EA040919B1 - 177Lu-DOTA-HYNIC-iPSMA AS A THERAPEUTIC RADIOPHARMACEUTICAL AGENTS TARGETING PROSTATE SPECIFIC MEMBRANE ANTIGEN - Google Patents

Description

The new radiopharmaceutical ¹⁷⁷ Lu-DOTA-HYNIC-iPSMA accumulates with high affinity in vivo in tumors overexpressing the PSMA protein, acting as a radiotherapeutic agent. The object of the present invention is to provide a novel radiopharmaceutical (molecular target radiopharmaceutical) for the treatment of PSMA overexpressing tumors.

The field of technology to which the present invention relates

The present invention relates to a novel lutetium-177 based therapeutic radiopharmaceutical as an inhibitor of prostate specific membrane antigen (iPSMA) wherein 1,4,7,10-tetraazacyclolodecano-N,N',N,N-tetraacetic acid (DOTA) , associated with a molecule of hydrazinonicotinamide (HYNIC), which is heterocyclic in nature, forms a rigid chemical structure that minimizes the number of conformers and intramolecular hydrogen bonds, thus leading to a spatial orientation of the active site (Lys(Nal)-NH-CO-NH- Glu) in a molecule that promotes biological recognition by the PSMA protein. The novel radiopharmaceutical ¹⁷⁷ Lu-DOTA-HYNIC-iPSMA accumulates in tumors overexpressing the PSMA protein with high affinity in vivo, thus acting as a radiotherapeutic agent.

Background of the Invention

Prostate cancer (PC) is the second most common cancer among men worldwide [Jemal A. et al., Cancer statistics, 2010; Cancer C.A., J. Clin., 2010, 60: 277-300]. In patients with localized PC, the five-year survival rate is close to 100%, while in patients with metastases, the five-year survival rate is 31% [Wei Q. et al., Global analysis of differentially expressed genes in androgen-independent prostate cancer, Prostate Cancer Prostatic Dis., 2007, 10: 167-174]. Almost all patients with metastases initially respond well to antiandrogen therapy. However, the main cause of death in patients with MS is the development of androgen independence.

The enzyme glutamate carboxypeptidase II, also known as prostate specific membrane antigen (PSMA), is expressed in prostate epithelial cells and is highly overexpressed in 95% of advanced prostate cancers. PSMA expression levels directly correlate with androgen independence, metastasis, and progression of PC [Santoni M. et al., Targeting prostate-specific membrane antigen for personalized therapies in prostate cancer: morphologic and molecular backgrounds and future promises, J. Biol. Regul. homeost. Agents., 2014, 28: 555-563]. Thus, PSMA is a suitable molecular target for image analysis-based detection and radiotherapy of metastatic prostate cancer using specific radiopharmaceuticals. The PSMA gene consists of 19 exons, representing approximately 60 kb of genomic DNA. This gene encodes a type II transmembrane protein with a short cytoplasmic fragment (19 amino acids), a hydrophobic transmembrane domain (24 amino acids) and a large extracellular domain (707 amino acids). PSMA contains Zn in the active site of the enzyme, so the sequence Glu-NH-CO-NH-Lys(β-naftulalanine)=Glu-NHCO-NH-Lys(Nal) has been proposed as an effective inhibitor of its activity [Benesovd M. et al. , Preclinical evaluation of a tailor-made DOTA-conjugated PSMA inhibitor with optimized linker moiety for imaging and endoradiotherapy of prostate cancer, J. Nucl. Med., 56, 2015: 914-920]. In a specific chemical interaction, the three carboxyl groups of the Glu-NH-CO-NH-Lys fragment electrostatically interact with the peptide side chains in the PSMA active site, the urea oxygen coordinates with zinc, and the aromatic structure in Nal interacts to provide binding to the active hydrophobic site of the enzyme. Recent clinical studies have shown that the use of two different Lu-177-labeled PSMA inhibitor derivatives, namely ¹⁷⁷ Lu-PSMA-617 and ¹⁷⁷ Lu-PSMA-I&T, results in a significant decrease in prostate antigen (PSA) levels in 50-70% of patients with PC without serious side effects, which significantly increases patient survival [Ahmadzadehfar H. et al., Early side effects and first results of radioligand therapy with ¹⁷⁷ Lu-DKFZ-617 PSMA of castrate-resistant metastatic prostate cancer: a two-center study , EJNMMI Res., 2015, 5:36; Kratochwil C. et al., [ ¹⁷⁷ Lu] Lutetium-labelled PSMA ligand-induced remission in a patient with metastatic prostate cancer, Eur. J. Nucl. Med. Mol. Imaging, 42, 2015: 987-988; Weineisen M. et al., ⁶⁸ Ga- and ¹⁷⁷ Lu-Labeled PSMA I&T: Optimization of a PSMA-Targeted Theranostic Concept and First Proof-of-Concept Human Studies, J. Nucl. Med., 2015, 56: 1169-1176; Baum RP et al., Lutetium-177 PSMA radioligand therapy of metastatic castration-resistant prostate cancer: safety and efficacy, J. Nucl. Med., 2016, 57: 1006-1013; Kratochwil C. et al., PSMA-targeted radionuclide therapy of metastatic castration-resistant prostate cancer with Lu177 labeled PSMA-617, J. Nucl. Med., 2016, 57: 1170-1176; Rahbar K. et al., Response to and tolerability of a single dose of ¹⁷⁷ Lu-PSMA-617 in patients with metastatic castration-resistant prostate cancer: a multicenter retrospective analysis, J. Nucl. Med., 2016, 57: 1334-1338; Rahbar K. et al., German Multicenter Study Investigating ¹⁷⁷ Lu-PSMA-617 Radioligand Therapy in Advanced Prostate Cancer Patients, J. Nucl. Med., 2017, 58: 85-90]. The PSMA protein is multifunctional in that it can act as an internalization receptor, a nutrient absorption enzyme, or as a peptidase that plays a role in signal transduction in epithelial cells and in cell migration [Rajasekaran A. et al., Is prostatespecific membrane antigen a multifunctional protein ?, American Journal of Physiology - Cell Physiology, 2005, 288: C975-C981]. Thus, PSMA-inhibiting radiopharmaceuticals can also be used in other neoplasms other than PC, such as metastatic breast cancer, osteosarcoma, glioma, and differentiated thyroid cancer, among others [la Fougere et al., In vivo visualization of prostate-specific membrane antigen in glioblastoma, Eur. J. Nucl.

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Med. and Mol. Imaging, 2015, 42: 170-171; Verburg FA et al., First evidence of PSMA expression in differentiated thyroid cancer using [ ⁶⁸ Ga] PSMA-HBED-CC PET/CT, Eur. J. Nucl. Med. and Mol. Imaging, 2015,

42: 1622-1623; Zeng C. et al., Prostate-specific membrane antigen: a new potential prognostic marker of osteosarcoma, Medical Oncology, 2012, 29: 2234-2239; Sathekge M. el al, ⁶⁸ Ga-PSMA imaging of metastatic breast cancer, Eur. J. Nucl. Med. and Mol. Imaging, 2015, 42:1482-1483].

However, prior to any radiotherapy treatment, it is necessary to evaluate the uptake of the radiopharmaceutical in tumors or their metastases by radionuclide imaging to confirm whether the treatment will be beneficial to the patient or not, and to determine the activity that should be administered to provide an ablative dose of radiation in tumors, other in other words, personalized and theranostic medicine is used. To this end, PSMA-inhibiting diagnostic radiopharmaceuticals need to be used for molecular imaging by positron emission tomography (PET) or single photon emission computed tomography (SPECT), with ⁶⁸ Ga-PSMA-11 (PET) being the most widely used in in clinical practice due to its high sensitivity and specificity [Eder M. et al., Novelpreclinical and radiopharmaceutical aspects of [ ⁶⁸ Ga] Ga-PSMA-HBED-CC: a new PET tracer for imaging of prostate cancer, Pharmaceuticals, 2014, 7 : 779-796; Eder M. et al., 68Ga-complex lipophilicity and the targeting property of a urea-based PSMA inhibitor for PET imaging, Bioconjugate Chem, 2012, 23: 688-697; Weineisen et al., ⁶⁸ Ga- and ¹⁷⁷ Lu-labeled PSMA I&T: optimization of a PSMA-targeted theranostic concept and first proof-of-concept human studies, J. Nucl. Med., 2015, 56: 1169-1176; Afshar-Oromieh A. et al., Comparison of PET/CT and PET/MRI hybrid systems using ⁶⁸ Ga-labeled PSMA ligandfor the diagnosis of recurrent prostate cancer: initial experience, Eur. J. Nucl. Med. and Molecular Imaging, 41.5 (2014), 887-897].

However, both nationally and internationally, SPECT research accounts for more than 70% of all research conducted in nuclear medicine, due to its lower cost and greater availability of equipment and radionuclides, since there is no need for a cyclotron in or near hospitals. The most widely used radionuclide for SPECT imaging is ^99m Tc, and recently ^99m Tc EDDA/HYNIC-iPSMA has been introduced as a radiopharmaceutical that inhibits prostate specific membrane antigen (iPSMA) containing hydrazinonicotinamide (HYNIC) as the main chemical group to increase the lipophilicity of the molecule for binding to hydrophobic sites in PSMA, in combination with the conventional use of HYNIC as a chelating agent for the ^99m Tc radiometal, with ethylenediaminoacetic acid (EDDA) being used to complete the coordination sphere of the radiometal. ^99m Tc-EDDA/HYNIC/iPSMA radiopharmaceutical detects PSMA protein overexpressed in prostate cancer cells with high affinity in vivo using nuclear medicine SPECT molecular imaging techniques [Ferro-Flores G. et al., Clinical translation of a PSMA inhibitor for ^99m Tc-based SPECT, Nucl. Med. Bici, 2017, 48: 36-44; Santos-Cuevas et al., ^99m Tc-EDDA/HYNIC-iPSMA: Biokinetics and Radiation Dosimetry in Healthy Subjects and Tumor Imaging in Patients with Prostate Cancer, Nucl. Med. Biol., 2017, 52: 1-6; Lawal IO et al., Diagnostic sensitivity of Tc-99m HYNIC PSMA SPECT/CT in prostate carcinoma: A comparative analysis with Ga-68 PSMA PET/CT, The Prostate, 2017, 1-8; Ferro-Flores G. et al., 99mTc-EDDA/HYNIC-iPSMA as a radiopharmaceuticai for detecting the overexpression of prostate-specific membrane antigen, WO 2017222362, PCT/MX2017/000068].

In order to develop a theranostic pair for the HYNIC-iPSMA ligand that can be labeled with Lu-177, it is proposed herein to link the DOTA molecule to HYNIC, thus forming a rigid chemical structure that minimizes the number of conformers and intramolecular hydrogen bonds, thus leading to spatial orientation of the active site (Lys(Nal)-NH-CO-NH-Glu) in the molecule, which promotes biological recognition by the PSMA protein.

Detailed disclosure of the present invention

The present invention relates to a novel lutetium-177 radiopharmaceutical that can inhibit prostate specific membrane antigen (iPSMA) and which contains 1,4,7,10-tetraazacyclododecano-N,N',N,N-tetraacetic acid (DOTA) , bound to a hydrazinonicotinamide (HYNIC) molecule that is heterocyclic in nature, thus forming a rigid chemical structure that minimizes the number of conformers and intramolecular hydrogen bonds, thus leading to a spatial orientation of the active site (Lys(Nal)-NH-CO- NH-Glu) in a molecule that promotes biological recognition by the PSMA protein. The new radiopharmaceutical ¹⁷⁷ Lu-DOTA-HYNIC-iPSMA accumulates in tumors overexpressing the PSMA protein with high affinity in vivo, thus acting as a radiotherapeutic agent. The structure of the radiopharmaceutical of the present invention ( ¹⁷⁷ Lu-DOTA-HYNIC-iPSMA) is shown in FIG. 1.

It is well known that, due to its heterocyclic nature, pyridine has a dipole moment and a lower resonance energy than benzene (117 kJ-mol' ¹ for pyridine compared to 150 kJ-mol' ¹ for benzene), as well as a shorter C-N bond (137 pm) compared to 139 pm

- 2 040919 for C-C bonds in benzene and cyclohexane [Elschenbroich C., Organometallchemie, 6th ed., 2008, ISBN 3-83510167-6]. The ¹⁷⁷ Lu-DOTA-HYNIC-iPSMA derivative was designed and synthesized to provide a poorly reactive and rigid chemical structure in the HYNIC region that minimizes the number of conformers and intramolecular hydrogen bonds compared to the ¹⁷⁷ Lu-PSMA-617 and ¹⁷⁷ Lu-PSMA-I&T derivatives. . The table below presents comparative results of molecular properties and optimal structural geometry of various PSMA inhibitors. The PSMA617, DOTA-HYNIC-iPSMA and PSMA-I&T ligands were designed based on valency, binding type, charge and hybridization. The lowest energy conformer (obtained using extended MM3) and the lowest energy conformer (CONFLEX method) according to the optimal geometry of their structures were obtained using CAChe Work System Pro software. The optimal geometric structures were confirmed using quantum mechanical methods using the Schrödinger equation with MOPAC (molecular orbital), by which the heat of formation in water (COSMO) is calculated. Lutetium complexes were constructed from these structures, and the results of extended MM3 (molecular mechanics), the CONFLEX technique, and the most stable and optimal geometric structure are presented for radiopharmaceuticals Lu-PSMA-617, Lu DOTA-HYNIC-iPSMA and Lu-PSMA-I&T. Based on the data presented in the table, it can be seen that the Lu DOTA-HYNIC-iPSMA molecule is more stable than Lu-PSMA-617 according to the energy of the most stable conformer (lower energy) and the lower total number of conformers and Lu-DOTA-HYNIC-iPSMA forms less hydrogen bonds than Lu-PSMA-617 and Lu-PSMA-I&T. It should be noted that hydrogen bonds play a key role in the spatial conformation

Molecular properties of three PSMA protein inhibitory ligands with evidence of tumor uptake and radiotherapeutic effect demonstrated in clinical studies when coordinated with Lu-177

Calculation (kcal/mol) PSMA-617 Lu-PSMA-617 DOTA-HYNIC- IPSMA Lu-DOTA- HYNIC-IPSMA PSMA-I&T Lu-PSMA-I&T Minimum energy (MM3) 87.795 -49.038 106.412 -76.360 105.652 -81.031 electrostatic charge -20.447 -197.887 -10.061 -206.795 -22.131 -210.822 hydrogen bond 25.317 27.070 22.253 19.984 27.304 35.499 Van der Waals 45.671 58.033 50.036 71.704 50,840 127.435 Strength (tensile) 6.994 10.184 7.398 26.970 9.471 50,100 Corner 16.360 36.203 20.704 84.579 20.504 143.558 Flexural strength 0.937 1.196 1.117 4.282 1.180 8.849 Dihedral 14.232 32.247 15.863 42.282 20.508 83.716 Wrong twist 0.173 0.375 0.264 0.290 0.207 1.064 Torsional strength -1.288 -1.925 -1.159 -3.269 -1,803 -6.234 Link binding -0.154 0.841 -0.003 3.044 -0.426 8.513 CONFLEX Energy of the most stable conformer Number of stored conformers 74.127 1131 -48.229 46 78.386 438 -76.241 24 39.006 498 -275.044 9 MORAS/PM5 (heat of formation) -715.945 -623.942 -1033.201 MOPAC/PM5/COSMO (heat of formation in water) -788.083 -698,534 -1136.015

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Optimal Geometry for Lu-PSMA-617 Radiopharmaceutical

Optimal Geometry for Lu-DOTA-HYNIC-IPSMA Radiopharmaceutical

Optimal Geometry for a Radiopharmaceutical

Lu-PSMA-I&T

Lu-PSMA-I&T shows the lowest number of conformers with the lowest minimum energy, and the hydrophobic rings of the molecule break their conformation upon orientation, mainly due to these weak hydrogen interactions with the ¹⁷⁷ Lu-DOTA ring (benzene-[myodophenol] ^-177 interactions). Lu-DOTA). Thus, the optimal structural geometry of the various radiopharmaceuticals presented in the table indicates a suitable spatial conformation for Lu-DOTA-HYNIC-iPSMA, which leads to a spatial orientation (without significant intramolecular interactions) for the active site (Lys(Nal)-NH- CO-NH-Glu) a molecule that promotes biological recognition by the PSMA protein. In other words, the three carboxyl groups of the Glu-NH-CO-NH-Lys fragment remain free for electrostatic interaction with the peptide side chains in the PSMA active site, the urea oxygen coordinates to zinc, and the aromatic structure in Nal binds to the active hydrophobic site in the enzyme.

Moreover, in the structure of the radiopharmaceutical of the present invention, HYNIC is not used as a radiometal chelating molecule, while in other radiopharmaceuticals, HYNIC is used only as a bifunctional ^99m Tc labeling agent [Decristoforo C. et al., 99mTc-EDDA/HYNIC -TOC: a new ^99m Tc-labelled radiopharmaceutical for imaging somatostatin receptor-positive tumours; first clinical results and intra-patient comparison with ¹¹¹ Inlabelled octreotide derivatives, 2000, J. Nucl. Med., 27, 1318-25; Ferro-Flores G. et al., Preparation and Evaluation of ^99m Tc-EDDA/HYNlC-[Lys ³ ]-Bombesin for Imaging of GRP Receptor-Positive Tumors, Nucl. Med. Comm., 2006, 27: 371-376; Gonzalez-Vazquez A. et al., Dosimetry and Biokinetics of ^99m Tc-EDDA/HYNICTyr ³ -Octreotide Prepared from Lyophilized Kits, Appl. red. Isot., 2006, 64: 792-79; Ortiz-Arzate Z. et al., Kit preparation and biokinetics in women of ^99m Tc-EDDA/HYNIC-E-[c(RGDfK)] ₂ for breast cancer imaging, Nucl. Med. Common., 2014, 35: 423-32; Medina-Garcia V. el al., A Freeze-Dried Kit Formulation for the Preparation of Lys ²⁷ ( ^99m Tc-EDDA/HYNIC)-Exendin(9-39)/ ^99m Tc-EDDA/HYNIC-Tyr ³ -Octreotide to Detect Benign and Malignant Insulinomas, Nucl. Med. Biol., 2015, 42: 911-916].

A method for producing a radiopharmaceutical agent according to the present invention.

The p-tert-butyl ester of glutamic acid was first used to synthesize the molecule, said ester being reacted with carbonyldiimidazole (CDI) in the presence of triethylamine (TEA) to form an acylimidazole derivative which was activated with methyl triflate (MeOTf) to react with (S)-tert -butyl-2-amino-6-(benzyloxycarbonylamino)hexanoate (Cbz-Lys-Ot-Bu) followed by removal of the Cbz protecting group by hydrogenolysis, thus obtaining a Glu-Urea-Lys derivative, which was reacted with the amino acid Fmoc-in -naphthylalanine (HBTU/HOBt) in solid phase (MBHA resin) and then with 6-Boc-hydrazinopyridine-3-carboxylic acid

- 4 040919 (Boc-HYNIC) in the presence of diisopropylethyleneamine (DIPEA) and dimethylformamide (DMF) followed by the addition of TFA. This last addition step was repeated to introduce DOTA-tris (tert-butyl ester). Finally, the compound was deprotected with TFA, purified by HPLC and lyophilized. The end product was Glu-NH-CO-NH-Lys(enaphthalanine)-HYNIC-DOTA (DOTA-HYMC-iPSMA) which showed the expected mass spectrum shown in FIG. 2. Analysis of the lyophilized solid by reverse phase HPLC indicated a chemical purity of 98.8% for the compound.

DOTA-HYNIC-iPSMA (0.6 mg) was prepared as a lyophilized pharmaceutical form containing 50 mg of mannitol and 100 mg of ascorbic acid. After reconstitution in 1.1 ml of 1 M sodium acetate buffer pH 5.0 containing a sterile and apyrogenic solution of lutetium-177 chloride ( ¹⁷⁷ LuCl ₃ ), and incubation in a dry bath at 95°C for 30 min, the indicated composition provided a clear aqueous solution of the compound of the present invention ¹⁷⁷ Lu-DOTA-HYNIC-iPSMA (FIG. 1) with radiochemical purity greater than 98% as determined by reverse phase HPLC which showed the radiochromatogram shown in FIG. 3.

The radiopharmaceutical remains stable with a radiochemical purity greater than 98% for more than 7 days after labeling. In vitro stability studies in human serum have shown serum protein binding of 6.5±1.8% and high radiochemical stability (>98%). The affinity of ¹⁷⁷ Lu-DOTA-HYNIC-iPSMA, as determined from saturation studies in PSMA protein (LNCaP) positive cancer cells, showed a Kd of 6.33±2.69 nM and a maximum number of binding sites (B _max ) equal to 5.89±0.47 nM.

The compound showed no toxicity or side effects when administered at a dose of 40 mg/kg to balb-C laboratory mice. Biodistribution analyzes of ¹⁷⁷ Lu-DOTA-HYNIC-iPSMA in athymic mice with LNCaP-induced tumors showed an uptake in these tumors equal to 9.74±1.13% of the activity introduced per gram of tissue (% ID/g), mainly by excretion by the kidneys.

To determine the biokinetics and dosimetry of the radiopharmaceutical, whole body images were obtained from five healthy subjects at 20 min and 6, 24, 48, and 120 h after administration of ¹⁷⁷ Lu-DOTA-HYNIC-iPSMA (185 MBq). The image sequence was used to extrapolate activity versus time curves in each organ to correct the biokinetic model and calculate the total number of decays (N) that occurred in the emitting regions. N values were used in the OLINDA/EXM code to calculate internal doses. Images in healthy volunteers showed a rapid elimination with a half-life of 1.1 h for the fast component (T1/2a=ln2/0.614), 9.2 h for the first slow component (T1/2e=ln2/0.075) and 79.6 h for the second slow component (T1/2y=ln2/0.008). Absorption and elimination mainly occur through the kidneys, with less absorption by the liver and high absorption by the parathyroid, salivary, and lacrimal glands. The mean absorbed doses were 0.23, 0.28, 0.88, and 1.17 mGy/MBq for the spleen, liver, kidneys, and salivary glands, respectively.

In order to evaluate the radiotherapeutic potential, eleven patients (mean age 66 years; range 45-86) received one to four cycles of ¹⁷⁷ Lu-DOTA-HYNICiPSMA (3.7 or 7.4 GBq) every 8-10 weeks. Response was assessed using ⁶⁸ Ga-PSMA-11 PET/CT imaging (a radiopharmaceutical with proven affinity in clinical practice and a high-resolution method for the specific detection of lesions in metastatic prostate cancer) and determining serum prostate specific antigen (PSA) before and after treatment. Approximately 60% of patients experienced a decrease in PSA levels and approximately 70% of patients experienced a decrease in the number and size of metastatic lesions and/or the rate of uptake of the radiopharmaceutical by metastases and the primary tumor, as determined by imaging.

In FIG. 4 shows the SPECT image for radiopharmaceutical ¹⁷⁷ Lu-DOTAHYNIC-iPSMA obtained from a healthy volunteer at various time points. In FIG. 5 is a PET and SPECT image of the same patient with advanced metastatic prostate cancer who received both ⁶⁸ Ga-PSMA-11 (PET, 1 h) and ¹⁷⁷ Lu-DOTA-HYNIC-iPSMA (SPECT, 24 h), showing that both radiopharmaceuticals detect tumors and metastases of prostate cancer associated with overexpression of PSMA protein, thus confirming the ability of radiopharmaceutical ¹⁷⁷ Lu-DOTA-HYNIC-iPSMA to detect PSMA protein overexpressed in prostate cancer cells in vivo. Finally, in FIG. 6 shows images for a patient with metastatic prostate cancer after the third cycle of treatment with ¹⁷⁷ Lu-DOTA-HYNIC-iPSMA. An image-based study of ⁶⁸ Ga-PSMA-11 (PET) shows that the size and number of prostate cancer metastatic sites (indicated by an arrow) decrease after each administration of ¹⁷⁷ Lu-DOTA-HYNIC-iPSMA until completely eliminated. This image confirms and is the main evidence of the radiotherapeutic potential of ¹⁷⁷ Lu-DOTA-HYNIC-iPSMA for the treatment of tumor lesions overexpressing the PSMA protein.

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In conclusion, it should be noted that the resulting ¹⁷⁷ Lu-DOTA-HYNIC-iPSMA has the following properties:

radiochemical purity over 98%;

the ability of the radiopharmaceutical to detect tumors overexpressing prostate-specific membrane antigen in vivo associated with the favorable spatial orientation of the active site (Lys(Nal)-NH-CO-NH-Glu) of the molecule induced by the presence of HYNIC associated with the DOTA molecule;

as a result of molecular recognition associated with the favorable spatial orientation of the active site (Lys(Nal)-NH-CO-NH-Glu) of the molecule, induced by the presence of HYNIC associated with the DOTA molecule and labeled with lutetium-177, the radiopharmaceutical agent ¹⁷⁷ Lu-DOTA- HYNIC-iPSMA exhibits radiotherapeutic properties as shown by significantly reducing serum PSA levels and reducing the number and size of metastatic lesions seen in prostate cancer patients treated with ¹⁷⁷ Lu-DOTA-HYNICiPSMA.

Claims (3)

1. A compound having a structure 2. Radiopharmaceutical composition, characterized in that it contains a compound according to claim 1. 3. The use of a compound according to claim 1 for the treatment of tumors that overexpress the PSMA (Prostate Specific Membrane Antigen) protein.