture once. By connecting two layers of hydrogen balloons (1 atmosphere), the nitrogen atmosphere and saturated with hydrogen atmosphere were replaced, and the reaction mixture was then placed under vacuum (close the hydrogen balloon), then flushed with hydrogen (close the vacuum), and the cycle was repeated many times. After about 6 hours, another hydrogen balloon was connected to the reaction mixture to make it a double (two-layer) hydrogen balloon. The reaction mixture was stirred at room temperature for 36 h under a hydrogen atmosphere. After reaction 36h finishes, the hydrogen atmosphere of reaction mixture is replaced with nitrogen, then it is placed under vacuum (nitrogen is closed), and then flushed with nitrogen (vacuum is closed).This cycle is repeated many times.Reaction mixture is filtered through diatomite pad, and filter cake is rinsed with a large amount of methanol for another 3 times.The filtrate containing required product is concentrated under reduced pressure to provide rough (2-(2-(3-amino-5-(di-tert-butylsilyl)-1H-pyrazole-1-yl) ethoxy) ethyl) t-butyl carbamate (8,30.2g, 95%, 95% purity is determined by LCMS, method 10A)) as yellow oil, it can be used for next step without purification.The LCMS characterization of the required compound obtained here is consistent with previous batch (small scale, see above).

[0625] Synthesis of (1-(2-(2-((tert-butoxycarbonyl)amino)ethoxy)ethyl)-5-(di-tert-butylsilyl)-1H-pyrazol-3-yl)glycine (9).

[0626]

[0627] 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. The mixture was stirred at 0°C for 30 minutes, then sodium cyanoborohydride (276 mg, 4.17 mmol) was added, and the reaction mixture was then warmed to room temperature. After stirring at room temperature for 1 hour, the reaction mixture was concentrated under reduced pressure, and the crude residue was purified by reverse phase chromatography using a 40 g C18 column and eluted with a 10 mM ammonium formate / acetonitrile gradient. The product eluted in 55% ACN, which was concentrated to a suspension, diluted with water, then diluted with water and lyophilized over the weekend to provide (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 (400MHz, CD3CN) δ5.76 (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 N4O5Si + [M+H] + Calculated value: 471.3, measured value: 471.4. Rt = 1.46 min.

[0628] 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. The mixture was stirred at 0°C for 1 h, then sodium cyanoborohydride (2.40 g, 36.2 mmol) was added portionwise (about 500 mg each time) (caution). At the end of the addition, the mixture was stirred at 0°C for another 30 min. H2O (150 mL) was slowly added to the reaction mixture, 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 with ethyl acetate two more times. (Note: The aqueous layer obtained after extraction and the methanol-rich fraction after evaporation under reduced pressure were treated with bleach before disposal). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to provide (1-(2-(2-((tert-butoxycarbonyl)amino)ethoxy)ethyl)-5-(di-tert-butylsilyl)-1H-pyrazol-3-yl)glycine (9, 33.0 g, 82% purity as determined by LC 103-min run) as a white foam, which was used in the next step without purification. The characterization of the desired compound obtained here was consistent with the previous batch (small scale, see above).

[0629] Synthesis of (1-(2-(2-((tert-butoxycarbonyl)amino)ethoxy)ethyl)-5-(di-tert-butylfluorosilyl)-1H-pyrazol-3-yl)glycine (PPI-24068).

[0630]

[0631] 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 hours 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 eluted in 67% ACN, which was concentrated to a suspension, diluted with minimal ACN and lyophilized overnight to provide (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, CD3CN) δ5.77 (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), COOH proton signal is weak, and the NH proton at 4.54 ppm is very broad. 19 F-NMR (376 MHz, CD3CN) δ-181.96 (s). LCMS (Method 10A): C 22 H 42 FN4O5Si + [M+H] + Calculated value: 489.3, measured value: 489.4. C 22 H 40 FN4O5Si - [MH] - Calculated value: 487.3, measured value: 487.4. Rt = 1.43 min.

[0632] 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). Effervescence and exotherm (about 5 °C from room temperature) were observed after addition of potassium fluoride and crown ether.

[0633] After stirring at room temperature for 2 hours, think that reaction ends.Reaction mixture is concentrated under reduced pressure, and thick residue is distributed between a large amount of ethyl acetate and water.Water layer is extracted with ethyl acetate twice more and the organic layer merged is through Na SO Drying, filter and concentrate under reduced pressure.Crude residue is used 400g C18 post by reverse phase chromatography purification, and with 10mM ammonium formate / acetonitrile gradient (0-55%) wash-out required compound.Product wash-out is in about 45% ammonium formate.Interested fraction is collected and concentrated to remove as much acetonitrile / water as possible, and then divided (two fractions) according to purity.Smaller second fraction (about 5g, about 80% purity) is used identical gradient but slower elution rate is re-purified, and 120gC18 post is used to replace 400g C18 post. Overall, after two separate purifications, (1-(2-(2-((tert-butoxycarbonyl)amino)ethoxy)ethyl)-5-(di-tert-butylfluorosilyl)-1H-pyrazol-3-yl)glycine (PPI-24068, 21 g, ca. 30% over 4 steps, ca. 93% purity as determined by LC 103-min run) was obtained as a white powder after freeze drying. The characterization of the desired compound obtained here was consistent with a previous batch (small scale, see above). Note: This compound exhibits some instability after long-term storage, and attempts to purify the title compound using a gradient of 10 mM AmB and ACN in deionized water under alkaline media were unsuccessful.

[0634] 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).

[0635]

[0636] 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 minutes, the reaction mixture was cooled to room temperature and then concentrated to provide the Boc deprotected intermediate (not shown). The reaction was concentrated under reduced pressure and the residue was resuspended in about 50 mL of DCM, sonicated and then concentrated under reduced pressure, and the cycle was repeated another 3 times to provide a colorless gum, and the gum was further dried in vacuum overnight and then used in the next step (Fmoc coupling) without purification. The gum was dissolved in DCM (70.0 mL), Fmoc chloride (3.10 g, 11.7 mmol) was added in two equal portions (one portion was added before adding DIPEA, and the other portion was added after adding about 4 equivalents of DIPEA, or added when half of the process was completed) at 0°C, and N,N-diisopropylethylamine (DIPEA) (8.00 mL, 45.5 mmol) was added portionwise every 15 to 30 minutes (about 1.0 mL was added every about 15 to 30 minutes). The reaction progress was followed using LC10 until SM was completely consumed.

[0637] After keeping for about 3h at 0°C, the reaction mixture was diluted with a large amount of DCM and washed with saturated aqueous ammonium chloride solution. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by reverse phase chromatography (C18, 120g) and eluted with a 50-100% 10mM ammonium formate / acetonitrile gradient. The title compound was eluted in 90-100% ACN, and then the fractions were concentrated and lyophilized to provide N-(((9H-fluorene-9-yl)methoxy)carbonyl)-N-(1-(2-(2-((((9H-fluorene-9-yl)methoxy)carbonyl)amino)ethoxy)ethyl)-5-(di-tert-butylfluorosilyl)-1H-pyrazole-3-yl)glycine (PPI-24069, 2.90g, 56%, about 95% purity was determined by LCMS, method 10A). It was used for peptide coupling without further purification. LCMS (Method 10A): C 47 H 54 FN4O7Si + [M+H] + Calculated value: 833.4, measured value: 833.6. Rt = 2.01 min.

[0638]

[0639] Resin activation and first amino acid coupling. PPI-24073 was synthesized on the solid phase using an Fmoc-based protocol. In a glass reactor with a frit, 2-chlorotrityl chloride resin (10, 1.2 mmol / g, 100-200 mesh, 12 mmol) was swollen in dichloromethane, drained, and activated by shaking in 100 mL of dichloromethane for 10 min, and drained again. Fmoc-Thr(tBu)-OH (8.60 g, 21.0 mmol) was dissolved in dichloromethane (80 mL) in a separate flask, DIPEA (12.6 mL, 72 mmol) was added, and the solution was mixed for 5 minutes (sonication was performed to aid dissolution). This was then poured into the activated 2-chlorotrityl chloride resin (10) and reacted by shaking for 4.5 hours. Methanol (20 mL, HPLC grade) was then added and the mixture was shaken for 30 minutes (this step was performed to cap unreacted resin, if any). The reaction vessel was evacuated and the resin was washed with dichloromethane (2 X 120 mL), DMF (2 X 120 mL), methanol (2 X 120 mL), and again with dichloromethane (2 X 120 mL). Resin 11 was used in the next step.

[0640]

[0641] Peptide chain extension. Resin 11 was treated twice with a mixture of piperidine and DMF (1:2 ratio) for 45 minutes each time to remove the Fmoc group protection. The Kaiser test showing a positive test confirmed the Fmoc removal. After washing the resin with DMF (2X 120mL), methanol (2X 120mL) and dichloromethane (2X 120mL) in sequence. Fmoc-Cys(Trt)-OH (1.5 equivalents) was preactivated with HATU (1.5 equivalents), HOAt (1.5 equivalents) and DIPEA (4 equivalents) in DMF (100mL), and the resulting solution was then added to the reaction vessel containing the resin and shaken at room temperature for at least 4 hours to perform 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 then coupled to the peptide sequence to give 12. The resin was then washed with DMF (2X 120 mL), methanol (2X 120 mL) and dichloromethane (2X 120 mL). If necessary, the reaction was paused after amino acid coupling and the air-dried resin was stored in a refrigerator. The sequence was restored after the resin was activated for 30 minutes using DCM.

[0642] Kaiser test solution formula: [(0.5 g ninhydrin / 10 mL ethanol) + 0.4 mL, 0.001 M KCN ​​aqueous solution / 20 mL pyridine]. The two solutions were mixed in a 1:1 ratio, the resin was suspended and heated to observe the color of the resin.

[0643]

[0644] PEG12-linker coupling. Resin 12 (1.2 mmol / g, 0.4 mmol) was treated twice with a 1:2 mixture of piperidine and DMF (3 mL) to remove the Fmoc group protection, followed by washing 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), and the resulting solution was added to the reaction vessel containing the resin and shaken overnight at room temperature. The resin was then washed with DMF (2X 120 mL), methanol (2X 120 mL) and dichloromethane (2X 120 mL). The reaction was confirmed to be complete by a negative Kaiser test.

[0645]

[0646] Peptide bridge formation.In a glass reactor, resin 13 (1.2mmol / g, 0.4mmol) suspended in DMF (20.0mL) was added portionwise to a stirred solution of iodine (500mg, 1.97mmol) in DMF (40.0mL) for 30min. The whole mixture was gently shaken at room temperature for 4 hours. The resin was then drained and DMF (3X 20mL) and DCM (3X 20mL) were used to wash off excess iodine. After a small amount of deprotection mixture containing TFA was treated overnight, a small amount of resin was analyzed using LCMS.

[0647]

[0648] 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).

[0649] 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, followed by washing with DMF, methanol and dichloromethane (positive Kaiser test). PPI-24069 (1.0 eq) was preactivated with HATU (1.0 eq), HOAt (1.0 eq) and DIPEA (2.7 eq) in DMF (3 mL), and the resulting solution was added to the reaction vessel containing the resin and shaken at room temperature overnight. Resin 15 was then washed with DMF (2×10 mL), methanol (2×10 mL) and dichloromethane (2×10 mL).

[0650] Completion of the reaction was confirmed by a negative Kaiser test.

[0651]

[0652] 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 remove the Fmoc group protection, followed by washing with DMF, methanol and dichloromethane (positive Kaiser test). DOTAGA-tetra(t-Bu)-COOH (1.4 eq.) was preactivated with HATU (1.4 eq.), HOAt (1.4 eq.) and DIPEA (3.8 eq.) in DMF (3 mL), and the resulting solution was added to the reaction vessel containing the resin and shaken overnight at room temperature. Resin 16 was then washed with DMF (2X 10 mL), methanol (2X 10 mL) and dichloromethane (2X 10 mL). The reaction was confirmed to be complete by a negative Kaiser test.

[0653]

[0654] The peptide was deprotected and removed 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 Synthesis of triacetic acid (PPI-24074) : 1-(4-(di-tert-butylfluorosilyl)-1H-pyrazol-1-yl)- ...

[0655] Resin 16 was treated with a pre-prepared deprotection mixture (15 mL, 446 μmol) at room temperature overnight as follows. The solvent was collected by filtration and reduced on a rotary evaporator. The peptide was precipitated by adding cold ether, centrifuged and the solid was washed twice with cold ether to obtain the desired peptide product PPI-24074 (650 mg, 59% yield). The resulting solid was analyzed using LCMS and used as is for the next step.

[0656] LCMS (Method 8B): EM=C 112 H 178 FN 19 O 36 S2Si; [M+2H] 2+ Calculated value = 1239.1, found = 1239.5; [M+3H] 3+ Calculated value = 826.4, found = 826.4; [M-2H] 2- Calculated value = 1237.1, measured value = 1237.5; Rt = 2.02min.

[0657] Deprotection mixture: [88% TFA + 5% water + 5% phenol + 2% triisopropylsilane].

[0658]

[0659] Formation of Lutetium Chelate (PPI-24073). To a solution of PPI-24074 (50.0 mg, 20.2 μmol) in DMSO (1.00 mL) was added LuCl3 aqueous solution (250 μL, 200 mM) 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 reverse phase column (C18, 30 g) with a gradient elution of 10 mM ammonium formate (pH 3.8) and acetonitrile. The pure product fractions collected in 36% acetonitrile were combined and lyophilized overnight to obtain the desired product PPI-24073 (7 mg, 13% yield).

[0660] LCMS (Method 8B): EM=C 112 H 175 FWf 19 O 36 S2Si; [M+2H] 2+ Calculated value = 1325.1, found = 1325.2; [M+3H] 3+ Calculated value = 883.7, measured value = 883.7; Rt = 2.05min.

[0661] HRMS: Observed mass of [M+2Na-2H] 2692.0625, calculated value 2692.0689. Observed mass of [M+3Na-3H] 2714.0625, calculated value 2714.0508. Observed mass of [M+4Na-4H] 2736.0313, calculated value 2736.0327.

[0662]

[0663] BAL resin synthesis. In a glass reactor 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 another flask, 5-(4-formyl-3,5-dimethoxyphenoxy)pentanoic acid (18, 1.5 eq.), DIC (1.5 eq.) and HOBt (1.5 eq.) were mixed in DMF (25.0 mL) for 5 minutes, and then the solution was added to the resin. The resin was shaken at room temperature for 4 hours, drained, and the resin was treated again with fresh reagents as above. The solvent was drained, and the resulting BAL resin 19 was subsequently washed with DMF (3X 25 mL), methanol (3X 25 mL) and dichloromethane (3X 25 mL). The end of the reaction was confirmed by a negative Kaiser test.

[0664]

[0665] Synthesis of product resin 23. Product resin 23 was synthesized from Bal resin 19 using the protocol described in the referenced paper (ACS Omega 2019, 4, 1470-1478). After coupling the Fmoc-protected pABzA-DIG linker, the resulting resin 23 was used for further functionalization.

[0666]

[0667] Synthesis of product resin 24. Fmoc-L-His(Trt)-OH (3 eq.) was preactivated with HATU (3 eq.), HOAt (3 eq.) and DIEA (8 eq.) in DMF (6 mL) and then added to the reaction vessel containing resin 23 in two equal portions and shaken at room temperature for 4 hours and overnight, respectively. Fmoc deprotection was performed using piperidine / DMF (1:2) solution in two reaction cycles for a total of 1.5 hours. Using a similar procedure, Fmoc-L-Glu(tBu)-OH, Fmoc-L-His(Trt)-OH and Fmoc-L-Glu(tBu)-OH were subsequently coupled to the peptide sequence. The formation of product resin 24 was confirmed by the Kaiser test.

[0668]

[0669] 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).

[0670] Resin 24 (1.2 mmol / g, 0.65 mmol) was treated twice with a 1:2 mixture (3 mL) of piperidine and DMF to deprotect the Fmoc group, followed by washing with DMF, methanol and dichloromethane (positive Kaiser test). PPI-24069 (1.5 eq) was preactivated with HATU (1.0 eq), HOAt (1.5 eq) and DIPEA (4 eq) in DMF (3 mL), and the resulting solution was added to the reaction vessel containing the resin and shaken overnight at room temperature. Resin 25 was subsequently washed with DMF (2X 10 mL), methanol (2X 10 mL) and dichloromethane (2X 10 mL). The reaction was confirmed to be complete by a negative Kaiser test.

[0671]

[0672] 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 remove the Fmoc group protection, followed by washing with DMF, methanol and dichloromethane (positive Kaiser test). DOTA-tris(t-Bu)-COOH (1.5 eq.) was preactivated with HATU (1.5 eq.), HOAt (1.5 eq.) and DIPEA (4 eq.) in DMF (3 mL), and the resulting solution was added to the reaction vessel containing the resin and shaken overnight at room temperature. The resulting resin 26 was then washed with DMF (2X 10 mL), methanol (2X 10 mL) and dichloromethane (2X 10 mL). The reaction was confirmed to be complete by a negative Kaiser test.

[0673]

[0674] The peptide was deprotected and removed 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, Synthesis of triacetic acid (27): 20,23,26-octaoxo-3-oxa-6,9,12,15,18,21,24,27-octaazatriacontanoylamino)phenyl)-7,13-bis(2-carboxyethyl)-3,6,9,12,15-pentaoxo-2,5,8,11,14-pentaazahexadecane-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)

[0675] The resin 26 from the previous step was treated with a pre-prepared deprotection mixture (15 mL, 446 μmol) at room temperature overnight as follows. The solvent was collected by filtration and reduced on a rotary evaporator. The peptide was precipitated by adding cold ether, centrifuged and the solid was washed twice with cold ether to give the desired product 27. It was used as is in the next step.

[0676] A deprotection cocktail was prepared by mixing the following reagents: [88% TFA + 5% water + 5% phenol + 2% triisopropylsilane].

[0677]

[0678] Formation of lutetium chelate (PPI-24082). To a solution of 27 (69.0 mg, 20.2 μmol) in DMSO (1.38 mL) was added LuCl3 aqueous solution (552 μL, 200 mM) 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 with a gradient elution of 0.1% TFA and acetonitrile. The pure product fractions collected in 30% acetonitrile were combined and lyophilized overnight to give the desired product PPI24082 (1.04 mg, yield to be optimized).

[0679] LCMS (Method 8B): EM=C 116 H 166 FWf 30 O 28 Si; [M+2H] 2+ Calculated value = 1325.6, measured value = 1325.5; Rt = 2.79min.

[0680] Fig.29 A synthetic scheme of PPI-24069 according to one embodiment of the present invention is explained.

[0681] Fig.30 A synthetic scheme of PPI-24073 / FTX-181 according to one embodiment of the present invention is explained.

[0682] Fig.31 A synthetic scheme of PPI-24082 / FTX-219 according to one embodiment of the present invention is explained.

[0683] Principle of Equivalence

[0684] From the above discussion, it can be inferred that, according to embodiments of the present invention, the above concepts can be realized with multiple arrangements. Therefore, although the present invention has been described in some specific aspects, many other modifications and variations will be understood by those skilled in the art. Therefore, it should be understood that the present invention can be put into practice in a manner different from that specifically described. Therefore, embodiments of the present invention should be considered as exemplary and non-restrictive in all respects.

Claims

1. A compound comprising: a silicon fluoride acceptor; and heteroaromatic ring; wherein the heteroaromatic ring is selected from the group consisting of pyridine, pyridinium, pyrazole, fused pyrazole derivatives, benzofuran, benzothiophene, indole, azaindole, imidazole and pyrimidine; Wherein the pyridine, pyridine oxide or pyridinium compound has the following formula I: The pyrazole compound has the following formula II: The fused pyrazole derivative compound has the following formula III: Wherein the benzofuran, benzothiophene, indole or azaindole compound has the following formula IV: The imidazole compound has the following formula V: The pyrimidine compound has the following formula VI: in: Each F is independently: F or 18 F or 19 F; each A is independently: H, CH3, CH2-CH3, CH3-CH2-CH(CH3), CH(CH3)2 and C(CH3)3; Each U is independently: O-CH3, CH3, CH2CH3, H, I, Br, Cl, F, N(CH3)2, and CH2CH(NH2)CO2H; Each X is independently: O, S and N; Each Y is independently: C and N; Each R 1 or R 2 or R 3 independently: CH3, CH2-CH3, H, L 1 -CH2-C≡C, L 1 -CH3, L 1 -G, L 1 -H, L 1 -L 2 -CH2-C≡C, L 1 -L 2 -CH3, L 1 -L 2 -G, L 1 -L 2 -H, L 1 -L 2 -H2, 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 -N3, L 1 -L 2 -OH, L 1 -L 2 -Q, L 1 -L 2 -QG, 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 -Q-L 2 -L 3 -L 4 -G、L 1 -Q-L 2 -G、NH2、O - 、O-CH3、OH、 Each L 1 or L 2 or L 3 or L 4 or L 5 Independently: -(O-CH2-CH2) p -、-(CH2-CH2-O) p -、-(Glu-His) p -、-(His-Glu) p -、-(Glu-Trp) p -、-(Trp-Glu) p -, -NH-CH2-C6H4-NH-(C=O)-CH2-O-CH2-(C=O)-, -(C=O)-CH2-O-CH2-(C=O)-NH-C6H4-CH2 -NH-, -(C=O)-CH2-CH2-(C=O)-, -NH-C5H9N-CH2-(C=O)-, -(C=O)-CH2-NC5H9-NH-, -(Gly) p -, -CH2-CH2-NH-, -NH-CH2-(C=O)-, -(Glu)-, -NH-CH2-CH2-, -(C=O)-, NH-CH2-CH2-(O-CH2-CH2) p -(C=O)-, -(C=O)-(CH2-CH2-O) p -CH2-CH2-NH-, -NH-(C=O)-CH2-, -NH-(C=O)-NH-CH2-, -NH-(C=S)-NH-CH2-, -NH-(CH2-CH2-O) p -CH2-(C=O)-, -(C=O)-CH2-(O-CH2-CH2) p -NH-, -Asp-, -NH-, -NH-(CH2-CH2-O) p -CH2-CH2-(C=O)-, -(C=O)-CH2-CH2-(O-CH2-CH2) p -NH-, -CH2-(C=O)-, -(C=O)-CH2-, -O-(C=O)-, -(C=O)-O-, -CH2-O-, -NH-(C=O)-O-, -O-(C=O)-NH-, -(C=O)-CH2-(O-CH2-CH2) p -O-CH2-(C=O)-, -NH-(C=O)-NH-, -NH-(C=S)-NH-, -CH2-N(CH3)-CH2-, -N(CH3)-, -(C=O)-C6H4-(C=O)-, -C6H4-(C=O)-, -(C=O)-C6H4-, -O-CH2-(C=O)-, -(C=O)-CH2-O-, -CH2-C2N3-CH2-, -CH2-CH2-(C=O)-, -(C=O)-CH2-CH2-, -CH2-N + (CH3)2-CH2-, -CH2-N(CH3)-, -(C=O)-CH2-(O-CH2-CH2) p -, -(CH2-CH2-O) p -CH2-CH2-NH- or p = 0 to 12; each G is a disease binding ligand, wherein 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; and Each Q is a chelating agent.

2. The compound of claim 1, wherein each Q is independently: -DOTA, -DOTAGA, -Dap(DOTA), -Lys(DOTA), -3p-C-NETA, -di-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, -deferoxamine B (DFO) mesylate, -deferoxamine-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-H4octapa, -HEHA-NCS, or -Macropa-NCS.

3. The compound of claim 1, wherein Q is unchelated or optionally chelated with M, wherein M is a cation of a metal selected from: 43 Sc, 44 Sc, 45 Sc, 47 Sc, 51 Cr, 52m Mn, 68 Co. 52 Fe, 56 You, 57 You, 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 Such as 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 2. 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, and including 18 The cationic molecules of F and 18 F[AlF] 2+ .

4. The compound of claim 1, wherein A is C(CH3)3.

5. The compound of claim 1, wherein G has a formula selected from the group consisting of: wherein Z is H, CH3 or CF3.

6. The compound of claim 1, wherein: R 1 Independently: CH3, H, L 1 -CH2-C≡C, L 1 -CH3, L 1 -H, L 1 -L 2 -CH2-C≡C, L 1 -L 2 -CH3, L 1 -L 2 -G, L 1 -L 2 -H, L 1 -L 2 -H2, 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 -N3, 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, NH2, O-CH3, OH, R 2 Independently: CH3, H, L 1 -CH2-C≡C, L 1 -G, L 1 -H, L 1 -L 2 -CH2-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 -N3, L 1 -L 2 -Q, L 1 -L 2 -QG, L 1 -L 2 -QL 3 -G, L 1 -OH, L 1 -Q, L 1 -QL 2 -G, NH2, O - or O-CH3; and R 3 are independently: CH3, CH2-CH3 or O - .

7. The compound of claim 1, wherein the compound is a small molecule having a formula selected from the group consisting of:

8. The compound of claim 1, wherein the compound is used for positron emission tomography (PET) imaging and has the formula:

9. The compound of claim 1, wherein the compound is a theranostic compound having a formula selected from:

10. The compound of claim 1, wherein the compound is a dual-targeted theranostic compound having the formula:

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

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

13. The compound of claim 2, wherein: 3p-C-NETA is constructed with 177 Lu chelation is used for treatment; DOTA and DOTAGA are constructed with 177 Lu or 225 Ac chelation is used therapeutically; and DOTA and DOTAGA are constructed with 68 Ga, 89 Zr or 64 Cu chelation for PET imaging.

14. A method for synthesizing a radiopharmaceutical compound, the method comprising: Providing a fluorinated silicon compound containing a heteroaromatic ring; conjugating a disease binding ligand G to the fluorinated silicon compound to form the radiopharmaceutical compound; wherein the heteroaromatic ring is selected from the group consisting of pyridine, pyridinium, pyrazole, fused pyrazole derivatives, benzofuran, benzothiophene, indole, azaindole, imidazole and pyrimidine; Wherein the pyridine, pyridine oxide or pyridinium compound has the following formula I: The pyrazole compound has the following formula II: The fused pyrazole derivative compound has the following formula III: Wherein the benzofuran, benzothiophene, indole or azaindole compound has the following formula IV: The imidazole compound has the following formula V: The pyrimidine compound has the following formula VI: in: Each F is independently: F or 18 F or 19 F; each A is independently: H, CH3, CH2-CH3, CH3-CH2-CH(CH3), CH(CH3)2 and C(CH3)3; Each U is independently: O-CH3, CH3, CH2CH3, H, I, Br, Cl, F, N(CH3)2, and CH2CH(NH2)CO2H; Each X is independently: O, S and N; Each Y is independently: C and N; Each R 1 or R 2 or R 3 independently: CH3, CH2-CH3, H, L 1 -CH2-C≡C, L 1 -CH3, L 1 -G, L 1 -H, L 1 -L 2 -CH2-C≡C, L 1 -L 2 -CH3, L 1 -L 2 -G, L 1 -L 2 -H, L 1 -L 2 -H2, 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 -N3, L 1 -L 2 -OH, L 1 -L 2 -Q, L 1 -L 2 -QG, 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 -Q-L 2 -L 3 -L 4 -G、L 1 -Q-L 2 -G、NH2、O - 、O-CH3、OH、 Each L 1 or L 2 or L 3 or L 4 or L 5 Independently: -(O-CH2-CH2) p -、-(CH2-CH2-O) p -、-(Glu-His) p -、-(His-Glu) p -、-(Glu-Trp) p -、-(Trp-Glu) p -, -NH-CH2-C6H4-NH-(C=O)-CH2-O-CH2-(C=O)-, -(C=O)-CH2-O-CH2-(C=O)-NH-C6H4-CH2 -NH-, -(C=O)-CH2-CH2-(C=O)-, -NH-C5H9N-CH2-(C=O)-, -(C=O)-CH2-NC5H9-NH-, -(Gly) p -, -CH2-CH2-NH-, -NH-CH2-(C=O)-, -(Glu)-, -NH-CH2-CH2-, -(C=O)-, NH-CH2-CH2-(O-CH2-CH2) p -(C=O)-, -(C=O)-(CH2-CH2-O) p -CH2-CH2-NH-, -NH-(C=O)-CH2-, -NH-(C=O)-NH-CH2-, -NH-(C=S)-NH-CH2-, -NH-(CH2-CH2-O) p -CH2-(C=O)-, -(C=O)-CH2-(O-CH2-CH2) p -NH-, -Asp-, -NH-, -NH-(CH2-CH2-O) p -CH2-CH2-(C=O)-, -(C=O)-CH2-CH2-(O-CH2-CH2) p -NH-, -CH2-(C=O)-, -(C=O)-CH2-, -O-(C=O)-, -(C=O)-O-, -CH2-O-, -NH-(C=O)-O-, -O-(C=O)-NH-, -(C=O)-CH2-(O-CH2-CH2) p -O-CH2-(C=O)-, -NH-(C=O)-NH-, -NH-(C=S)-NH-, -CH2-N(CH3)-CH2-, -N(CH3)-, -(C=O)-C6H4-(C=O)-, -C6H4-(C=O)-, -(C=O)-C6H4-, -O-CH2-(C=O)-, -(C=O)-CH2-O-, -CH2-C2N3-CH2-, -CH2-CH2-(C=O)-, -(C=O)-CH2-CH2-, -CH2-N + (CH3)2-CH2-, -CH2-N(CH3)-, -(C=O)-CH2-(O-CH2-CH2) p -, -(CH2-CH2-O) p -CH2-CH2-NH- or 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; and Each Q is a chelating agent.

15. The method of claim 14, wherein each Q is independently: -DOTA, -DOTAGA, -Dap(DOTA), -Lys(DOTA), -3p-C-NETA, -di-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, -deferoxamine B (DFO) mesylate, -deferoxamine-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-H4octapa, -HEHA-NCS, or -Macropa-NCS.

16. The method of claim 14, further comprising chelating Q with M, wherein M is a cation of a metal selected from: 43 Sc, 44 Sc, 45 Sc, 47 Sc, 51 Cr, 52m Mn, 68 Co. 52 Fe, 56 You, 57 You, 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 Such as 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 2. 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, and including 18 The cationic molecules of F and 18 F[AlF] 2+ .

17. The method of claim 14, wherein A is C(CH3)3.

18. The method of claim 14, wherein G has a formula selected from the group consisting of: wherein Z is H, CH3 or CF3.

19. The method of claim 14, wherein: R 1 Independently: CH3, H, L 1 -CH2-C≡C, L 1 -CH3, L 1 -H, L 1 -L 2 -CH2-C≡C, L 1 -L 2 -CH3, L 1 -L 2 -G, L 1 -L 2 -H, L 1 -L 2 -H2, 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 -N3, 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, NH2, O-CH3, OH, R 2 Independently: CH3, H, L 1 -CH2-C≡C, L 1 -G, L 1 -H, L 1 -L 2 -CH2-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 -N3, L 1 -L 2 -Q, L 1 -L 2 -QG, L 1 -L 2 -QL 3 -G, L 1 -OH, L 1 -Q, L 1 -QL 2 -G, NH2, O - or O-CH3; and R 3 are independently: CH3, CH2-CH3 or O - .

20. The method of claim 14, wherein the radiopharmaceutical compound is a small molecule having a formula selected from:

21. The method of claim 14, wherein the radiopharmaceutical compound is for positron emission tomography (PET) imaging and has the formula:

22. The method of claim 14, wherein the radiopharmaceutical compound is a theranostic compound having a formula selected from:

23. The method of claim 14, wherein the radiopharmaceutical compound is a dual targeted theranostic compound having the formula:

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

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

26. The method of claim 15, further comprising: Make 3p-C-NETA with 177 Lu chelation is used for treatment; Make DOTA and DOTAGA compatible 177 Lu or 225 Ac chelation is used therapeutically; and Make DOTA and DOTAGA compatible 68 Ga, 89 Zr and 64 Cu chelate is used for PET imaging.

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