EP4351663A1 - Trislinker-konjugierte dimere markierungsvorläufer und daraus abgeleitete radiotracer - Google Patents

Trislinker-konjugierte dimere markierungsvorläufer und daraus abgeleitete radiotracer

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Publication number
EP4351663A1
EP4351663A1 EP22734235.9A EP22734235A EP4351663A1 EP 4351663 A1 EP4351663 A1 EP 4351663A1 EP 22734235 A EP22734235 A EP 22734235A EP 4351663 A1 EP4351663 A1 EP 4351663A1
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EP
European Patent Office
Prior art keywords
derivatives
μmol
fapi
glu
acid
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EP22734235.9A
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German (de)
English (en)
French (fr)
Inventor
Frank RÖSCH
Marcel Martin
Tilmann Grus
Euy Sung Moon
Chandra Sekhar Bal
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Medianezia GmbH
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Medianezia GmbH
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/0497—Organic compounds conjugates with a carrier being an organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/041—Heterocyclic compounds
    • A61K51/044—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K51/0455—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/0489—Phosphates or phosphonates, e.g. bone-seeking phosphonates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
    • A61K51/088—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins conjugates with carriers being peptides, polyamino acids or proteins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to dimeric label precursors and radiotracers derived therefrom by complexation with a radioisotope for the diagnosis and treatment of cancer diseases.
  • the tag precursor has the structure TV1-S1-TL-S2-TV2
  • the marker precursors and radiotracers according to the invention are intended for imaging nuclear medicine diagnostics, in particular positron emission tomography (PET) and single photon emission computed tomography (SPECT), and radionuclide therapy/endoradiotherapy of carcinomas and metastases of various types of cancer.
  • nuclear medicine diagnostics tumor cells or metastases are marked and imaged using a radioactive isotope such as gallium-68 ( 68 Ga), technetium-99m ( 99m Tc) or scandium-44 ( 44 Sc).
  • a radioactive isotope such as gallium-68 ( 68 Ga), technetium-99m ( 99m Tc) or scandium-44 ( 44 Sc).
  • Complex-forming chelators are used for metallic radionuclides of the above type.
  • Non-metallic radioisotopes such as Fluorine-18 ( 18 F), Iodine-123 ( 123 I), Iodine-131 ( 131 I) and Astatine-211 ( 211 At) are covalently bound, ie no chelator is needed.
  • higher doses of radiation are used in nuclear medicine therapy to destroy tumor tissue.
  • beta-minus emitting radioisotopes such as lutetium-177 ( 177 Lu), yttrium-90 ( 90 Y) and iodine-131 ( 131 I) or alpha emitters such as actinium-225 ( 225 Ac) are used.
  • Alpha and beta minus rays have a short range in tissue.
  • the short range enables localized irradiation of tumors and metastases with a low radiation dose and damage to the surrounding healthy tissue.
  • the combination of diagnostics and therapy - referred to as theranostics in specialist circles - has become increasingly important.
  • the same marker precursor can be used for both diagnostics and therapy.
  • the marking precursor is only marked with different radioisotopes, for example with 68 Ga and 177 Lu, so that PET diagnostics and radiotherapy can be carried out with essentially chemically identical compounds. This allows a transmission (translation) of the results of imaging nuclear medicine diagnosis in nuclear medicine treatment (theranostics) with improved dose setting.
  • the configuration and chemical properties of a target vector conjugated with the labeling group are modified by the labeling group - in particular by chelators - and its affinity for tumor cells is usually influenced. Accordingly, the label precursor needs to be re-evaluated in terms of complexation with radioisotopes and, most importantly, in terms of its in vitro and in vivo biochemical and pharmacological properties.
  • the labeling group and its chemical coupling with the target vector are decisive for the biological and nuclear medicine potency of the associated radiotracer.
  • the marker precursor labeled with the radioisotope also referred to below as radiotracer—accumulates on or in tumor cells or metastases.
  • radioisotopes In order to minimize the radiation dose in healthy tissue, radioisotopes with a short half-life of a few hours to a few days are used.
  • the label precursor and radiotracers derived from it must meet the following requirements: 1. Fast and effective complexation or binding of the respective radioisotope; 2. high selectivity for tumor cells and metastases relative to healthy tissue; 3. in vivo stability, ie biochemical stability in blood serum under physiological conditions; 4. high accumulation in the tumor and any metastases, which enables precise diagnosis and effective therapy; 5. low retention and rapid clearance from healthy tissues and the blood to minimize dose and toxicity to these organs.
  • Prostate cancer For men in industrialized countries, prostate cancer is the most common type of cancer and the third leading cause of death from cancer.
  • PSA prostate-specific antigen
  • PSMA prostate-specific membrane antigen
  • NAAG N-acetyl-aspartyl-glutamate
  • folic acid-(poly)- ⁇ -glutamate PSMA is rarely found in normal tissue, but is highly overexpressed by prostate carcinoma cells, with expression being closely correlated with the stage of the tumor disease.
  • Lymph node and bone metastases from prostate carcinomas also show 40% expression of PSMA.
  • One strategy for molecular targeting of PSMA is to bind antibodies to the protein structure of PSMA.
  • ligands are used which address the enzymatic binding pocket of PSMA.
  • the central enzymatic binding pocket of PSMA contains two Zn 2+ ions that bind glutamate.
  • the central binding pocket is preceded by an aromatic binding pocket.
  • the PSMA protein is able to expand and adapt to different ligands, such as inhibitors or enzymatically cleavable ones (induced fit).
  • PSMA also binds folic acid, with the pteroic acid group docking in the aromatic binding pocket.
  • PSMA inhibitors are particularly suitable as target vectors for imaging diagnostic and theranostic radiopharmaceuticals or radiotracers.
  • the radioactively labeled inhibitors dock onto the central PSMA binding pocket, where they are not converted or cleaved enzymatically and the inhibitor/target vector is not detached from the radioactive label.
  • the inhibitor with the radioactive label is absorbed into the tumor cell and accumulates there.
  • Inhibitors with high affinity for PSMA (Scheme 1) usually contain a glutamate motif and an enzymatically non-cleavable structure.
  • a highly effective PSMA inhibitor is 2-phosphonomethylglutaric acid or 2-phosphonomethylpentanedioic acid (2-PMPA), in which the glutamate motif is linked to a phosphonate group that cannot be cleaved by PSMA.
  • urea-based PSMA inhibitors are used, such as in clinically relevant radiotracers of the type PSMA-11 (Scheme 2) and PSMA-617 (Scheme 3). It has proven advantageous to target the aromatic binding pocket of PSMA in addition to the central binding pocket.
  • the binding motif L-lysine-urea-L-glutamate (KuE) is linked via hexyl (hexyl spacer) to an aromatic HBED chelator (N,N'-bis[2-hydroxy -5-carboxy-ethyl)benzyl)ethylene-diamine-N,N'-diacetate).
  • aromatic HBED chelator N,N'-bis[2-hydroxy -5-carboxy-ethyl)benzyl
  • L-lysine-urea-L-glutamate (KuE) is bound to the non-aromatic chelator DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate)
  • DOTA 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate
  • the spacer has to be adjusted.
  • Tumor stroma Malignant epithelial cells are part of many tumors and tumor types and form a tumor stroma surrounding the tumor at the latest from a size of 1 – 2 mm.
  • the tumor stroma (tumor microenvironment or TME) comprises various non-malignant types of cells and can account for up to 90% of the total tumor mass. It plays an important role in tumor progression, tumor growth and metastasis.
  • the main cellular components of the tumor stroma are the extracellular matrix including various cytokines, endothelial cells, pericytes, macrophages, immune regulatory cells and activated fibroblasts.
  • the activated fibroblasts surrounding the tumor are called cancer-associated fibroblasts (CAF).
  • CAFs cancer-associated fibroblasts
  • FAP Fibroblast activation protein
  • inhibitors exhibits both dipeptidyl peptidase (DPP) and prolyl oligopeptidase (PREP) activity. Accordingly, inhibitors can be considered which reduce the DPP and/or inhibit the PREP activity of FAP. The key is the selectivity of the inhibitor over other similar enzymes such as the dipeptidyl peptidases DPPII, DPPIV, DPP8 and DPP9, as well as over prolyloligopeptidase (PREP). However, in cancers in which both FAP and PREP are overexpressed, inhibitors that do not have high selectivity between PREP and FAP but inhibit both enzymes can also be used.
  • Scheme 5 shows another FAP-tag precursor comprising the chelator DOTA.
  • the chelator DOTA is coupled to the quinoline unit of the pharmacophoric FAPi target vector via a 4-aminobutoxy, a squaric acid and an ethylenediamine group.
  • Bone Metastases Bone metastases express farnesyl pyrophosphate synthase (FPPS), an enzyme in the HMG-CoA reductase (mevalonate) pathway. Inhibiting FPPS suppresses the production of farnesyl, an important molecule for signaling proteins to dock at the cell membrane. As a result, apoptosis of cancerous bone cells is induced. FPPS is inhibited by bisphosphonates such as alendronate, pamidronate and zoledronate. For example, the tracer BPAMD with the target vector pamidronate is regularly used in the treatment of bone metastases.
  • FPPS farnesyl pyrophosphate synthase
  • mevalonate HMG-CoA reductase
  • Zoledronate (ZOL), a hydroxy-bisphosphonate with a heteroaromatic imidazole moiety, has proven to be a particularly effective tracer for theranostics of bone metastases.
  • Zoledronate conjugated with the chelators NODAGA and DOTA (Scheme 6) are currently the most potent radiotheranostics for bone metastases.
  • a variety of label precursors for diagnosis and theranostics of cancers with radioactive isotopes are known in the art.
  • WO 2015055318 A1 discloses radiotracers for the diagnosis and theranostics of prostate or epithelial carcinomas, such as, inter alia, the marker precursor PSMA-617 shown in Scheme 3.
  • homo- and heterodimeric marking precursors are provided for the first time, which comprise two identical or two different target vectors, which are conjugated to a marking group via a tris linker (TL).
  • An amino acid residue such as in particular a lysine or glutamic acid residue, serves as a tris linker (TL).
  • the trislinkers (TL) decouple the chelator and the target vectors from one another with regard to steric and electronically induced interactions.
  • the Trislinker (TL) is coupled to the chelator in such a way that it does not impair complexation with clinically relevant radioisotopes. For this purpose, couplings can be used that have proven themselves for monomeric labeling precursors.
  • the invention enables an independent (orthogonal) optimization of the radioisotope complexation, the affinity and the pharmacokinetics and pharmacodynamics of homo- and heterodimeric radiotracers.
  • the known linear, homodimeric marking precursors require complex molecular engineering that is often associated with functional impairments.
  • FAP-addressing marker precursors and radiotracers according to the invention are also characterized by: 1. A high binding affinity to FAP with IC 50 values in the nanomolar and sub-nanomolar range. 2.
  • this also guarantees low radiation exposure for the patients.
  • the inventive concept can be easily applied to compounds with two different target vectors.
  • a bone metastasis-addressing targeting vector bisphosphonate
  • PSMA inhibitor prostate cancer-addressing targeting vector
  • heterodimeric marker precursors with an FAP target vector and a PSMA target vector are also provided within the scope of the invention.
  • Such heterodimeric label precursors target both PSMA-expressing tumor tissue and tumor-associated FAP-expressing stromal cells.
  • prostate carcinomas and metastases that do not overexpress PSMA can also be detected and visualized using PET and SPECT. It is an object of the present invention to provide label precursors and radiotracers for improved diagnosis and theranostics of cancer diseases.
  • marker precursors and radiotracers with increased selectivity and specificity, effective radioisotope complexation and conjugation as well as rapid absorption and systemic excretion are to be created.
  • This object is achieved by a marker precursor with the structure TV1-S1-TL-S2-TV2
  • a linker of the type with a dismounting group 18 e X is for substitution with F, 1 31 I or 211 At;
  • - MG contains a leaving group X selected from a residue of bromo (Br), chloro (Cl) or iodo (I), tosyl (Ts), brosylate (Bs), nosylate (Nos), 2-(N-morpholino )ethanesulfonic acid (MES), triflate (Tf) and nonaflate (Non);
  • the Trislinker TL is chosen from one of the structures [52] to [64], with
  • Trislinker TL is chosen from one of the structures [65] to [116], with
  • a labeling group MG for the covalent binding of the radioisotopes 18 F, 131 I or 211 At comprises in particular a leaving group X selected from a residue of bromine (Br), chlorine (Cl), iodine (I), tosyl (-SO 2 -C 6 H 4 -CH 3 ; abbreviated "Ts”), brosylate (- SO 2 -C 6 H 4 -Br; abbreviated "Bs”), nosylate or
  • the inventors have surprisingly found that the dimeric label precursors described above or the radiotracers derived from them with two target vectors TV1 and TV2 compared to monomeric radiotracers with a target vector at the same systemic dose and non-specific accumulation (off-target exposure) have a significantly higher accumulation in tumor tissue (target exposure). It is believed that this advantageous property is due to an increased probability of docking and/or selectivity.
  • the target vectors TV1 and TV2 used according to the invention have a high binding affinity to membrane-bound tumor markers, such as in particular PSMA (prostate-specific membrane antigen), FAP (fibroblast activation protein) and FPPS (farnesyl pyrophosphate synthase).
  • heterodimeric label precursors and radiotracers of the invention can be addressed with the heterodimeric label precursors and radiotracers of the invention.
  • This is advantageous for the treatment of bone metastases induced by prostate carcinoma.
  • marker precursors or radiotracers with a first target vector TV1 for PSMA (PSMA target vector) and a second osteotropic target vector TV2 for FPPS (FPPS target vector) are particularly suitable.
  • the label precursors and radiotracers of the present invention are useful for targeting the tumor stroma.
  • triple negative breast cancer (TNBC) lacks specific receptors on the surface of cancerous cells that allow for direct targeting.
  • an "indirect" addressing of the tumor stroma comes into consideration.
  • the tumor stroma comprises cancer-associated fibroblasts (CAFs) and altered endothelial cells (ECs) that overexpress FAP and PSMA, respectively.
  • CAFs cancer-associated fibroblasts
  • ECs altered endothelial cells
  • both homodimeric precursors with PSMAi, FAPi or bisphosphonate vectors and heterodimeric marker precursors with a first PSMA target vector and a second FAP target vector are suitable for the diagnosis and treatment of TNBC.
  • PSMA-negative tumors and metastases can be diagnosed and treated by targeting the tumor stroma using FAP targeting vectors.
  • a heterodimeric tag precursor with a first PSMA target vector and a second FAP target vector is useful for the comprehensive diagnosis and treatment of PSMA-positive as well as PSMA-negative prostate cancers.
  • Theranostic targeting of the tumor stroma with radioisotopes such as 177 Lu and 225 Ac directly damages the tumor microenvironment essential for progression and induces "indirect” radiation damage (radiation induced bystander effect, RIBE) in neighboring cancer cells.
  • Spacers S1, S2, and S3 act as steric spacers and pharmacokinetic modulators that optimize the biochemical function of the target vectors (binding affinity to the target), the radiochemical function of the labeling group (stable complexation or conjugation of the radioisotope), and the half-life in blood serum (hydrophilicity).
  • the spacers S1, S2, S3 preferably contain structural elements such as B. squaric acid amides or other aromatic moieties which improve the affinity for PSMA.
  • the Trislinker TL creates the prerequisite for the orthogonal, sterically and pharmacokinetically optimized coupling of the marker group MG and the two target vectors TV1 and TV2 in analogy to established monomeric radiopharmaceuticals with only one target vector.
  • the invention enables the synthesis of effective label precursors and radiotracers with high theranostic potency.
  • the invention includes radiotracers consisting of one of the labeling precursors described above and a radioisotope complexed with the labeling precursor selected from the group consisting of 43 Sc, 44 Sc, 47 Sc, 55 Co, 62 Cu, 64 Cu, 67 Cu, 66 Ga, 67 Ga, 68 Ga, 89 Zr, 86 Y, 90 Y, 89 Zr, 90 Nb, 9 9m Tc, 111 In, 135 Sm, 140 Pr 159 Gd, 149 Tb, 160 Tb, 161 Tb, 165 Er, 166 Dy , 166 Ho, 175 Yb, 177 Lu, 186 Re, 188 Re, 211 At, 212 Pb, 213 Bi, 225 Ac and 232 Th; or ⁇ radioisotope covalently bonded to the label precursor selected from the group consisting of 18 F, 131 I and 211 At.
  • the radiotracer consists of one of the labeling precursors described above with - a labeling group MG selected from the group comprising NOTA (nona-1,4,7-triamine triacetate), DATA 5m (5-[[ 6-(N-methyl)amino]-1,4-diacetate-1,4-diazepan]pentanoic acid-N,N',N'-triacetate) and NODAGA (1,4,7-triazacyclononane,1-glutaric acid, 4,7-acetate); and - the radioactive compound aluminum[ 18 F]fluoride (or [ 18 F]AlF) complexed with the label precursor.
  • a labeling group MG selected from the group comprising NOTA (nona-1,4,7-triamine triacetate), DATA 5m (5-[[ 6-(N-methyl)amino]-1,4-diacetate-1,4-diazepan]pentanoic acid-N,N',N'-triacetate)
  • the chelator is used for labeling with a radioisotope selected from the group comprising 43 Sc, 44 Sc, 47 Sc, 55 Co, 62 Cu, 64 Cu, 67 Cu, 66 Ga , 67 Ga, 68 Ga, 89 Zr, 86 Y, 90 Y, 89 Zr, 90 Nb, 99m Tc, 111 In, 135 Sm, 140 Pr, 159 Gd, 149 Tb, 160 Tb, 161 Tb, 165 Er, 166 Dy, 166 Ho, 175 Yb, 177 Lu, 186 Re, 188 Re, 211 At, 212 Pb, 213 Bi, 225 Ac and 232 Th.
  • a radioisotope selected from the group comprising 43 Sc, 44 Sc, 47 Sc, 55 Co, 62 Cu, 64 Cu, 67 Cu, 66 Ga , 67 Ga, 68 Ga, 89 Zr, 86 Y, 90 Y, 89 Zr, 90 Nb, 99m Tc, 111 In, 135
  • the invention encompasses radiotracers obtainable from the label precursors described above by complexation with a radioisotope are, wherein the radioisotope is selected from the group consisting of 43 Sc, 44 Sc, 47 Sc, 55 Co, 62 Cu, 64 Cu, 67 Cu, 66 Ga, 67 Ga, 68 Ga, 89 Zr, 86 Y, 90 Y, 89 Zr, 90 Nb, 99m Tc, 111 In, 135 Nm, 140 Pr 159 Gd, 149 Tb, 160 Tb, 161 Tb, 165 Er, 166 Dy, 166 Ho, 175 Yb, 177 Lu, 186 Re, 188 Re, 211 At, 212 Pb, 213 Bi, 225 Ac and 232 Th.
  • Chelators A variety of chelators f Known for the complexation of radioisotopes. Scheme 7 shows examples of chelators used according to the invention.
  • Amide coupling In the invention, functional groups such as the chelator Chel, the target vectors TV1 and TV2, the spacers S1, S2, S3, and the trislinker TL are preferably conjugated by means of an amide coupling reaction.
  • Amide coupling the backbone of proteins, is the most commonly used reaction in medicinal chemistry.
  • a generic example of an amide coupling is shown in Scheme 8. Due to a virtually unlimited set of readily available carboxylic acid and amine derivatives, amide-coupling strategies provide a facile route to the synthesis of new compounds. Numerous reagents and protocols for amide couplings are known to those skilled in the art. The most common amide coupling strategy relies on the condensation of a carboxylic acid with an amine.
  • the carboxylic acid is usually activated for this purpose. Remaining functional groups are protected prior to activation.
  • the reaction takes place in two steps either in a reaction medium (single pot) with direct reaction of the activated carboxylic acid or in two steps with isolation of an activated “trapped” carboxylic acid and reaction with an amine.
  • the carboxylic acid reacts with a coupling agent to form a reactive intermediate that can be isolated or reacted directly with an amine.
  • Numerous reagents are available for carboxylic acid activation, such as acid halides (chloride, fluoride), azides, anhydrides, or carbodiimides.
  • esters such as pentafluorophenyl or hydroxysuccinimido esters can be formed as reactive intermediates.
  • Intermediates derived from acyl chlorides or azides are highly reactive.
  • harsh reaction conditions and high reactivity often prevent their use for sensitive substrates or amino acids.
  • amide coupling strategies that use carbodiimides such as DCC (dicyclohexylcarbodiimide) or DIC (diisopropylcarbodiimide) open up a wide range of applications.
  • additives are used to improve reaction efficiency.
  • Aminium salts are highly efficient peptide coupling reagents with short reaction times and minimal racemization.
  • Aminium reagents are used in equimolar amounts to the carboxylic acid to prevent excessive reaction with the free amine of the peptide.
  • Phosphonium salts react with carboxylate, typically requiring two equivalents of a base such as DIEA.
  • a key advantage of phosphonium salts over iminium reagents is that phosphonium does not react with the free amino group of the amine component. This enables couplings in equimolar ratios of acid and amine and helps to avoid intramolecular cyclization of linear peptides and excessive use of expensive amine components.
  • chelators used according to the invention such as. B. DOTA and derivatives thereof, have one or more carboxy or amine groups. Accordingly, these chelators can be readily conjugated to spacer S3 using any of the amide coupling strategies known in the art. Some terms are used within the scope of the present invention, the meaning of which is explained below.
  • Theranostics Diagnostics and therapy of cancer diseases using nuclear medical radiotracers with analog targeting vectors.
  • Precursor Label A chemical compound containing a first and second targeting vector and a chelator or radioisotope labeling functional group.
  • Radiotracer A radioisotope-labeled tracer precursor for nuclear medicine diagnostics or theranostics that is used at low concentrations without affecting a patient's metabolism.
  • Target Biological target structure, in particular (membrane-bound) receptor, protein, enzyme or antibody in the living organism, to which a target vector binds.
  • Target Vector A chemical group or moiety that acts as a ligand, agonist, antagonist, or inhibitor for a biological target (eg, a protein, enzyme, or receptor) and has high binding affinity for that target.
  • Trislinker Structural unit with three functional groups for conjugation with a first, second and third spacer for a first and second target vector and a labeling group.
  • Spacer A structural unit, group or residue that links a first and second target vector and a labeling group to a tris-linker and functions as a steric and/or pharmacokinetic modulator.
  • NMR Nuclear magnetic resonance spectroscopy
  • ESI-LC/MS ESI-LC/MS mass spectra were acquired using the Agilent Technologies 1220 Infinity LC coupled to an Agilent Technologies 6130B Single Quadruple LC/MS system with an Agilent Zorbax SB-C18 column (21x50 mm, 1.8 ⁇ m ) with linear gradients of acetonitrile (ACN) / Milli-Q ® water (H 2 O) + 0.05% formic acid (HFo) and a flow rate of 0.5 mL/min.
  • ACN acetonitrile
  • Milli-Q ® water H 2 O + 0.05% formic acid (HFo)
  • HPLC-MS measurements were performed using an Agilent Technologies G6545A Q-ToF with electrospray ionization coupled to a 1260 Infinity II HPLC system (Agilent Technologies) with G7111B 1260 Quaternary Pump, G7129A 1260 Vialsampler and G7116A Multicolumn Thermostat.
  • the separation was performed with an Agilent Poroshell 120 EC-C8 column (2.1x100 mm, 2.7 ⁇ m) with H 2 O + 2% ACN / ACN + 2% H 2 O + 0.05% HFo and a flow rate of 0.1 mL/min .
  • Radio DC Radio DCs were evaluated using a CR-35 Bio Test imager and Raytest's AIDA software.
  • Radio-HPLC Analytical radio-HPLC was performed with an identical Merck Hitachi LaChrom-HPLC (7000 series). The separation was carried out using a Phenomenex Luna C18 column (250x4.6 mm, 5 ⁇ m) and a linear gradient of ACN/H 2 O + 0.1% TFA and a flow rate of 1 mL/min.
  • the radio-HPLC is additionally equipped with an analogue radio detector Ramona from Elysia Raytest, whose energy window is set to 100-1200 keV for 68 Ga measurements and to 100-250 keV for 177 Lu measurements.
  • Example 1 FAPi-NH 2 Scheme 10 shows the synthesis of FAPi-NH 2 .
  • 4-Bromobutylamine 4-aminobutanol (5.39 g, 60.47 mmol, 1.00 eq) was slowly treated with 70 mL of 47% hydrobromic acid and then heated under reflux for 4 h.
  • tert-butyl-(4-bromobutyl)carbamate 4-bromobutylamine (7.01 g, 30.09 mmol, 1.0 eq.) together with di-tert-butyldicarbonate (Boc 2 O, 7.34 g, 33.63 mmol, 1.12 eq.) under argon in dry THF (34 mL). Then TEA (4.6 mL, 36.12 mmol, 1.2 eq.) was added. MeOH (36 mL) was added to the resulting suspension until the solution became clear again and the mixture was then stirred at RT for 19 h.
  • Boc-Gly-Pro-CONH 2 (tert-Butyl-(S)-(2-(2-carbamoyl-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamate) Boc-Gly-OH (1.38 g , 7.88 mmol, 1.05 eq.) and HBTU (3.12 g, 8.20 mmol, 1.1 eq.) were dissolved in dry DCM (8 mL) and DMF (8 mL) under argon.
  • Boc-Gly-Pro-CN (tert-Butyl-(S)-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamate) Boc-Gly-Pro-CONH 2 ( 1.97 g, 6.41 mmol, 1.0 eq.) was dissolved in dry THF (50 mL) under argon and cooled to 0°C. Pyridine (4.1 mL, 51.3 mmol, 8.0 eq.) was added.
  • 6-Hydroxyquinoline-4-carboxylic acid hydrobromide 6-Methoxyquinoline-4-carboxylic acid (2.46 g, 12.1 mmol, 1.0 eq.) was dissolved in 47% HBr (28.18 mL, 242.42 mmol, 20 eq.) and heated under reflux for 1 d . After cooling to RT, the hydrobromic acid was partially removed in vacuo and the precipitate was then filtered and washed first with cold EA (20 mL) and then with a little cold EA/MeOH (90:10). A yellow solid (3.25 g, 12.1 mmol, 100%) was obtained.
  • Methyl 6-hydroxyquinoline-4-carboxylate First, dry MeOH (20 mL) was cooled to 0°C under argon and then SOCl2 (4.43 mL, 61.09 mmol, 5.0 eq.) was added dropwise. 6-Hydroxyquinoline-4-carboxylic acid hydrobromide was dissolved in dry MeOH (20 mL) and cooled to 0°C also under argon. Thereafter, the SOCl 2 -MeOH solution was added dropwise. the Reaction solution was warmed to RT and heated under reflux for 1 d. SOCl 2 (2.91 g, 24.44 mmol, 2 eq.) and MeOH (20 mL) were again combined at 0° C.
  • Boc-Chino-COOMe (6-(4-((tert-Butoxycarbonyl)amino)butoxy)quinoline-4-carboxylic acid methyl ester) Under argon, 6-hydroxyquinoline-4-carboxylic acid methyl ester (2.48 g, 12.1 mmol, 1.0 eq.) and Cs2CO3 (4.37 g, 13.4 mmol, 1.25 eq.) suspended in dry DMF (55 mL). The reaction solution was heated to 70°C.
  • tert-butyl-(4-bromobutyl)carbamate (3.76 g, 14.91 mmol, 1.22 eq.) was dissolved in dry DMF (80 mL) and added dropwise to the hot reaction mixture. The solution was stirred at 70°C for 3 h. After checking the reaction, tert-butyl-(4-bromobutyl)carbamate (1.23 g, 4.88 mmol, 0.4 eq.) was again dissolved in dry DMF (20 mL) and added to the reaction mixture. It was stirred at 70°C overnight.
  • HOBt (0.68 g, 5.01 mmol, 1.1 eq.) and HBTU (1.90 g, 5.01 mmol, 1.1 eq.) were added and the reaction mixture was stirred at RT for 1 h.
  • Gly-Pro-CN also dissolved in dry DMF (10 mL) and treated with DIPEA (1.93 mL, 11.38 mmol, 2.5 eq.), was then added and the entire reaction mixture was stirred at RT for a further 1 d. Thereafter, the solvent was removed in vacuo and the residue taken up in EA. The organic phase was washed with 1M citric acid, saturated Na 2 CO 3 and brine.
  • FAPi-NH 2 ((S)-6-(4-aminobutoxy)-N-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)quinoline-4-carboxamide)
  • FAPi- NHBoc (531.6 mg, 1.0 mmol, 1.0 eq) was dissolved in dry acetonitrile (10 mL) at 0 °C and under argon. 4 M HCl in 1,4-dioxane (5.0 mL, 5.0 mmol, 5.0 eq) and slowly warmed to RT.
  • Example 2 DOTA.Glu.(FAPi) 2 , DOTAGA.Glu.(FAPi) 2 , DATA 5m .Glu.(FAPi) 2
  • the following is the synthesis of the tag precursors DOTA.Glu.(FAPi) 2 , DOTAGA.Glu. (FAPi) 2 and DATA 5m .Glu.(FAPi) 2 described.
  • the initial synthetic steps are identical for all 3 compounds and a representative synthesis is shown in Scheme 11.
  • Boc-Glu.(FAPi) 2 (tert-butyl-((S)-1,5-bis((4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidine- 1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)amino)-1,5-dioxopentan-2-yl)carbamate) tert-butoxycarbonyl-L-glutamic acid (Boc-Glu-OH, 40 mg, 162 ⁇ mol, 1.0 eq), 1- hydroxybenzotrazole (HOBt, 55 mg, 405 ⁇ mol, 2.5 eq) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC*HCl, 78 mg, 405 ⁇ mol, 2.5 eq) were dissolved in dry N,N-dimethylformamide (DMF
  • Glu.(FAPi) 2 ((S)-2-amino-N 1 ,N 5 -bis(4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1- yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)pentanediamide)
  • Boc-Glu.(FAPi) 2 127 mg, 118 ⁇ mol
  • DOTA(tBu) 3 -NHS (2,2',2''-(10-(2-((2,5-dioxopyrrolidin-1-yl)oxy)-2-oxoethyl)-1,4,7,10 - tetraazacyclododecane-1,4,7-triyl)triacetic acid tert-butyl ester)
  • DOTA-tris(tert-butyl ester) 129 mg, 224 ⁇ mol, 1.0 eq
  • 2-(1H-benzotriazol-1-yl)-1, 1,3,3-Tetramethyluronium hexafluorophosphate (HBTU, 87 mg, 229 ⁇ mol, 1.0 eq) was dissolved in dry ACN (5 mL).
  • DOTA.Glu.(FAPi) 2 (2,2',2''-(10-(2-(((S)-1,5-bis((4-((4-((2-((S )-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)amino)-1,5-dioxopentan-2-yl)amino)-2 - oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid)
  • DOTA(tBu) 3 DOTA(tBu) 3 .
  • Glu.(FAPi) 2 50 ⁇ L Milli-Q ® water, 50 ⁇ L TIPS and 1.9 mL TFA (TFA:TIPS:H 2 O (95:2.5:2.5)) and stirred at RT for 8 h
  • a high radiochemical conversion of >98% could be achieved.
  • the stability is more than 98% after 2 hours in HS and PBS (see FIG. 3).
  • the logD value was determined to be -2.08 ⁇ 0.07.
  • DOTAGA(tBu)4.Glu.(FAPi) 2 (2,2',2''-(10-(5-(((S)-1,5-bis((4-((4-((2 -((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)amino)-1,5-dioxopentan-2-yl) amino)-1-(tert-butoxy)-1,5-dioxopentan-2-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid tert-butyl ester) DOTAGA(tBu) 4 (60 mg, 85.6 ⁇ mol, 1.0 eq) and O-(7-(7-
  • DOTAGA.Glu.(FAPi) 2 (2,2',2''-(10-(4-(((S)-1,5-bis((4-((4-((2-((S )-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)amino)-1,5-dioxopentan-2-yl)amino)-1 - carboxy-4-oxobutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid)
  • DOTAGA(tBu) 4 .
  • Glu.(FAPi) 2 add 50 ⁇ L Milli-Q ® water, 50 ⁇ L TIPS and 1.9 mL TFA (TFA:TIPS:H 2 O (95:2.5:2.5)) and stirred at RT for 7 h.
  • a high radiochemical conversion of >97% could be achieved.
  • the stability is more than 95% after 2 hours in HS and PBS (see FIG. 9).
  • the logD value was determined to be -2.48 ⁇ 0.05.
  • AMC Z-Gly-Pro-7-amino-4-methylcumaine
  • Table 2 summarizes the results of the IC 50 measurements.
  • the selectivity index (SI) results from the ratio of the IC 50 value of FAP and the respective competitor enzyme (PREP, DPP4, DPP8, DPP9).
  • Table 2 IC 50 measured values of the compounds DOTAGA.Glu.(FAPi) 2 , DOTA.Glu.(FAPi) 2 and DATA 5m .Glu.(FAPi) 2 and the established FAP inhibitor UAMC1110 (see scheme 4 right) .
  • Example 3 DOTA.NPyr.(FAPi) 2 , DOTAGA.NPyr.(FAPi) 2
  • the synthesis of the tag precursors DOTA.NPyr.(FAPi) 2 , DOTAGA.NPyr.(FAPi) 2 is described below. The initial synthetic steps are identical for both compounds and a representative synthesis is shown in Scheme 14.
  • Boc-NPyr(OBzl) 2 ((S)-2,2'-((1-(tert-Butoxycarbonyl)pyrrolidin-3-yl)azanediyl)-diacetic acid benzyl ester) (S)-1-Boc-3-aminopyrrolidine (1.07 g, 5.74 mmol, 1.0 eq) and DIPEA (1.5 mL) were dissolved in acetonitrile (6 mL).
  • Boc-NPyr(OBzl) 2 (1.31 g, 2.71 mmol, 47%) as a side product along with Boc-NPyr-OBzl (benzyl-(S)- N-(pyrrolidine-3-tert-butoxy-carbamate)glycine, 680 mg, 2.03 mmol, 35%).
  • Boc-NPyr.(FAPi) 2 (tert-butyl (S)-3-(bis(2-((4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidine- 1-yl)-2- oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)amino)-2-oxoethyl)amino)pyrrolidine-1- carboxylate)
  • Boc-NPyr (30.2 mg, 100 ⁇ mol, 1.0 eq)
  • HOBt 36 mg, 266 ⁇ mol, 2.7 eq
  • EDC*HCl 50 mg, 260 ⁇ mol, 2.6 eq
  • NPyr.(FAPi) 2 (6,6'-((((2,2'-(((S)-pyrrolidin-3-yl)azanediyl)bis(acetyl))bis(azanediyl)))bis(butane-4 ,1-diyl))bis(oxy))bis(N-(2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)quinoline-4-carboxamide) Zu Boc -NPyr.(FAPi) 2 (102 mg, 90 ⁇ mol) was added to 50 ⁇ L Milli-Q ® water, 50 ⁇ L triisopropylsilane (TIPS) and 1.9 mL TFA (TFA:TIPS:H 2 O (95:2.5:2, 5)) and stirred for 1 h at RT.
  • TIPS triisopropylsilane
  • DOTA(tBu) 3 .NPyr.(FAPi) 2 (2,2',2''-(10-(2-((S)-3-(Bis(2-((4-((4-((4-(( 2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)amino)-2-oxoethyl)amino)pyrrolidine-1 -yl)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7- triyl)triacetic acid tert-butyl ester) DOTA(tBu) 3 -NHS (33.5 mg, 50 ⁇ mol, 1.25 eq) was dissolved in dry DMF (1 mL)
  • DOTA.NPyr.(FAPi) 2 (2,2',2''-(10-(2-((S)-3-(Bis(2-((4-((4-((4-((2-(( S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)amino)-2-oxoethyl)amino)pyrrolidin-1-yl)- 2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid)
  • DOTA(tBu) 3 NOTA(tBu) 3 .
  • NFA Triacetic acid
  • DOTAGA(tBu) 4 .NPyr.(FAPi) 2 (2,2',2''-(10-(5-((S)-3-(Bis(2-((4-((4-((4-(( 2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)amino)-2-oxoethyl)amino)pyrrolidine-1 -yl)-1-(tert-butoxy)-1,5-dioxopentan-2-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid tert-butyl ester) DOTAGA(tBu ) 4 (23.5 mg, 33.5 ⁇ mol, 1.0 eq), NHS (8.0 mg, 70 ⁇ mol, 2.0 eq) and HB
  • DOTAGA.NPyr.(FAPi) 2 (2,2',2''-(10-(4-((S)-3-(bis(2-((4-((4-((4-((2-(( S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)amino)-2-oxoethyl)amino)pyrrolidin-1-yl)- 1-carboxy-4-oxobutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid)
  • DOTA(tBu) 3 .NPyr.(FAPi) 2 was added 50 ⁇ L of Milli-Q ® water , 50 ⁇ L TIPS and 1.9 mL TFA (TFA:TIPS:H 2 O (95:2.5:2.5)) and
  • Example 4 DOTA.PEG2.Glu.(FAPi) 2 , DOTAGA.PEG2.Glu.(FAPi) 2
  • the following describes the synthesis of the tag precursors DOTA.PEG2.Glu.(FAPi) 2 , DOTAGA.PEG2.Glu.(FAPi ) 2 described.
  • the initial synthetic steps are identical for both compounds and a representative synthesis is shown in Scheme 17.
  • Fmoc-PEG2.Glu(OBzl) 2 ((1-(9H-Fluoren-9-yl)-3-oxo-2,7,10-trioxa-4-azatridecan-13-oyl)-L-glutamic acid dibenzyl ester)
  • the Fmoc -N-amido-dPEG2-acid 450.0 mg, 1.1 mmol, 1.00 eq.
  • DIPEA 182.0 mg, 240 ⁇ L, 1.4 mmol, 1.25 eq.
  • HBTU 470.3 mg, 1.2 mmol, 1.10 eq.
  • HOBt 167.6 mg, 1.2 mmol, 1.10 eq.
  • the colorless solution was stirred under an argon atmosphere at 25° C. for 24 h. After one hour, dibenzyl glutamate (460.6 mg, 1.4 mmol, 1.25 eq.) and DIPEA (320.5 mg, 422 ⁇ L, 4.5 mmol, 2.20 eq.) dissolved in dry DMF (3.0 mL) were added. After the reaction had ended, the solvent was removed under reduced pressure and the yellowish oil was purified by column chromatography (DCM:MeOH (100:2)). The Fmoc-PEG2.Glu(OBzl) 2 (795.1 mg, 1.1 mmol, 99%) was obtained as a colorless oil.
  • THF dry tetrahydrofuran
  • Fmoc-PEG2.Glu.(FAPi) 2 ((9H-Fluoren-9-yl)methyl ((11S)-19-((4-((2-(2-cyano-4,4-difluoropyrrolidin-1-yl )-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)-11-((4-((4-((2-(2-cyano-4,4-difluoropyrrolidin-1-yl))-2-oxoethyl )carbamoyl)quinolin-6-yl)oxy)butyl)carbamoyl)-9,14-dioxo- 3,6-dioxa-10,15-diazanonadecyl)carbamate) Fmoc-PEG2.Glu (32.0 mg, 60.0 ⁇ mol, 1.00 eq .) was dissolved in dry DMF (1.0 mL) together with HOBt (2
  • DOTA.PEG2.Glu.(FAPi) 2 (2,2',2''-(10-(2-(((S)-1,5-bis((4-((4-((2-( (S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)amino)-1,5-dioxopentan-2-yl)amino) -2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid)
  • DOTA(tBu) 3 50 ⁇ L water, 50 ⁇ L TIPS and Added 1.5 mL trifluoroacetic acid (TFA).
  • the brown solution was stirred at room temperature for 5 h and the solvents removed under reduced pressure.
  • HBTU 0.8 mg, 28.6 ⁇ mol, 2.00 eq.
  • NHS 3.3 g, 28.6 ⁇ mol, 2.00 eq.
  • the colorless solution stirred under an argon atmosphere.
  • more HBTU 5.4 mg, 14.3 ⁇ mol, 1.00 eq.
  • NHS 1.6 mg, 14.3 ⁇ mol, 1.00 eq.
  • DOTAGA.PEG2.Glu.(FAPi) 2 (2,2',2''-(10-((20S)-28-((4-((2-(2-cyano-4,4-difluoropyrrolidine-1 -yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)-20-((4-((4-((2-(2-cyano-4,4-difluoropyrrolidin-1-yl))-2 - oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)carbamoyl)-2,2-dimethyl-4,8,18,23-tetraoxo-3,12,15-trioxa-9,19,24-triazaoctacosane- 5-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid)
  • Example 5 DOTA.Glu.Glu.(FAPi) 2 , DOTAGA.Glu.Glu.(FAPi) 2
  • the synthesis of the tag precursors DOTA.Glu.Glu.(FAPi) 2 and DOTAGA.Glu.Glu.(FAPi) 2 is illustrated below in Scheme 20. The first synthetic steps are identical for both compounds.
  • Fmoc-Glu(OtBu).Glu(OBzl) 2 ((S)-4-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-5-(tert-butoxy)-5-oxopentanoyl) -L-glutamic acid dibenzyl ester)
  • Fmoc-Glu-OtBu (400.0 mg, 0.94 mmol, 1.00 eq.) was dissolved in dry DMF (2.0 mL) and DIPEA (151.9 mg, 200 ⁇ L, 1.2 mmol, 1.25 eq.) and HATU (393.2 mg, 1.0 mmol, 1.10 eq.) was added. The solution was then stirred at 25° C.
  • Fmoc-Glu(OtBu).Glu.(FAPi) 2 (N 2 -(((9H-Fluoren-9-yl)methoxy)carbonyl)-N 5 -((2S)-1,5-bis((4- ((4-((2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)amino)-1,5-dioxopentane-2 -yl)-L-glutamic acid tert-butyl ester) Fmoc-Glu(OtBu).Glu (33.3 mg, 60.0 ⁇ mol, 1.00 eq.) was combined with HOBt (20.4 mg, 15.0 ⁇ mol, 2.50 eq.) and EDC*HCl (28.8 mg, 15.0 ⁇ mol, 2.50 eq.) dissolved in dry DMF (2.5 mL
  • FAPi*TFA (65.4 mg, 12.0 ⁇ mol, 2.00 eq.) and DIPEA (23.3 mg, 31 ⁇ L, 18.0 ⁇ mol, 3.00 eq.) dissolved in dry DMF (0.5 mL) were added.
  • DIPEA 7.8 mg, 60.0 ⁇ mol, 1.00 eq.
  • EDC*HCl 11.4 mg, 60.0 ⁇ mol, 1.00 eq.
  • 30 min later half an equivalent of FAPi*TFA (16.5 mg, 30.0 ⁇ mol , 0.50 eq.) dissolved in one equivalent of DIPEA (7.8 mg, 10 ⁇ L, 60.0 ⁇ mol, 1.00 eq.) and 0.5 mL DMF added.
  • HOBt (3.9 mg, 30.0 ⁇ mol, 0.50 eq.) and EDC*HCl (5.7 mg, 30.0 ⁇ mol, 0.50 eq.) were added again and after one hour further FAPi*TFA (16.5 mg, 30.0 ⁇ mol, 0.50 eq .) and DIPEA (3.9 mg, 5 ⁇ L, 30.0 ⁇ mol, 0.50 eq.) dissolved in DMF (0.5 mL). This step was repeated one more time the next day. The slightly yellowish solution was then stirred for a further day and then the solvent removed under reduced pressure.
  • Glu(OtBu).Glu.(FAPi) 2 N 5 -((2S)-1,5-bis((4-((4-((2-(2-cyano-4,4-difluoropyrrolidine-1- yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)amino)-1,5-dioxopentan-2-yl)-L-glutamic acid tert-butyl ester) Fmoc-Glu(OtBu).Glu.
  • DOTA(tBu) 3 .Glu(OtBu).
  • Glu.(FAPi) 2 (2,2',2''-(10-(2-(((2S)-5-(((2S)-1,5 -bis((4-((4-((2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)amino)-1 ,5-dioxopentan-2-ylamino)-1-(tert-butoxy)-1,5-dioxopentan-2-ylamino)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1, 4,7-triyl)triacetic acid tert-butyl ester)
  • the DOTA(tBu) 3 .Glu(OtBu).
  • Glu.(FAPi) 2
  • the slightly yellowish solution was stirred under an argon atmosphere at 40° C. for 24 h and then the solvent was removed under reduced pressure.
  • the yellowish oil obtained was then dissolved in 0.5 mL dry DMF and DIPEA (3.4 mg, 4 ⁇ L, 26.1 ⁇ mol, 1.00 eq.) was added.
  • DOTA (17.5 mg, 26.1 ⁇ mol, 1.00 eq.
  • HATU (14.9 mg, 39.2 ⁇ mol, 1.50 eq.
  • DIPEA 6.7 mg, 9 ⁇ L, 52.2 ⁇ mol, 2.00 eq.
  • the colorless solution was stirred under an argon atmosphere for 4 h and HBTU (12.4 mg, 32.6 ⁇ mol, 1.00 eq.) and NHS (3.8 mg, 32.6 ⁇ mol, 1.00 eq.) dissolved in DMF (0.2 mL) were added. Then the Glu(OtBu).Glu.(FAPi) 2 (30.3 mg, 26.1 ⁇ mol, 1.00 eq.) dissolved in DMF (1.0 mL) and 1 vol% DIPEA (19 mg, 25 ⁇ L, 147.0 ⁇ mol) was added. The colorless solution was stirred at room temperature overnight and the next day the solvent was removed under reduced pressure. A yellowish oil was obtained and reacted further without working up.
  • DOTAGA.Glu.Glu.(FAPi) 2 (2,2',2''-(10-(4-(((1S)-4-(((2S)-1,5-bis((4-( (4-((2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)amino)-1,5-dioxopentane-2- yl)amino)-1-carboxy-4-oxobutyl)amino)-1-carboxy-4-oxobutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid)
  • TFA trifluoroacetic acid
  • Example 7 Examples of compounds according to the invention with a spacer unit (S3) are shown below.
  • Example 8 Examples of compounds according to the invention with two spacer units (S1+S2) are shown below.
  • Example 9 Examples of compounds according to the invention with three spacer units (S1+S2+S3) are shown below.

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CN113880810B (zh) * 2021-09-24 2023-02-28 厦门大学 一种核素标记的配合物及其制备方法和应用

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AU2022288744A1 (en) 2023-12-14
WO2022258637A1 (de) 2022-12-15
JP2024522200A (ja) 2024-06-11
KR20240019301A (ko) 2024-02-14
BR112023023149A2 (pt) 2024-01-23
DE102021114711B4 (de) 2023-11-02
DE102021114711A1 (de) 2022-12-08
CA3222226A1 (en) 2022-12-15

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