Acid phosphatase 3 ligands for targeted delivery applications

Abstract

The present invention relates to ligands against Acid Phosphatase 3 (ACP3 or ACPP), also known as Prostatic Acid Phosphatase (PAP). Selective ACP3 ligands may be able to exclusively interact with antigens expressed on the surface of tumor cells for in vivo pharmaco-delivery applications. The ligand may display very high affinity and selectivity towards ACP3 to enable targeted delivery of a payload, including therapeutic and diagnostic payloads, to a site afflicted by or at risk of a disease characterized by the expression of ACP3.

Description

ACID PHOSPHATASE 3 LIGANDS FOR TARGETED DELIVERY APPLICATIONSFIELD OF THE INVENTIONThe present invention relates to ligands against Acid Phosphatase 3 (ACP3 or ACPP), also known as Prostatic Acid Phosphatase (PAP). Selective ACP3 ligands may be able to exclusively interact with antigens expressed on the surface of tumor cells for in vivo pharmaco-delivery applications. The ligand may display very high affinity and selectivity towards ACP3 to enable targeted delivery of a payload, including therapeutic and diagnostic payloads, to a site afflicted by or at risk of a disease characterized by the expression of ACP3.BACKGROUND OF THE INVENTIONThe use of cytotoxic agents is at the basis of the treatment of cancer and other pathological conditions. Ideally, cytotoxic agents should accumulate at site of disease, sparing normal tissues. However, many anticancer drugs do not preferentially accumulate in solid tumors. Indeed, it has been demonstrated in tumorbearing mice and in human patients that only a minimal portion of the injected drug reaches the neoplastic mass in comparison to the amount of cytotoxic agent that reaches healthy organs.The targeted delivery of highly potent cytotoxic agents into diseased tissues is therefore desirable for the treatment of cancer and other serious conditions. By attaching a therapeutic effector through a site-specific cleavable linker to a binding moiety specific to a marker of disease, the effector preferentially accumulates and acts at the intended site of action, thus increasing the effectively applied dose while reducing side effects.To date, monoclonal antibodies have been considered as the ligands of choice and, indeed, research in the field of Antibody-Drug Conjugates (ADCs) has led to the approval of thirteen ADCs for applications in oncology. However, antibodies are large macromolecules which may have difficulties penetrating deeply into solid tumors. In addition, they can be immunogenic and long circulation times can lead to premature drug release and undesired side effects. Moreover, the production of ADCs is expensive, reflecting the need for clinical-grade manufacturing of antibodies, drugs and the resulting conjugates. Nevertheless, they remain the method of choice for delivering cytotoxic drugs to tumor sites.Ligand-based pharmacodelivery strategies fundamentally rely on the identification of good-quality markers of pathology, allowing a clear-cut discrimination between diseased tissues and healthy organs. Monoclonal antibodies and their fragments represent the preferred agents for pharmacodelivery applications!1-2], but globular protein mutants13], peptides14] and even small organic binding moieties[5l are also increasingly being used.When high-affinity small organic binding moieties are available for tumor-associated antigens16], Small Molecule-Drug Conjugates (SMDCs) can be considered as an alternative to antibodies for ligand-based pharmacodelivery applications. Promising results have been reported for the targeting of the folate receptor and Carbonic Anhydrase IX, both specific tumor-associated antigens, with SMDCs.[7'1°] The efficient extravasation and non-immunogenicity of small organic binding moieties can overcome the problems above mentioned for antibodies-based systems. Radionuclides can also be considered as payloads to generate Small Molecule-Radio Conjugates (SMRCs) for imaging (diagnostic) or therapeutic applications.Acid phosphatase 3 is a tyrosine phosphatase expressed as homodimer for which five distinct isoenzymes have been reported in humans, mostly involved in immune defense, growth regulation and bone resorption. I11-13] A. and E. Gutman observed elevated serum levels of acid phosphatases in prostate cancer patients and ACP3 eventually emerged as a clinically validated prognostic marker for prostate cancer which was later replaced by prostate-specific antigen.114-161Based on immunohistochemistry, low ACP3 expression has been detected in most human tissues while exceptionally high expression was observed in prostate and prostate cancer.1171ACP3 isoform 1 is expressed as secreted form or with a transmembrane domain (type I, TM-PAP) as a result of alternative splicing of the same gene. TM-PAP has been shown to localize to the plasma membrane and to vesicles, likely due to internalization as suggested by the presence of a short intracellular lysosomal targeting motif.1181According to the International Agency for Research on Cancer, prostate cancer (PCa) is the second most common cancer in men (GLOBOCAN 2020) and is a significant cause of morbidity and mortality.Thus far, prostate cancer treatments include surgery, radiation therapy, hormonal therapy (androgen deprivation therapy) and chemotherapy.1191More recently, SMRCs targeting Prostate Specific Membrane Antigen (PSMA) have been developed up to registration in the field of prostate cancer. Those agents are limited by their strong accumulation in healthy tissues such as salivary glands and kidneys. The unwanted accumulation of PSMA-targeting agents in those healthy tissues causes side effects and limits the escalation of their dose to curative regimens.1581Pluvicto™ (INN: lutetium (177Lu) vipivotide tetraxetan) has been approved as first radioligand therapeutic for which the phase III Vision® trial showed a survival benefit compared to individuals treated with the standard of care.1201Nevertheless, Pluvicto™ does not cure and the accumulation of the radioligand in healthy organs such as salivary glands and kidneys prevents the administration of higher doses.1211Considering the limitation of prostate cancer therapy using PSMA binders, there is a need for therapeutics that can efficiently accumulate on tumors while sparing normal organs. This is particularly true in the context of radioligand therapeutics delivering alpha emitters. When used to deliver alpha-emitter radionuclide payloads such as Actinium-225 (225Ac) and Lead-212 (212Pb), PSMA-targeting agents are more efficacious in patients relapsing from Lutetium-177-based PSMA targeting agents, but more toxic.1591The accumulation of PSMA-targeted alpha emitters in the kidney limits the development of those therapeutic candidates, leading to severe and irreversible damage to this vital healthy organ.ACP3 has been recognized as a therapeutic target for the development of vaccines to generate anti-tumor immunity. Ongoing clinical trials investigate the effect of ACP3 immunization in prostate cancer patients (www.clinicaltrials.gov identifier: NCT03600350 and NCT01706458) and a significant survival benefit could be identified in a placebo-controlled phase III trial.1221Furthermore, antibody fragments and whole IgG antibodies targeting ACP3 have been shown to accumulate in prostate cancer lesions, both in mouse models and in human patients with metastatic prostate cancer.123-261Small organic molecule ACP3 ligands reported in literature are mainly based on aromatic phosphates, phosphonates (e.g., benzylaminophosphonic acids) or tartrate derivatives which, however, lack sufficient potency and / or functionality that would enable the attachment of therapeutic or diagnostic pay loads.127-301SUMMARY OF THE INVENTIONThe present invention aims at solving the problem of identifying and developing binders for ACP3 (PAP, ACPP, TM-ACP3, TM-PAP) which may serve as targeting moiety suitable for applications in the background of targeted delivery of diagnostic or therapeutic payloads to a site afflicted or at risk of a disease characterized by the expression of ACP3.Furthermore, functional inhibition by the ligands may have therapeutic purpose on its own.BRIEF DESCRIPTION OF THE DRAWINGSFIG. 1 : Enzymatic inhibition measurements with compounds 1 , 2, 3, and 5. The assay was performed according to protocol 1 .FIG. 2: Enzymatic assay experiments with compounds 1 , 5, 6a-c, and 7a-c. DOTA-GA moieties were introduced in the ortho, meta, and para positions of the benzyl (A) and phenyl (B) sides of a- aminophosphonic acid 1 and their IC50 values were compared. IC50 value for compound 7c (meta, not shown): 36 nM. The assay was performed according to protocol 1 .FIG. 3: Advantages of using 4-azido proline as a scaffold extension approach (A). Enzymatic assay experiment with compounds 1 , 9, and 10 were performed according to protocol 1 (B).FIG. 4: Enzymatic assay experiments with compounds O1a-d, O2a-d, 6c, 11 , and 12. The stereochemical impact of the proline scaffold was studied on-DNA along with the gain in activity brought by the N, A / -di benzyl glycine building block. The assay in (A) was performed according to protocol 1 ; in (B) according to protocol 2 as higher sensitivity was needed to detect the sub-nanomolar inhibitor.FIG. 5: (A) Advantages of using 3-lodo-phenylalanine as scaffold extension approach. (B) Enzymatic assay experiment with on-DNA compounds O3a, b, O4a, b and 05a, b were performed according to protocol 2. (C, D) The 4 new ligands bearing DOTA-GA (14a,b and 16a,b) were evaluated against DOTA-GA metaderivative 6b via enzymatic assay- protocol 2, revealing IC50 values in the low nanomolar range.FIG. 6: FP Selectivity screening of FITC labelled compound 4 against a panel of serum proteins and phosphatases (A). FP binding comparison between FITC labelled compounds 4, 8, and 13 against ACP3. (B) FP binding comparison between FITC labelled compounds 4, 8, and 13 against ACP3. (C) FP binding comparison between FITC labelled compounds 8, 15a,b and 17a,b against ACP3. (D) FP Selectivity screening of FITC labelled compounds 15a against a panel of serum proteins and phosphatases. (E) FP Selectivity screening of FITC labelled compounds 15b against a panel of serum proteins and phosphatases. (F) FP Selectivity screening of FITC labelled compounds 17a against a panel of serum proteins and phosphatases. (G) FP Selectivity screening of FITC labelled compounds 17b against a panel of serum proteins and phosphatases.FIG. 7: Flow cytometry experiment with compounds 8, 13, 15a, b, 17a, b against HT1080.hACP3 cells. A clear shift was observed for all molecules.FIG. 8: Flow cytometry experiment with compounds 8, 13, 15a,b, 17a,b against HT1080 wild type cells. No shift was observed for the compounds.FIG. 9: SPR sensograms of compounds 6c (A), 12a (B), 12b (C), 14a (D), 14b (E), 16a (F), 16b (G) against human ACP3, immobilized on a CM5 chip. The dissociation constants (Kd) of each compound are reported in brackets.FIG. 10: Radiosynthesis of compound 19 and HPLC chromatogram of the final product (Compound 19) as recorded with a radio-detector.FIG. 11 : Radiosynthesis of compounds 20a and 20b, and HPLC chromatogram of Compound 20a (SS) as recorded with a radio-detector.FIG. 12: HPLC chromatogram of Compound 20b (RR) as recorded with a radio-detector.FIG. 13: Radiosynthesis of compounds 21a and 21 b, and HPLC chromatogram of Compound 21a (S) as recorded with a radio-detector.FIG. 14: HPLC chromatogram of Compound 21 b (R) as recorded with a radio-detector.FIG. 15: Radiosynthesis of compounds 22a and 22b, and HPLC chromatogram of Compound 22a (S) as recorded with a radio-detector.FIG. 16: HPLC chromatogram of Compound 22b (R) as recorded with a radio-detector.FIG. 17: Dose-escalation study with compound 20a in nude mice, bearing HT1080.hACP3 xenografts. Mice were sacrificed 2h after injection (n=3).FIG. 18: Timecourse study with compound 20a (A) and 19 (B) in nude mice, bearing HT1080.hACP3 xenografts. Mice were injected with a dose of 1 .25 nmol / mouse (corresponding to 62.5 nmol / kg) (n=3).FIG. 19: Comparative study with the affinity-matured molecules (21a, b and 22a, b) in nude mice, bearing HT1080.hACP3 xenografts. Mice were injected with a dose of 1.25 nmol / mouse (corresponding to 62.5 nmol / kg) and sacrificed 2h after injection (n=3 for 21a and 22a, n=1 for 21 b and 22b).FIG. 20: Timecourse study with compound 22a in nude mice, bearing HT1080. hACP3 xenografts. Mice were injected with a dose of 1.25 nmol / mouse (corresponding to 62.5 nmol / kg) (n=3).FIG. 21 : Comparative study with the affinity-matured molecules (20a, 20b, 22a, and 19) in nude mice, bearing HT1080.hACP3 xenografts. Mice were injected with a dose of 1.25 nmol / mouse (corresponding to 62.5 nmol / kg) and sacrificed 24h after injection (n=3).FIG. 22: Timecourse study with (A) compound 20a (177Lu-ProX1-(SS)-DOTAGA) and (B) compound 22a in BALB / c nu / nu male mice, bearing PC3.hACP3 xenografts. Mice were injected with a dose of 62.5 nmol / kg. Data are presented as mean of %ID / g ± standard error of the mean (SEM) (n = 3 mice / group).FIG. 23: Dose-escalation study with compounds 20a, 28a, and 26a in BALB / c nu / nu male mice, bearing HT1080.hACP3 xenografts. Compounds were injected at different doses (i.e., 4.5 or 50 nmol / kg). Data are presented as mean of %ID / g ± standard error of the mean (SEM) (n = 3 mice / group).FIG. 24: In vivo biodistribution study with compounds 19, 20a, 22a, in male mice bearing HT1080.hACP3 xenografts. Compounds were injected at the dose of 62.5 nmol / kg and data were collected 2 hours after injection. Data are presented as mean of %ID / g ± standard error of the mean (SEM) (n = 3 mice / group).FIG. 25: Therapeutic experiments in male BALB / c nu / nu mice bearing HT1080.hACP3 xenografts. (A) Compound 20a (177Lu-ProX1-(SS)-DOTAGA) injected at molar activities of 250 MBq / kg or 1000 MBq / kg, and compound 22a (177Lu-ProX3-(S)-DOTAGA) injected at molar activity of 1000 MBq / kg. Black arrows indicate the day of intravenous administration of compound 20a, 22a, or vehicle (PBS). Data are presented as mean values ± SEM (n = 4 mice / group). CR = Complete remission. (B) Body weight changes of animals throughout the therapy study.FIG. 26: Autoradiography ex vivo results after exposure of (i) HT1080.hACP3 xenografts (ii) HT1080.hPSMA xenografts (iii) human prostate cancer, and (iv) human salivary gland tissues to compounds 19, 20a, 22a. and177Lu-PSMA-617 (177Lu vipivotide tetraxetan)FIG. 27: Confocal microscopy images of cancer cell lines stained with ProX1 -(SS)-FITC (13). Top row: green = fluoresceine-bearing compound staining; blue = Hoechst 33342 staining. Bottom: black / white version of the top row images; white = fluoresceine-bearing compound staining. Scale bar = 20 pm.FIG. 28: Confocal microscopy images of cancer cell lines stained with (A) ProX2-(S)-Fluo (15a) and (B) ProX2-(R)-Fluo (15b). Top rows: green = fluoresceine-bearing compound staining; blue = Hoechst 33342 staining. Bottom rows: black / white versions of the top row images; white = fluoresceine-bearing compound staining. Scale bar = 20 pm.FIG. 29: Confocal microscopy images of cancer cell lines stained with (A) ProX3-(S)-Fluo (17a) and (B) ProX3-(R)-Fluo (17b). Top rows: green = fluoresceine-bearing compound staining; blue = Hoechst 33342 staining. Bottom: black / white version of the top row images; white = fluoresceine-bearing compound staining. Scale bar = 20 pm.FIG. 30: Ex vivo biodistribution of ProX1-(SS)-AF488 (29a, 30 nmol in 150 μL sterile PBS) in HT1080.hACP3 tumor-bearing mice 2 h after intravenous administration. Green = compound 29a staining, Blue = DAPI staining. Scale bar = 100 pm.FIG. 31 : Ex vivo biodistribution of ProX3-(S)-AF488 (30a, 30 nmol in 150 μL sterile PBS) in HT1080.hACP3 tumor-bearing mice 2 h after intravenous administration. Green = compound 30a staining, Blue = DAPI staining. Scale bar = 100 pm.FIG. 32: Radiosynthesis of compounds 26a and 26b, and HPLC chromatogram of Compound 26a as recorded with a radio-detector.FIG. 33: Radiosynthesis of compounds 28a and 28b, and HPLC chromatogram of Compound 28a as recorded with a radio-detector.FIG. 34: Radiosynthesis of68Ga-ProX1-(SS)-DOTA (compound 44), and HPLC chromatogram of Compound 44 as recorded with a radio-detector.FIG. 35: In vivo biodistribution studies with ProX1 -(SS)-DOTA, labeled with either177Lu (28a) or68Ga (44). Data are presented as mean of %ID / g ± standard error of the mean (SEM) (n = 3 mice / group).FIG. 36: a. In vivo biodistribution study with68Ga-ProX1-(SS)-DOTA (44) at 1 and 2 hours post-injection (n = 3 mice / group) b. MicroPET images obtained 1 h post-injection of68Ga-ProX1-(SS)-DOTA (44) in the HT1080.hACP3 xenograft model. The subcutaneous tumor is highlighted by the cross section of the green (coronal), red (transversal) and yellow (para sagittal) planes. Dose: 62.5 nmol / kg (600 MBq / kg).FIG. 37: In vivo biodistribution studies with68Ga-ProX1-(SS)-DOTA (44). Mice in the pre-blocking group were injected with cold ProX1-(SS)-DOTA (27a) (50 nmol / mouse, ~2.5 μmol / kg - corresponding to a 40-fold molar excess as compared to the radioactive compound) 30 min before the administration of68Ga-ProX1-(SS)- DOTA (44). Individual values are represented by circles for which bars display the average group %ID / g values. Error bars indicate the standard error of the mean (SEM) (n = 3 mice / group for the68Ga-ProX1-(SS)- DOTA, n = 2 mice / group for the pre-blocking and ACP3-negative SK-RC-52.wt groups).FIG. 38: Radioligand bead-based assay with177Lu-ProX1-(SS)-DOTA (28a) and177Lu-ProX3-(S)-DOTAGA (22a). Magnetic Streptavidin-coated DynabeadsTM M-280 were functionalized with recombinant ACP3 and exposed to test compounds 28a and 22a, without (full bars) or with (dashed bars) a 5000-fold molar excess of blocking cold ACP3 ligands.FIG. 39: Tumor growth and body weight change (%) were measured in a therapeutic setting in the HT 108O.hACP3 model (n = 4 mice / group for SMDCs 31 , n = 3 for the vehicle group and SMDC 36). Black arrows indicate intravenous administrations of SMDCs 31 and 36 at 5 nmol / mouse (250 nmol / kg) or 100 μL of PBS (vehicle). Data is presented as mean ± standard error of the mean (SEM).FIG. 40: Tumor growth and body weight change (%) were measured in a therapeutic setting in the PC3.hACP3 model (n = 6 mice / group for SMDC 31 , n = 5 for the vehicle group). Black arrows indicate intravenous administrations of SMDC 31 at 5 nmol / mouse (250 nmol / kg) or 100 μL of PBS (vehicle). Data is presented as mean ± standard error of the mean (SEM).FIG. 41 : Tumor growth and body weight change (%) were measured in a therapeutic setting in the PC3.hACP3 model (n = 3 mice / group). Black arrows indicate intravenous administrations of compound 27a at 5 nmol / mouse (250 nmol / kg) or 100 μL of PBS (vehicle). Data is presented as mean ± standard error of the mean (SEM).FIG. 42: Enzymatic inhibition measurements with compounds 1 , 47, 48, 49 and 50. The assay was performed according to protocol 2.FIG. 43: Enzymatic inhibition measurements with compounds 27a, 51 , 53, 55a, 55b, 55c and 55d. The assay was performed according to protocol 2.FIG. 44: Enzymatic inhibition measurements with compounds 27a, 56a and 56b. The assay was performed according to protocol 2.FIG. 45: Enzymatic inhibition measurements with compounds 27a, 57a and 57b. The assay was performed according to protocol 2.FIG. 46: Enzymatic inhibition measurements with compounds 27a, 58, 59 and 60. The assay was performed according to protocol 2.FIG. 47: In vivo biodistribution study with compounds 52 and 54, in male mice bearing HT1080.hACP3 xenografts. Compounds were injected at a concentration of 1 .25 nM and data were collected 2 hours after injection. Data are presented as mean of %ID / g ± standard error of the mean (SEM) (n = 1 mouse / group).FIG. 48: Radiosynthesis of compound 52 and HPLC chromatogram of the final product (Compound 52) as recorded with a radio-detector.FIG. 49: Radiosynthesis of compound 54 and HPLC chromatogram of the final product (Compound 54) as recorded with a radio-detector.FIG. 50: Colorimetric ACP3 inhibition assay with compounds 1 , 12a, and 16a was performed against hACP3 (a) and mACP3 (b). IC50 values are given as mean ± standard error of the mean (SEM) (n = 3).DETAILED DESCRIPTIONThe present inventors have found high-affinity small organic binding moieties specific for ACP3, which can be readily functionalized with several payloads without compromising target specificity and target affinity. Advantageously, the ligands can bind and / or inhibit ACP3 in the nano- to subnanomolar concentration range, thereby facilitating targeting applications. The present compounds can be useful as valuable ACP3-targeting agents for tumor therapy and / or diagnostics.In particular, the binders of the present invention can rapidly accumulate to ACP3-positive tumors. Preferably, the compounds do not substantially accumulate in healthy organs such as kidneys, salivary glands, or normal prostate. This is advantageous both for diagnostic applications (e.g., to visualize tumor lesions in normal prostate) and therapeutic applications (e.g., to minimize toxicity in vital healthy organs).Without wishing to be bound to theory, while in the context of prostate cancer PSMA ligands typically internalize (and thus achieve long residence time in the tumor), the binders of the present invention can achieve surprisingly long residence time in the tumor and promote potent in vivo anti-cancer activity without internalization. Their high affinity and slow dissociation from the ACP3 target, along with their noninternalizing nature, make them particularly suitable for the targeted delivery of diagnostic or therapeutic agents.Further particular advantages of the compounds, especially of radiolabeled conjugates, preferably include accumulation to ACP3-positive solid cancer lesions with long residence time (e.g., t1 / 2 >72 hours) and high selectivity (e.g., tumor-to-blood ratio >148 at 2 hours after administration). Further, in the prior art, bone marrow toxicity has been observed as a common side effect of Lutetium-177-based RLT products. In contrast, radiolabeled compounds of the present invention tend not to accumulate in healthy bones, while offering highly selective tumor uptake at early time points (e.g., 1 h post-injection).Further particular advantages of the compounds, especially of conjugates with cytotoxic or cytostatic payloads, such as MMAE, include potent in vivo anti-cancer activity.Compounds of the present invention may provide low healthy organ toxicity and highly selective tumor uptake. Considering the efficient tumor targeting and the lack of uptake observed in healthy organs salivary glands and kidneys, compounds of the present invention may offer an improvement to prostate-specific membrane antigen ligands, e.g., for the targeting of metastatic prostate cancer.Prostate cancer patients with low PSMA levels or relapsing from therapy, e.g., with PSMA-617 (77Lu vipivotide tetraxetan), may particularly benefit from the administration of the therapeutics of the present invention.According to an embodiment of the present invention, a compound is provided that specifically binds ACP3, and has a molecular weight of 5000 Da or less and / or a dissociation constant (Kd) of 50 nM or less. Preferably, the compound specifically binding ACP3 has a molecular weight of 5000 Da or less and an ACP3 dissociation constant (Kd) of 50 nM or less. The molecular weight and the dissociation constant are as defined below.According to another embodiment, the molecular weight is 4000 Da or less, or 3000 Da or less. In another embodiment, the molecular weight is 500 Da or more, 600 Da or more, or 800 Da or more. In another embodiment, the molecular weight is of from 500 Da to 5000 Da, from 600 Da to 3000 Da, or from 800 to 3000 Da.In another embodiment, the dissociation constant (K^) is 45 nM or less, 40 nM or less, 35 nM or less, 30 nM or less, 25 nM or less, 20 nM or less, 15 nM or less, 10 or less, or 5 nM or less. In a preferred embodiment, the dissociation constant is 5 nM or less.Further, in another embodiment the dissociation constant (K^) is 0.5 nM or more, 1 nM or more, or 2 nM or more. In a preferred embodiment, the dissociation constant is 2 nM or more.The compound according to the present invention may specifically bind ACP3 on the membrane of tumor cells and / or may be not substantially internalized. In this disclosure, the term “not substantially internalized” is used to indicate that a compound or substance is taken up by cells in an amount relative to the sum of internalized and non-internalized amount of s 20%, preferably s 10%, more preferably wherein the internalized amount is non-detectable, e.g., as measured by confocal microscopy, a radioactivity-based internalization assay, mass spectrometry, and the like.The compound according to the present invention may show a higher uptake in tumor(s) than in healthy organ(s) after administration, e.g., intravenous administration.In one embodiment, the compound according to the present invention shows an uptake of 10% ID / g or more, 15% ID / g or more, 20% ID / g or more, 25% ID / g or more, 30% ID / g or more, 35% ID / g or more, or 40% ID / g or more in tumor(s) after administration, e.g., intravenous administration, in male mice bearing HT1080.hACP3 xenografts.In one embodiment, the compound according to the present invention shows an uptake of less than 10% I D / g , 8% I D / g or less, 5% ID / or less in healthy organ(s) after administration, e.g., intravenous administration. In a preferred embodiment, the healthy organ(s) do not include gall bladder and / or urinary bladder.In particular, the uptake in tumor(s) and healthy organ(s) may be determined after 1 hour, 2 hours, 6 hours or 24 hours, preferably 1 hour, after administration, e.g., intravenous administration.The compound according to the present invention preferably does not substantially accumulate in kidneys and / or salivary glands and / or healthy prostate after administration, e.g., intravenous administration.Preferably, and unless defined otherwise, the phrase “does not substantially accumulate” is used herein to indicate that the compound is taken up by these organs in an amount of less than 10% I D / g , 8% I D / g or less, more preferably 5% ID / or less after administration, e.g., intravenous administration.Exemplary compounds according to the present invention are listed in Table 1 .Table 1. Exemplary compoundsAmong these, particularly preferred are compounds 12a, 20a, 27a, 28a, 44, 62a, b, 63a, b, 64, 65, 66, 67, 92, 93, 94, 97, more preferably 20a, 28a or 44, most preferably 28a or 44. This applies correspondingly also with respect to the groups R1-Y-Z contained in each of these compounds. Further compounds are listed in Table 2.Further compounds useful in the context of the present disclosure are shown in Tables 2.1, 2.2 and 2.3. These may be particularly useful in imaging / tracing applications (e.g., PET imaging and / or diagnostics), when comprising a suitable nuclide, such as18F (Table 2.2.); or as cold versions (Table 2.1) of such compounds (e.g., as standards during GMP manufacturing); or as intermediates or precursors for18F labeling (Table 2.3).Table 2.1.Table 2.2.Table 2.3.Further exemplary compounds (conjugates) according to the present invention are listed in Tables 3.1-3.7.The numbering of these conjugates is independent from the numbering of the remaining compounds in the present specification. The following abbreviations will be used, throughout the entire specification:B-1: bondTable 3.1. Exemplary conjugatesTable 3.2. Exemplary conjugatesTable 3.3. Exemplary conjugatesTable 3.4. Exemplary conjugatesTable 3.5. Exemplary conjugates126 ble 3.6. Exemplary conjugates150153154155156157158159160161162163164165166167168169170171172173174175Moiety BMoiety B is a covalent bond or a moiety comprising a chain of atoms that covalently attaches moiety R1-Y or R1to the payload C, e.g., through one or more covalent bond(s). The moiety B may be cleavable or non- cleavable, multifunctional moiety which can be used to link one or more payload and / or binder moieties to form the targeted conjugate of the invention.Specifically, moiety B is a multifunctional moiety linking at least one moiety C with at least one moiety R1-Y or R1. B can be a single bond, or an optionally substituted C-1-50 aliphatic group, in which optionally one or more carbon atoms can be replaced by a heteroatom, a carbocyclic or a C-1-12 heterocyclic group, and which can be saturated, or optionally contain one or more double or triple bonds.When cleavable linker units are present within moiety B, release mechanisms can be identical to those specific to antibodies linked to cytotoxic payloads. Indeed, the nature of the binding moieties is independent in that respect. Therefore, there is envisaged pH-dependent [Leamon, C.P. et al (2006) Bioconjugate Chem. , 17, 1226; Casi, G. et al (2012) J. Am. Chem. Soc.. 134, 5887], reductive [Bernardes, G.J. et al (2012) Angew. Chem. Int. Ed. Engl., 51 . 941 ; Yang, J. et al (2006) Proc. Natl. Acad. Sci. USA, 103, 13872] and enzymatic release [Doronina S.O. et al (2008) Bioconjugate Chem, 19, 1960; Sutherland, M.S.K. (2006) J. Biol. Chem, 281 , 10540]. In a specific setting, when functional groups are present on either the binding moiety or payloads (e.g., thiols, alcohols) a linkerless connection can be established thus releasing intact payloads, which simplifies substantially pharmacokinetic analysis.By attaching a therapeutic effector (in particular: a cytotoxic or cytostatic payload) through a site-specific cleavable linker to a binding moiety specific to a marker of disease, the effector preferentially accumulates and acts at the intended site of action, thus increasing the effectively applied dose while reducing side effects. That is, moiety B generally may be cleavable or non-cleavable, yet it is preferred that when moiety C is a cytotoxic or cytostatic payload, e.g., a chemotherapeutic (cytotoxic or cytostatic) agent, such as MMAE, a cleavable moiety B is used, which is contemplated to be advantageous from the viewpoint of payload release, accumulation of (free) payload and / or anti-tumor activity. Nevertheless, while the presence of a cleavable linker can be advantageous where release of the payload C is desirable, e.g., in the case of chemotherapeutic (cytotoxic or cytostatic) agent, cleavable linkers should not be understood to be generally mandatory or essential for the functioning of the compounds of the present invention. For instance, in the cases of radioconjugates useful as radiotherapeutic and / or diagnostic agents, cleavable linkers are not contemplated to be particularly required.Moiety B can comprise or consist of a unit shown in Table 4 below wherein the substituents R and Rnshown in the formulae may suitably be independently selected from H, halogen, substituted or unsubstituted (hetero)alkyl, (hetero)alkenyl, (hetero)alkynyl, (hetero)aryl, (hetero)arylalkyl, (hetero)cycloalkyl, (hetero)cycloalkylaryl, heterocyclylalkyl, a peptide, an oligosaccharide or a steroid group. Preferably, each of R, Ri, R2 and R3 is independently selected from H, OH, SH, NH2, halogen, cyano, carboxy, alkyl, cycloalkyl, aryl and heteroaryl, each of which is substituted or unsubstituted. Suitably R and Rnare independently selected from H, or C1 -C7 alkyl or heteroalkyl. More suitably, R and Rnare independently selected from H, methyl or ethyl.Table 4Moiety B, unit(s) BL and / or unit(s) Bs may suitably comprise as a cleavable bond a disulfide linkage since these linkages are stable to hydrolysis, while giving suitable drug release kinetics at the target in vivo, and can provide traceless cleavage of drug moieties including a thiol group. Moiety B, unit(s) BL and / or unit(s) Bs may be polar or charged in order to improve water solubility of the conjugate. For example, the linker may comprise from about 1 to about 20, suitably from about 2 to about 10, residues of one or more known water-soluble oligomers such as peptides, oligosaccharides, glycosaminoglycans, polyacrylic acid or salts thereof, polyethylene glycol, polyhydroxyethyl (meth) acrylates, polysulfonates, etc. Suitably, the linker may comprise a polar or charged peptide moiety comprising e.g. from 2 to 10 amino acid residues. Amino acids may refer to any natural or non-natural amino acid. The peptide linker suitably includes a free thiol group, preferably a N-terminal cysteine, for forming the said cleavable disulfide linkage with a thiol group on the drug moiety. Any peptide containing L- or D-aminoacids can be suitable; particularly suitable peptide linkers of this type are Asp-Arg-Asp-Cys and / or Asp-Lys-Asp-Cys.In these and other embodiments, moiety B, unit(s) BL and / or unit(s) Bs may comprise a cleavable or non- cleavable peptide unit that is specifically tailored so that it will be selectively enzymatically cleaved from the drug moiety by one or more proteases on the cell surface or the extracellular regions of the target tissue. The amino acid residue chain length of the peptide unit suitably ranges from that of a single amino acid to about eight amino acid residues. Numerous specific cleavable peptide sequences suitable for use in thepresent invention can be designed and optimized in their selectivity for enzymatic cleavage by a particular tumor-associated enzyme e.g. a protease. Cleavable peptides for use in the present invention include those which are optimized toward the proteases MMP-1 , 2 or 3, or cathepsin B, C or D. Especially suitable are peptides cleavable by Cathepsin B. Cathepsin B is a ubiquitous cysteine protease. It is an intracellular enzyme, except in pathological conditions, such as metastatic tumors or rheumatoid arthritis. An example for a peptide cleavable by Cathepsin B is containing the sequence Val-Cit. Further examples of cleavable peptide units include cleavable peptide unit selected from Gly-Pro, Ala-Pro, Val-Pro, Arg-Pro, lle-Pro, Pro- Pro, Gly-Cit, Ala-Cit, Val-Cit, Arg-Cit, lle-Cit, and Pro-Cit; preferably Gly-Pro or Val-Cit.In these and other embodiments, moiety B, unit(s) BL and / or unit(s) Bs may comprise cleavable unit able of being enzymatically cleaved by one or more phosphatases, sulfatases or esterases. This can be particularly advantageous when targeting cells characterized by increased expression of phosphatases, including, e.g., ACP3. Exemplary cleavable units of this type (based on phosphate analogs) can be selected from:wherein Q1is independently selected from OPO3H2, OPO2N(R)2, OPO2NH2, OPO(OH)F, OC(O)OR, OC(O)R, OSO3H, OSO2N(R)2, and OSO2NH2; preferably OPO3H2, OC(O)OH or OSO3H, more preferably OPO3H2; most preferably OPO3H2; R^ is independently selected from H an electron withdrawing group, preferably from H, NO2, CN, halogen, C(O)R, CF3, and SO3H, more preferably from H and NO2; and each R is independently as defined for R herein. Preferable cleavable units of this type can be selected from:In any of the above embodiments, the moiety B and in particular, unit(s) BL suitably further comprised) self- immolative moiety can or cannot be present after the linker. The self-immolative linkers are also known as electronic cascade linkers. These linkers undergo elimination and fragmentation upon enzymatic cleavage of the peptide to release the drug in active, preferably free form. The conjugate is stable extracellularly in the absence of an enzyme capable of cleaving the linker. However, upon exposure to a suitable enzyme, the linker is cleaved initiating a spontaneous self-immolative reaction resulting in the cleavage of the bond covalently linking the self-immolative moiety to the drug, to thereby effect release of the drug in its underivatized or pharmacologically active form. In these embodiments, the self-immolative linker is coupled to the binding moiety through an enzymatically cleavable peptide sequence that provides a substrate for an enzyme to cleave the amide bond to initiate the self-immolative reaction. Suitably, the drug moiety is connected to the self-immolative moiety of the linker via a chemically reactive functional group pending from the drug such as a primary or secondary amine, hydroxyl, sulfhydryl or carboxyl group.Examples of self-immolative linkers are PABC or PAB (para-aminobenzyloxycarbonyl), attaching the drug moiety to the binding moiety in the conjugate (Carl et al (1981) J. Med. Chem. 24: 479-480; Chakravarty etal (1983) J. Med. Chem. 26: 638-644). The amide bond linking the carboxy terminus of a peptide unit and the para-aminobenzyl of PAB may be a substrate and cleavable by certain proteases. The aromatic amine becomes electron-donating and initiates an electronic cascade that leads to the expulsion of the leaving group, which releases the free drug after elimination of carbon dioxide (de Groot, et al (2001) Journal of Organic Chemistry 66 (26): 8815-8830). Further self-immolating linkers are described in W02005 / 082023.In cases where B is a cleavable linker moiety, it is particularly preferred that B comprises a cleavable peptide unit, (e.g., a dipeptide unit as detailed above), is directly bound to a self-immolative moiety (e.g., PABC or PAB), which, in turn, is bound to a drug moiety (e.g., a g a therapeutic effector, in particular: a cytotoxic or cytostatic payload moiety C), e.g., as shown below:In yet other embodiments, the linker comprises a glucuronyl group that is cleavable by glucuronidase present on the cell surface or the extracellular region of the target tissue. It has been shown that lysosomal betaglucuronidase is liberated extracellularly in high local concentrations in necrotic areas in human cancers, and that this provides a route to targeted chemotherapy (Bosslet, K. et al. Cancer Res. 58, 1195-1201 (1998)).In any of the above embodiments, the moiety B suitably further comprises a spacer unit. A spacer unit can be the unit Bs, which may be linked to the binding moiety R1-Y or R1, for example via an amide, amine or thioether bond. The spacer unit is of a length that enables e.g. the cleavable peptide sequence to be contacted by the cleaving enzyme (e. g. cathepsin B) and suitably also the hydrolysis of the amide bond coupling the cleavable peptide to the self-immolative moiety X. Spacer units may for example comprise a divalent radical such as alkylene, arylene, a heteroarylene, repeating units of alkyloxy (e.g., polyethylenoxy, PEG, polymethyleneoxy) and alkylamino (e.g., polyethyleneamino), or diacid ester and amides including succinate, succinamide, diglycolate, malonate, and caproamide.In any of the embodiments described therein, * represents a point of attachment to moiety R1-Y or R1or a point of attachment for which the shortest path to moiety R1-Y or R1comprises less atoms than that for •, as the case may be; and • represents a point of attachment a point of attachment to moiety C or a point of attachment to moiety C for which the shortest path to moiety C comprises less atoms than that for *, as the case may be. The same applies also for cases where a reactive moiety L is present rather than payload moiety C. The following notations and all have the meaning of a point of attachment of a certain group or atom (e.g., R) to a further moiety:As used herein, and unless specified otherwise the groups and fragments described herein may be combined in either orientation, but it is preferred that they are combined in the orientation as drawn herein, reading from left to right, for example: ; preferred combination of fragments (a) + (b):Ifthe structure of relevance is a peptide mono- or oligomer, each * represents a point of attachment for which the shortest path to moiety R1-Y or R1comprises less atoms than that for •; and each • represents a point of attachment for which the shortest path to moiety C comprises less atoms than that for *, with the proviso that when n is > 1 and a respective point of attachment is indicated on any one of Ra, Rband Rc, then it can be independently present in one or more of the peptide monomeric units, preferably in one peptide monomeric unit most distant from the other point of attachment indicated in the respective structure.In any of the embodiments described herein, the terms “peptide”, “dipeptide”, “tripeptide”, “tetrapeptide” etc. refer to peptide mono- or oligomers having a backbone formed by proteinogenic and / or a non-proteinogenic amino acids. As used herein, the terms “aminoacyl” or “aminoacid” generally refer to any proteinogenic or a non-proteinogenic amino acid. Preferably, in any of the embodiments disclosed therein, the side-chain residues of a proteinogenic or a non-proteinogenic amino acid are represented by any of Ra, Rband Rc, each of which is selected from the following list:wherein each of R, R1, R2and R3is independently selected from H, OH, SH, NH2, halogen, cyano, carboxy, alkyl, cycloalkyl, aryl and heteroaryl, each of which is substituted or unsubstituted; each Xis independently selected from NH, NR, S, O and CH2, preferably NH; and each n and m is independently an integer preferably selected from 0, 1 , 2, 3, 4, 5, 6, 7, 8, 9, 1 0, 11 , 12, 13, 14, 15, 16, 17, 18, 19 and 20, wherein the definitions of R, R1, R2, R3, X, m, and n here are independent from the definitions of R1, R2and R3, X, m, and n used elsewhere in the present specification.Preferably, in any of the embodiments disclosed therein, side-chain residues of a proteinogenic or a non- proteinogenic amino acid are represented by any of Ra, R^, Rc, R^ and Re, each of which may be part of a 3-, 4-, 5-, 6- or 7-membered ring. For instance, the side chain alpha, beta and / or gamma position of said proteinogenic or non-proteinogenic amino acid can be part of a cyclic structure selected from an azetidine ring, pyrrolidine ring and a piperidine ring, such as in the following aminoacids (proline and hydroxyproline):each of which may independently be part of an unsaturated structure (i.e. wherein the H atom geminal to the respective group Ra, Rband Rcis absent), e.g.:XyAs used herein, the following notation of peptide sequences refers to a sequence from N to C terminus, and attachment of group through a horizontal bond (here: moiety C) means covalent attachment to the peptide backbone via amide bond to the respective terminal amino acid (here: AA3):As used herein, the following notation of peptide sequences refers to a sequence from N to C terminus, and attachment of group through a vertical bond (here: moiety C) means covalent attachment via the sidechain of the respective amino acid (here: AA3):Further preferable non-proteinogenic amino acids can be selected from the following list:Particularly preferred embodiments for the moiety B as well as the compound according to the present invention are shown in the appended claims.Moiety CMoiety C in the present invention represents a payload, which can be generally any atom (including H), molecule or particle. Preferably, moiety C is not a hydrogen atom.The payload may be a chelator for radiolabeling. Suitably the radionuclide is not released. Chelators are well known to those skilled in the art, and for example, include chelators such as sulfur colloid, diethylenetriaminepentaacetic acid (DTPA), ethylenediaminetetraacetic acid (EDTA), 1 ,4,7,10- tetraazacyclododecane-N,N',N",N"'-tetraacetic acid (DOTA), 1 ,4,7, 10-tetraazacyclododececane,N-(glutaric acid)-N',N",N"'-triacetic acid (DOTAGA), 1 ,4,7-triazacyclononane-N,N',N"-triacetic acid (NOTA), 1 ,4,8,1 1 - tetraazacyclotetradecane-N,N',N",N"'-tetraacetic acid (TETA), or any of the preferred chelator structures recited in the appended claims or elsewhere herein.The payload may be a radioactive group comprising or consisting of radioisotope including isotopes such as223Ra,89Sr,94mTc,99mTc,186Re,188Re,208Pb,212Pb,67Ga,68Ga,47Sc,1111 n ,97Ru,62Cu,64Cu,65Cu,67Cu,54Cu, 86Y ji2iS nA|18F,149Tb,152Tb,155Tb,161Tb,158Sm,166Ho,105Rh,177Lu,128l,124l,125l ,131l,16F,18F,211At,225Ac,89Sr,117mSn,169Er,227Th,3H,11C,11 mN,13N,82Rb,89Zr and32P, or a cold nuclide, such as139La,69Ga or175Lu . Preferably, positron emitters, such as18F and124l, or gamma emitters, such as99mTc,111ln and123l , are used for diagnostic applications (e.g. , for PET), while beta-emitters, such as89Sr,131l , and177Lu, are preferably used for therapeutic applications. Alpha-emitters, such as21 1At,225Ac and223Ra may also be used for therapy. In one preferred embodiment the radioisotope is89Sr or223Ra. In a further preferred embodiment the radioisotope is68Ga. Cold nuclides may be useful to support GMP manufacturing as reference standards (e.g.,69Ga,175Lu), or as precursors (e.g.,139La) for other emitter nuclides.The payload may be a chelate of a radioactive isotope, preferably of an isotope listed above, with a chelating agent, preferably a chelating agent listed herein.The payload may be a fluorophore group, preferably selected from a xanthene dye, acridine dye, oxazine dye, cyanine dye, styryl dye, coumarine dye, porphine dye, fluorescent metal-ligand-complex, fluorescent protein, nanocrystals, perylene dye, boron-dipyrromethene dye and phtalocyanine dye, more preferably selected from the structures listed herein.The payload may be a cytotoxic and / or cytostatic agent. Such agents can inhibit or prevent the function of cells and / or cause destruction of cells. Examples of cytotoxic agents include radioactive isotopes, chemotherapeutic agents, and toxins such as small molecule toxins or enzymatically active toxins of bacterial, fungal, plant or animal origin, including synthetic analogues and derivatives thereof. The cytotoxic agent may be selected from the group consisting of an auristatin, a DNA minor groove binding agent, a DNA minor groove alkylating agent, an enediyne, a lexitropsin, a duocarmycin, a taxane, a puromycin, a dolastatin, a maytansinoid and a vinca alkaloid or a combination of two or more thereof. Preferred cytotoxic and / or cytostatic payload moieties are listed herein.In one embodiment the payload is a chemotherapeutic agent selected from the group consisting of a topoisomerase inhibitor, an alkylating agent (e.g., nitrogen mustards; ethylenimes; alkylsulfonates; triazenes; piperazines; and nitrosureas), an antimetabolite (e.g., mercaptopurine, thioguanine, 5-fluorouracil), an antibiotic (e.g., anthracyclines, dactinomycin, bleomycin, adriamycin, mithramycin. dactinomycin) a mitotic disrupter (e.g., plant alkaloids - such as vincristine and / or microtubule antagonists - such as paclitaxel), a DNA methylating agent, a DNA intercalating agent (e.g., carboplatin and / or cisplatin, daunomycin and / or doxorubicin and / or bleomycin and / or thalidomide), a DNA synthesis inhibitor, a DNA-RNA transcription regulator, an enzyme inhibitor, a gene regulator, a hormone response modifier, a hypoxia-selective cytotoxin (e.g., tirapazamine), an epidermal growth factor inhibitor, an anti-vascular agent (e.g., xanthenone 5,6- dimethylxanthenone-4-acetic acid), a radiation-activated prodrug (e.g., nitroarylmethyl quaternary (NMQ) salts) or a bioreductive drug or a combination of two or more thereof. In some embodiments, the payload (i.e., moiety C) is optionally not derived from an anthracycline, preferably not derived from PNU 159682.The chemotherapeutic agent may selected from the group consisting of Erlotinib (TARCEVA®), Bortezomib (VELCADE®), Fulvestrant (FASLODEX®), Sutent (SU11248), Letrozole (FEMARA®), Imatinib mesylate (GLEEVEC®), PTK787 / ZK 222584, Oxaliplatin (Eloxatin®.), 5-FU (5-fluorouracil), Leucovorin, Rapamycin (Sirolimus, RAPAMUNE®.), Lapatinib (GSK572016), Lonafarnib (SCH 66336), Sorafenib (BAY43-9006), and Gefitinib (IRESSA®.), AG1478, AG1571 (SU 5271 ; Sugen) or a combination of two or more thereof.The chemotherapeutic agent may be an alkylating agent - such as thiotepa, CYTOXAN® and / or cyclosphosphamide; an alkyl sulfonate - such as busulfan, improsulfan and / or piposulfan; an aziridine - such as benzodopa, carboquone, meturedopa and / or uredopa; ethylenimines and / or methylamelamines - such as altretamine, triethylenemelamine, triethylenepbosphoramide, triethylenethiophosphoramide and / or trimethylomelamine; acetogenin - such as bullatacin and / or bullatacinone; camptothecin; bryostatin; callystatin; cryptophycins; dolastatin; duocarmycin; eleutherobin; pancratistatin; sarcodictyin; spongistatin; nitrogen mustards - such as chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide and / or uracil mustard; nitrosureas - such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and / or ranimnustine; dynemicin; bisphosphonates - such as clodronate; an esperamicin; a neocarzinostatin chromophore; aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, carminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, ADRIAMYCIN®. doxorubicin - such as morpholinodoxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and / or deoxydoxorubicin, epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins - such as mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites - such as methotrexate and 5-fluorouracil (5- FU); folic acid analogues - such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogues - such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogues - such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens - such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; antiadrenals - such as aminoglutethimide, mitotane, trilostane; folic acid replenisher - such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elformithine; elliptinium acetate; an epothilone; etoglucid;gallium nitrate; hydroxyurea; lentinan; lonidainine; macrocyclic depsipeptides such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidanmol; nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllinic acid; 2-ethylhydrazide; procarbazine; razoxane; rhizoxin; sizofiran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2"-trichlorotriethylamine; trichothecenes - such as verracurin A, roridin A and / or anguidine; urethan; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside; cyclophosphamide; thiotepa; taxoids - such as TAXOL®. paclitaxel, abraxane, and / or TAXOTERE®, doxetaxel; chloranbucil; GEMZAR®. gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum analogues - such as cisplatin and carboplatin; vinblastine; platinum; etoposide; ifosfamide; mitoxantrone; vincristine; NAVELBINE®, vinorelbine; novantrone; teniposide; edatrexate; daunomycin; aminopterin; xeloda; ibandronate; topoisomerase inhibitor RFS 2000; difluoromethylomithine (DMFO); retinoids - such as retinoic acid; capecitabine; and pharmaceutically acceptable salts, acids, derivatives or combinations of two or more of any of the above.The payload may be a tubulin disruptor including but are not limited to: taxanes - such as paclitaxel and docetaxel, vinca alkaloids, discodermolide, epothilones A and B, desoxyepothilone, cryptophycins, curacin A, combretastatin A-4-phosphate, BMS 247550, BMS 184476, BMS 188791 ; LEP, RPR 109881 A, EPO 906, TXD 258, ZD 6126, vinflunine, LU 103793, dolastatin 10, E7010, T138067 and T900607, colchicine, phenstatin, chaicones, indanocine, T138067, oncocidin, vincristine, vinblastine, vinorelbine, vinflunine, halichondrin B, isohomohalichondrin B, ER-86526, pironetin, spongistatin 1 , spiket P, cryptophycin 1 , LU103793 (cematodin or cemadotin), rhizoxin, sarcodictyin, eleutherobin, laulilamide, VP-16 and D-24851 and pharmaceutically acceptable salts, acids, derivatives or combinations of two or more of any of the above.The payload may be a DNA intercalator including but are not limited to: acridines, actinomycins, anthracyclines, benzothiopyranoindazoles, pixantrone, crisnatol, brostallicin, CI-958, doxorubicin (adriamycin), actinomycin D, daunorubicin (daunomycin), bleomycin, idarubicin, mitoxantrone, cyclophosphamide, melphalan, mitomycin C, bizelesin, etoposide, mitoxantrone, SN-38, carboplatin, cisplatin, actinomycin D, amsacrine, DACA, pyrazoloacridine, irinotecan and topotecan and pharmaceutically acceptable salts, acids, derivatives or combinations of two or more of any of the above.The payload may be an anti-hormonal agent that acts to regulate or inhibit hormone action on tumors - such as anti-estrogens and selective estrogen receptor modulators, including, but not limited to, tamoxifen, raloxifene, droloxifene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, and / or fareston toremifene and pharmaceutically acceptable salts, acids, derivatives or combinations of two or more of any of the above. The payload may be an aromatase inhibitor that inhibits the enzyme aromatase, which regulates estrogen production in the adrenal glands - such as, for example, 4(5)-imidazoles, aminoglutethimide, megestrol acetate, AROMASIN®. exemestane, formestanie, fadrozole, RIVISOR®. vorozole, FEMARA®. letrozole, and ARIMIDEX® and / or anastrozole and pharmaceutically acceptable salts, acids, derivatives or combinations of two or more of any of the above.The payload may be an anti-androgen such as flutamide, nilutamide, bicalutamide, leuprolide, goserelin and / or troxacitabine and pharmaceutically acceptable salts, acids, derivatives or combinations of two or more of any of the above.The payload may be or comprise a protein, an antibody or an antibody fragment. Conjugates of the present invention comprising such payloads may be referred to as "bispecific conjugates”. Preferably, the payload is a cytokine (e.g., an interleukin such as IL2, IL10, IL12, IL15; a member ofthe TNF superfamily; a chemokine; or an interferon such as interferon gamma.).In one embodiment, the payload is or comprises an antibody or an antibody fragment. The antibody or antibody fragment is preferably characterized by an activity or function selected from: (i) immune cell engager, such as engager of one or more of T-cells (e.g., anti-CD3, anti-CD28, and / or anti-41 BB), B-cells (e.g., anti-CD40), NK-cells (e.g., anti-NKG2D, anti-CD16), and macrophages; (ii) binding to one or more immune checkpoint inhibitor(s), such as PD1 , CTLA-4, and / or PD-L1 ; (iii) binding to one or more cytokine(s); and (iv) binding to one or more chemokine(s).Any payload may be used in unmodified or modified form. Combinations of payloads in which some are unmodified and some are modified may be used. For example, the payload may be chemically modified. One form of chemical modification is the derivatisation of a carbonyl group - such as an aldehyde.In a preferred embodiment, the payload moiety C is a topoisomerase inhibitor; preferably camptothecin (CPT) or a derivative thereof; more preferably derived (e.g., by replacing a hydrogen atom) from topotecan, irinotecan, silatecan, cositecan, exatecan, lurtotecan, gimatecan, belotecan, rubitecan; even more preferably exatecan;In a preferred embodiment, moiety C is an auristatin (i.e., having a structure derived from an auristatin compound family member) or an auristatin derivative. More preferably, moiety C has a structure according to the following formula:wherein: is independently H or C1-6 alkyl; preferably H or CH3; is independently C1-6 alkyl; preferably CH3 or iPr;Rd^ is independently H or C1-6 alkyl; preferably H or CH3;Rd^ is independently H, C1-6 alkyl, COO(C1-6 alkyl), CON(H or C1-6 alkyl), C3-C 10 aryl or C3-C 10 heteroaryl; preferably H, CH3, COOH, COOCH3 or thiazolyl;RdS is independently H, OH, C1-6 alkyl; preferably H or OH; andR^ is independently C3-C-1 O aryl or C3-C-1 O heteroaryl; preferably optionally substituted phenyl or pyridyl.More preferably, moiety C is derived from MMAE or MMAF.In a preferred embodiment, moiety C has a structure according to the following formula:wherein: e is 0, 1 , 2, 3, 4 or 5; preferably 1 ;R^e’ is independently H, COOH, CONH2, aryl-COOH or heteroaryl-COOH; preferably COOH;R^6’ is independently H, COOH, CONH2, aryl-COOH or heteroaryl-COOH; preferably COOH; each R^eis independently H, COOH, CONH2, aryl-COOH or heteroaryl-COOH; preferably COOH;R^6’ is independently H, COOH, CONH2, aryl-COOH or heteroaryl-COOH; preferably COOH; and X is O, NH or S; preferably O.This type of chelator, which includes, e.g., DOTAGA, preferably has the configuration:In a preferred embodiment, moiety C has a structure according to the following formulae:wherein: f and g are each independently 0, 1 , 2, 3, 4 or 5; preferably 1 ;R^f is independently H, COOH, CONH2, aryl-COOH or heteroaryl-COOH; preferably COOH; R^f is independently H, COOH, CONH2, aryl-COOH or heteroaryl-COOH; preferably COOH;R^f is independently H, COOH, CONH2, aryl-COOH or heteroaryl-COOH; preferably COOH; and X is O, NH or S; preferably O.In a preferred embodiment, moiety C has a structure according to any of the following formulae:wherein:Ri h’ and R^h’ are each independently selected from COOH, CONH2, aryl-COOH, heteroaryl-COOH, heteroaryl-CH2COOH, wherein the heteroaryl is preferably pyridinyl; and each X is independently O, NH or S;In another preferred embodiment, moiety C is a chelator having a structure comprising DOTAM (2-[4,7,10- tris(2-amino-2-oxoethyl)-1 ,4,7,10-tetrazacyclododec-1 -yl]acetamide) or a derivative thereof, e.g.:ip y , p y p .Particularly preferred embodiments for the moiety C as well as the compound according to the present invention are shown in the appended claims or elsewhere herein.In some embodiments, moiety C comprises two or more therapeutically or diagnostically useful moieties, preferably with different mode of action. Moiety C may be a radiohybrid ligand moiety which can be labeled, e.g., with18F via isotopic exchange and / or with (radio)metals (such as68Ga,177Lu,225Ac). Exemplary ligands of this class include, e.g. the following structures and (radio)metal chelates thereof:A chelator (or a chelate) can significantly improve the hydrophilicity of an otherwise F-only-based tracer. Additional additional advantages of this radiohybrid concept include that, e.g., both the F-based moiety and the chelator can be labeled in an independent manner using the unprotected precursor, resulting in either a combination of 18F and metal or 19F an radiometal, the latter to be used for imaging (e.g.,68Ga for PET,111ln for SPECT), or for radioligand therapy (e.g.,177Lu). Corresponding radiopharmaceuticals, for example,18F / natGa and19F / 68Ga, are chemically identical molecules. Thus, they represent monozygotic chemical twins that should result in almost identical PET scans, with only slight differences determined by the nuclear properties of the chosen radioisotope. In addition, when using18F in combination with a therapeutic radioisotope, such as177Lu, the resulting twins may be useful to bridge18F PET and radioligand therapy. Such tracers are contemplated as advantageous tools for pretherapeutic patient stratification, pretherapeuticdosimetry, and radioligand therapy with a single tracer by exploiting18F and the most suitable therapeutic radioisotope (if also available as nonradioactive isotope).[54-57]Without wishing to be bound by any theory, it is contemplated that ligands of this class may identify true-positive prostate cancer lesions in patients with negative conventional imaging, may help to better define sites of disease recurrence, and / or may inform salvage therapy decisions than does conventional imaging, potentially leading to improved outcomes.C may also be a dual mode-of-action moiety, e.g., comprising a cytotoxic and a chelating or radioactive moiety as described elsewhere herein, attached to a common scaffold or linker moiety. An exemplary ligand of this class includes, e.g., the following structure and (radio)metal chelates thereof:C may also comprise, in addition to the therapeutic and / or diagnostic agent as described elsewhere herein, also a further targeting moiety, e.g., a PSMA binding moiety, attached to a common scaffold or linker moiety. An exemplary ligand of this class includes, e.g., the following structure and (radio)metal chelates thereof:In some embodiments, the compounds may comprise (macro)cyclic structure(s). Exemplary formats and examples are shown below, wherein linker and payload are preferably groups B and C as defined elsewhere herein:R' ^j— z compounds comprising a structure , e.g., wherein R1aand R1bare joined together to form a ring:compounds comprising a structure, e.g., wherein R1aand R1bare joined together to form a (macrocyclic) ring which is fused to one or more further (macrocyclic) rings, wherein the filled circles represent branching points (branched moiety J) and the hollow circle represents a ring (cyclic moiety J):compounds comprising one or more cyclic structure(s), e.g., a cyclic peptide, within moiety B or any of moieties BL and / or Bs:- compounds comprising one or more cyclic structure(s), e.g., a cyclic peptide, fused to one or more further (macro)cyclic structure(s) within moiety B or any of moieties BL and / or Bs, wherein the filled circles represent branching points (branched moiety J) and the hollow circle represents a ring (cyclic moiety J):Treatment and diagnosticsThe compounds described herein may be used to treat disease. The treatment may be therapeutic and / or prophylactic treatment, with the aim being to prevent, reduce or stop an undesired physiological change or disorder. The treatment may prolong survival as compared to expected survival if not receiving treatment. The disease that is treated by the compound may be any disease that might benefit from treatment. This includes chronic and acute disorders or diseases including those pathological conditions which predispose to the disorder.The term "cancer" and "cancerous" is used in its broadest sense as meaning the physiological condition in mammals that is typically characterized by unregulated cell growth. A tumor comprises one or more cancerous cells. When treating cancer, the therapeutically effect that is observed may be a reduction in the number of cancer cells; a reduction in tumor size; inhibition or retardation of cancer cell infiltration into peripheral organs; inhibition of tumor growth; and / or relief of one or more of the symptoms associated with the cancer.In animal models, efficacy may be assessed by physical measurements of the tumor during the treatment, and / or by determining partial and complete remission of the cancer. For cancer therapy, efficacy can, for example, be measured by assessing the time to disease progression (TTP) and / or determining the response rate (RR).Particularly preferred embodiments for the methods of treatment related to the present invention are shown in the appended claims.Herein disclosed are also methods for treatment of the human or animal body, e.g., by surgery or therapy, or diagnostic method practised on the human or animal body, the methods involving a step of administering a therapeutically or diagnostically effective amount of a compound or a pharmaceutical composition as described herein to a subject in need thereof. More specifically, herein disclosed are methods for treatment, e.g., by therapy or prophylaxis, of a subject suffering from or having risk for a disease or disorder; or by guided surgery practised on a subject suffering from or having risk for a disease or disorder; method for diagnosis of a disease or disorder, e.g., diagnostic method practised on the human or animal body and / or involving a nuclear medicine imaging technique, such as Scintigraphy, Positron Emission Tomography (PET) or Single Photon Emission Computed Tomography (SPECT); method for targeted delivery of a therapeutic or diagnostic agent to a subject suffering from or having risk for a disease or disorder.The results produced from said nuclear medicine techniques may be analyzed. Typically, a baseline PET or SPECT scan is obtained for each individual, optionally at randomization, and utilized to compare subsequent scans for the purpose of monitoring cancer metastasis or progression. The analysis of subsequent scans, may show lesions that were not present in the baseline scan such as positive distant lesions, loco-regionallesions which are indicative of progression of the cancer. Said patient subject to such diagnostic scans may then become eligible for a therapeutic treatment.In the aforementioned methods, said disease or disorder may be independently selected from cancer, preferably Prostate cancer, and other diseases associated with ACPP expression, preferably selected from pancreatitis, Paget's disease, sickle-cell disease, lysosomal storage diseases, and Gaucher's disease. More preferably, the disease is selected from prostate adenocarcinoma, ductal prostate cancer, ductal adenocarcinoma, clear cell adenocarcinoma, acinar adenocarcinoma, urothelial cancer, neuroendocrine prostate cancer, small cell prostate cancer, multiple myeloma.The course of Prostate cancer from diagnosis to death is best categorized as a series of clinical stages based on the extent of disease, hormonal status, and absence or presence of detectable metastases: localized disease, rising levels of prostate-specific antigen (PSA) after radiation therapy or surgery with no detectable metastases, and clinical metastases in the non-castrate or castrate stage. Although radical prostatectomy, primary definitive, radiation, or a combination of both can be curative for patients with localized disease, a significant proportion (up to 50%) of these patients have recurrent disease as evidenced by a rising level of PSA with no detectable metastases, called biochemical recurrence (BCR). The methods for diagnosis or treatment of Prostate Cancer contemplated herein, comprise all clinical stages (AJCC stage I, HA, IIB, IIC, IIIA, III B, IIIC, IVA, IVB) including all low stage disease and BCR.For the diagnosis or treatment of diseases or disorder, including the above cancers, it may be advantageous if the compound comprises a radioactive group comprising a radioisotope; preferably wherein moiety C is a chelate of a radioactive isotope with a chelating agent; more preferably a beta-emitter; most preferably177Lu. For instance, moiety C may be a DOTAGA chelate of a beta-emitter, such as177Lu. Such radioactive compounds (“radioconjugates”) may be suitably administered to a subject in need thereof at a dose of £ 250 MBq / kg, s 500 MBq / kg, or s 1000 MBq / kg, each expressed as a mouse dose, or an equivalent human dose. For instance, a mouse dose may be recalculated to a corresponding equivalent human dose based on the body surface ratio as follows:250 MBq / Kg (in mouse) 250 MBq / kg / 12.3 = 20.3 MBq / kg (in human);20.3 MBq / kg * 70 Kg = 1 .421 GBq per human patient.1000 MBq / Kg (in mouse) -> 1000 MBq / kg / 12.3 = 81.3 MBq / kg (in human);81.3 MBq / kg *70 Kg = 5.691 GBq per human patient.When R1-Y-Z is represented by a structure as defined in claim 13 or 14; preferably by structure A-7; more preferably when the compound is 20a or 28a, the compound may be administered to a subject at a dose of 2 250 MBq / kg; preferably S 500 MBq / kg, each expressed as a mouse dose, or an equivalent human dose, e.g., S 20.3 MBq / kg, preferably S 40.6 MBq / kg, to provide advantageous anticancer activity.When R1-Y-Z is represented by a structure as defined in any one of claims 15, 16 and 17; preferably by structure A-23; more preferably when the compound is 22a, the compound may be administered to a subject at a dose of S 500 MBq / kg; preferably 2 1000 MBq / kg, each expressed as a mouse dose, or an equivalent human dose, e.g., S 40.6 MBq / kg, preferably S 81 .3 MBq / kg, to provide advantageous anticancer activity.Pharmaceutical compositionsThe compounds described herein may be in the form of pharmaceutical compositions which may be for human or animal usage in human and veterinary medicine (e.g., as therapeutic or diagnostic compositions) and will typically comprise any one or more of a pharmaceutically acceptable diluent, carrier, or excipient. Acceptable carriers or diluents for therapeutic use are well known in the pharmaceutical art, and are described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co. (A. R. Gennaro edit. 1985). The choice of pharmaceutical carrier, excipient or diluent can be selected with regard to the intended route of administration and standard pharmaceutical practice. The pharmaceutical compositions may comprise as - or in addition to - the carrier, excipient or diluent any suitable binder(s), lubricant(s), suspending agent(s), coating agent(s), solubilising agent(s).Preservatives, stabilisers, dyes and even flavouring agents may be provided in the pharmaceutical composition. Examples of preservatives include sodium benzoate, sorbic acid and esters of p- hydroxybenzoic acid. Antioxidants and suspending agents may be also used.There may be different composition / formulation requirements dependent on the different delivery systems. By way of example, the pharmaceutical composition may be formulated to be administered using a minipump or by a mucosal route, for example, as a nasal spray or aerosol for inhalation or ingestable solution, or parenterally in which the composition is formulated by an injectable form, for delivery, by, for example, an intravenous, intramuscular or subcutaneous route. Alternatively, the formulation may be designed to be administered by a number of routes.If the agent is to be administered mucosally through the gastrointestinal mucosa, it should be able to remain stable during transit though the gastrointestinal tract; for example, it should be resistant to proteolytic degradation, stable at acid pH and resistant to the detergent effects of bile.Where appropriate, the pharmaceutical compositions may be administered by inhalation, in the form of a suppository or pessary, topically in the form of a lotion, solution, cream, ointment or dusting powder, by use of a skin patch, orally in the form of tablets containing excipients such as starch or lactose, or in capsules or ovules either alone or in admixture with excipients, or in the form of elixirs, solutions or suspensions containing flavouring or colouring agents, or the pharmaceutical compositions can be injected parenterally, for example, intravenously, intramuscularly or subcutaneously. For parenteral administration, the compositions may be best used in the form of a sterile aqueous solution which may contain other substances, for example, enough salts or monosaccharides to make the solution isotonic with blood. For buccal or sublingual administration, the compositions may be administered in the form of tablets or lozenges which can be formulated in a conventional manner.The compound of the present invention may be administered in the form of a pharmaceutically acceptable or active salt. Pharmaceutically-acceptable salts are well known to those skilled in the art, and for example, include those mentioned by Berge et al, in J.Pharm.Sci., 66, 1 -19 (1977). Salts include, but are not limited, to sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate,glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., 1 ,1 '-methylene-bis-(2-hydroxy-3-naphthoate)) salts.The routes for administration (delivery) may include, but are not limited to, one or more of oral (e.g. , as a tablet, capsule, or as an ingestable solution), topical, mucosal (e.g. , as a nasal spray or aerosol for inhalation), nasal, parenteral (e.g., by an injectable form), gastrointestinal, intraspinal, intraperitoneal, intramuscular, intravenous, intrauterine, intraocular, intradermal, intracranial, intratracheal, intravaginal, intracerebroventricular, intracerebral, subcutaneous, ophthalmic (including intravitreal or intracameral), transdermal, rectal, buccal, vaginal, epidural, sublingual.Typically, a physician will determine the actual dosage which will be most suitable for an individual subject. The specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the individual undergoing therapy.The formulations may be packaged in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water, for administration. Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules and tablets of the kind previously described. Exemplary unit dosage formulations contain a daily dose or unit daily sub-dose, or an appropriate fraction thereof, of the active ingredient.CombinationsIn certain embodiments, combination modalities are contemplated, involving using a compound according to the present invention, e.g., a radioconjugates or a compound comprising a chelator moiety C, in combination with one or more other radioligand therapeutics RLTs and / or diagnostics, e.g., PSMA-targeted RLT, such as gozetotide (PSMA-11) or vipivotide tetraxetan (PSMA-617). Advantages associated with such approaches may include, e.g., efficient production of radiochelated RLTs in one pots by mixing two precursors in the same vial, and / or improved antitumor activity and / or imaging quality due to the different modes of action (targeting different tumor proteins at the same time).Further combination modalities may use a compound according to the present invention, e.g., a cytotoxic conjugate, preferably a ProX1-(SS) MMAE-based conjugate (such as compound 31), in combination with one or more other radioligand therapeutics RLTs and / or diagnostics, e.g., PSMA-targeted RLT, such as gozetotide (PSMA-11) or vipivotide tetraxetan (PSMA-617). Advantages associated with such approaches may include, e.g., improved antitumor activity due to the different modes of action (targeting different tumor proteins at the same time and combining radioactivity with cytotoxicity).Further combination modalities may involve using a compound according to the present invention , e.g., a radioconjugate, preferably a ProX1-(SS)-DOTA-based radioconjugate (such as compound 27a and radiochelates thereof), or a cytotoxic conjugate, preferably a ProX1-(SS) MMAE-based conjugate (such ascompound 31), in combination with external beam radiation (radiotherapy). Advantages associated with such approaches may include, e.g., improved antitumor activity due to the different modes of action.Further combination modalities may involve using a compound according to the present invention, e.g., a radioconjugate, preferably a ProX1-(SS)-DOTA-based radioconjugate (such as compound 27a and radiochelates thereof), or a cytotoxic conjugate, preferably a ProX1-(SS) MMAE-based conjugate (such as compound 31), in combination with androgen deprivation therapy (e.g., enzalutamide, abiraterone acetate, flutamide, nilutamide, bicalutamide, leuprolide, goserelin and / or troxacitabine). An aim of such type of therapy is to prevent growth of prostate cancer tumors that are castration-resistant (or prevent potential metastasis). Without wishing to be bound by any theory, this is contemplated to work by stopping the growth of androgen-dependent cancer cell by blocking binding of hormones, such as testosterone. However, not all cancer cells are androgen-dependent. By introducing a combination partner such as the compounds of the present invention, it is contemplated that evolution of castration-resistant prostate cancer can be significantly further inhibited, preventing aggressive metastasis which results in high death rates of patients.Further combination modalities may involve using a compound according to the present invention, e.g., a radioconjugate, preferably a ProX1-(SS)-DOTA-based radioconjugate (such as compound 27a and radiochelates thereof), or a cytotoxic conjugate, preferably a ProX1-(SS) MMAE-based conjugate (such as compound 31), in combination with one or more immunocytokines.Further combination modalities may involve using a compound according to the present invention, e.g., a radioconjugate, preferably a ProX1-(SS)-DOTA-based radioconjugate (such as compound 27a and radiochelates thereof), or a cytotoxic conjugate, preferably a ProX1-(SS) MMAE-based conjugate (such as compound 31), in combination with one or more of: antibodies, bispecific antibodies, trispecific antibodies, and further bi- or trispecific conjugates of the present invention wherein the payload (C) is or comprises (i) an immune cell engager antibody or antibody fragment, such as engager of one or more of T-cells (e.g., anti- CD3, anti-CD28, and / or anti-41 BB), B-cells (e.g., anti-CD40), NK-cells (e.g., anti-NKG2D, anti-CD16), and macrophages, preferably Blinatumomab, Mosunetuzumab, Glofitamab, Epcoritamab, Odronexamab, Plamotamab, Zanidatamab ; (ii) an antibody or antibody fragment binding to one or more immune checkpoint inhibitor(s), such as PD1 , CTLA-4, and / or PD-L1 , preferably Pembrolizumab, Nivolumab, Ipilimumab, Avelumab, Cemiplimab, Atezolizumab, Durvalumab, Cadonilimab; (iii) a cytokine; (iv) an immunocytokine wherein a cytokine such as IL2, TNF, IL12, IFN or any other cytokine is conjugated to a tumor targeting agent such as an antibody or antibody fragment, (v) a chemokine, (v) a linear of cyclic peptide or (vi) CAR- T cell therapy.Further combination modalities may involve using a compound according to the present invention, e.g., a radioconjugate, preferably a ProX1-(SS)-DOTA-based radioconjugate (such as compound 27a and radiochelates thereof), or a cytotoxic conjugate, preferably a ProX1-(SS) MMAE-based conjugate (such as compound 31), in combination with conventional chemotherapy, e.g., as described with respect to chemotherapeutic, cytotoxic and / or cytostatic agents hereinabove.General techniquesThe practice of the present invention employs, unless otherwise indicated, conventional methods of chemistry, biochemistry, molecular biology, cell biology, genetics, immunology and pharmacology, known tothose of skill of the art. Such techniques are explained fully in the literature. See, e. g. , Gennaro, A. R., ed. (1990) Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing Co.; Hardman, J. G., Limbird, L. E., and Gilman, A. G., eds. (2001) The Pharmacological Basis of Therapeutics, 10th ed., McGraw-Hill Co.; CoIowick, S. et al., eds., Methods In Enzymology, Academic Press, Inc.; Weir, D. M. , and Blackwell, C. C., eds. (1986) Handbook of Experimental Immunology, Vols. I-IV, Blackwell Scientific Publications; Maniatis, T. et al., eds. (1989) Molecular Cloning: A Laboratory Manual, 2nd edition, Vols. I-III, Cold Spring Harbor Laboratory Press; Ausubel, F. M. et al., eds. (1999) Short Protocols in Molecular Biology, 4th edition, John Wiley & Sons; Ream et al., eds. (1998) Molecular Biology Techniques: An Intensive Laboratory Course, Academic Press; Newton, C. R., and Graham, A., eds. (1997) PCR (Introduction to Biotechniques Series), 2nd ed., Springer Verlag.Chemical synthesisThe compounds described herein may be prepared by chemical synthesis techniques. It will be apparent to those skilled in the art that sensitive functional groups may need to be protected and deprotected during synthesis of a compound. This may be achieved by conventional techniques, for example as described in "Protective Groups in Organic Synthesis" by T W Greene and P G M Wuts, John Wiley and Sons Inc. (1991), and by P.J.Kocienski, in "Protecting Groups", Georg Thieme Verlag (1994). It is possible during some of the reactions that any stereocentres present could, under certain conditions, be epimerised, for example if a base is used in a reaction with a substrate having an optical centre comprising a base-sensitive group. It should be possible to circumvent potential problems such as this by choice of reaction sequence, conditions, reagents, protection / deprotection regimes, etc. as is well-known in the art.DefinitionsAntibody. The term "antibody" is used in its broadest sense and covers monoclonal antibodies, polyclonal antibodies, dimers, multimers, multispecific antibodies (e.g., bispecific antibodies), veneered antibodies, antibody fragments and small immune proteins (SIPs) (see Int. J. Cancer (2002) 102, 75-85). An antibody is a protein generated by the immune system that is capable of recognizing and binding to a specific antigen. A target antigen generally has numerous binding sites, also called epitopes, recognized by CDRs on multiple antibodies. Each antibody that specifically binds to a different epitope has a different structure. Thus, one antigen may have more than one corresponding antibody. An antibody includes a full-length immunoglobulin molecule or an immunologically active portion of a full-length immunoglobulin molecule, i.e. a molecule that contains an antigen binding site that immunospecifically binds an antigen of a target of interest or part thereof. The antibodies may be of any type - such as IgG, IgE, IgM, IgD, and IgA) - any class - such as IgG 1 , lgG2, lgG3, lgG4, lgA1 and lgA2 - or subclass thereof. The antibody may be or may be derived from murine, human, rabbit or from other species.Antibody fragments. The term "antibody fragment" refers to a portion of a full length antibody, generally the antigen binding or variable region thereof. Examples of antibody fragments include, but are not limited to, Fab, Fab', F(ab')2, and Fv fragments; scFv’s, diabodies; linear antibodies; single domain antibodies, including dAbs, camelid VHH antibodies and the IgNAR antibodies of cartilaginous fish. Antibodies and their fragments may be replaced by binding molecules based on alternative non-immunoglobulin scaffolds,peptide aptamers, nucleic acid aptamers, structured polypeptides comprising polypeptide loops subtended on a non-peptide backbone, natural receptors or domains thereof.Analog. This term encompasses any enantiomers, racemates and stereoisomers, as well as all pharmaceutically acceptable salts and hydrates of such compounds.Unless otherwise stated, the following definitions apply to chemical terms used in connection of compounds of the invention and compositions containing such compounds.Alkyl refers to a branched or unbranched saturated hydrocarbyl radical. Suitably, the alkyl group comprises from 1 to 100, preferably 3 to 30, carbon atoms, more preferably from 5 to 25 carbon atoms. Preferably, alkyl refers to methyl, ethyl, propyl, butyl, pentyl, or hexyl.Alkenyl refers to a branched or unbranched hydrocarbyl radical containing one or more carbon-carbon double bonds. Suitably, the alkenyl group comprises from 2 to 30 carbon atoms, preferably from 5 to about 25 carbon atoms.Alkynyl refers to a branched or unbranched hydrocarbyl radical containing one or more carbon-carbon triple bonds. Suitably, the alkynyl group comprises from about 3 to about 30 carbon atoms, for example from about 5 to about 25 carbon atoms.Halogen refers to fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.Cycloalkyl refers to an alicyclic moiety, suitably having 3, 4, 5, 6, 7 or 8 carbon atoms. The group may be a bridged or polycyclic ring system. More often cycloalkyl groups are monocyclic. This term includes reference to groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, bicyclo[2.2.2]octyl and the like.Aryl refers to an aromatic carbocyclic ring system, suitably comprising 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15 or 16 ring carbon atoms. Aryl may be a polycyclic ring system, having two or more rings, at least one of which is aromatic. This term includes reference to groups such as phenyl, naphthyl fluorenyl, azulenyl, indenyl, anthryl and the like.Derivative. A derivative includes the chemical modification of a compound. Examples of such modifications include the replacement of a hydrogen by a halo group, an alkyl group, an acyl group or an amino group and the like. The modification may increase or decrease one or more hydrogen bonding interactions, charge interactions, hydrophobic interactions, van der Waals interactions and / or dipole interactions.Diastereomers or diastereoisomers, unless specified otherwise, preferably refer to stereoisomers of a compound having different configurations at one or more stereocenters in parts of the molecule other than moiety R1-Y or R1. That is, unless specified otherwise, the stereochemical configuration of moiety R1-Y or R1is as represented in the respective structure, and the individual diastereomers may differ in their stereochemical configuration in the in parts of the molecule other than moiety R1-Y or R1.The prefix (hetero) herein signifies that one or more of the carbon atoms of the group may be substituted by nitrogen, oxygen, phosphorus, silicon or sulfur. Heteroalkyl groups include for example, alkyloxy groups and alkythio groups. Heterocycloalkyl or heteroaryl groups herein may have from 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15 or 16 ring atoms, at least one of which is selected from nitrogen, oxygen, phosphorus, silicon andsulfur. In particular, a 3- to 10-membered ring or ring system and more particularly a 5- or 6-membered ring, which may be saturated or unsaturated. For example, selected from oxiranyl, azirinyl, 1 ,2-oxathiolanyl, imidazolyl, thienyl, furyl, tetra hydrofury I, pyranyl, thiopyranyl, thianthrenyl, isobenzofuranyl, benzofuranyl, chromenyl, 2H-pyrrolyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolidinyl, benzimidazolyl, pyrazolyl, pyrazinyl, pyrazolidinyl, thiazolyl, isothiazolyl, dithiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, piperidyl, piperazinyl, pyridazinyl, morpholinyl, thiomorpholinyl, especially thiomorpholino, indolizinyl, 1 ,3- Dioxo-1 ,3-dihydro-isoindolyl, 3H-indolyl, indolyl, benzimidazolyl, cumaryl, indazolyl, triazolyl, tetrazolyl, purinyl, 4H-q uinolizinyl, isoquinolyl, quinolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, decahydroquinolyl, octahydroisoquinolyl, benzofuranyl, dibenzofuranyl, benzothiophenyl, dibenzothiophenyl, phthalazinyl, naphthyridinyl, quinoxalyl, quinazolinyl, quinazolinyl, cinnolinyl, pteridinyl, carbazolyl, [beta] -carbolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl, furazanyl, phenazinyl, phenothiazinyl, phenoxazinyl, chromenyl, isochromanyl, chromanyl, 3,4-dihydro-2H-isoquinolin-1-one, 3,4-dihydro-2H-isoquinolinyl, and the like.“Substituted” signifies that one or more, especially up to 5, more especially 1 , 2 or 3, of the hydrogen atoms in said moiety are replaced independently of each other by the corresponding number of substituents. The term "optionally substituted" as used herein includes substituted or unsubstituted. It will, of course, be understood that substituents are only at positions where they are chemically possible, the person skilled in the art being able to decide (either experimentally or theoretically) without inappropriate effort whether a particular substitution is possible. For example, amino or hydroxy groups with free hydrogen may be unstable if bound to carbon atoms with unsaturated (e.g. , olefinic) bonds. Preferably, the term “substituted” signifies one or more, especially up to 5, more especially 1 , 2 or 3, of the hydrogen atoms in said moiety are replaced independently of each other by the corresponding number of substituents selected from OH, SH, NH2, halogen, cyano, carboxy, alkyl, cycloalkyl, aryl and heteroaryl. Additionally, the substituents described herein may themselves be substituted by any substituent, subject to the aforementioned restriction to appropriate substitutions as recognised by the skilled person. Preferably, any of the aforementioned substituents may be further substituted by any of the aforementioned substituents, each of which may be further substituted by any of the aforementioned substituents.Preferably, the term “substituted” used herein means any of the above groups (e.g.., alkyl, alkylene, alkylcycloalkyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, aryloxy, alkylaminyl, alkylcarbonylaminyl, alkylaminy lalkyl, aminylcarbonyl, alkylaminylcarbonyl, aminylcarbonylalkyl, aminylcarbonycycloalkylalkyl, thioalkyl, aryl, aralkyl, carboxyalkyl, cyanoalkyl, cycloalkyl, cyanocycloalkyl, cycloalkylaminylcarbonyl, cycloalkylalkyl, haloalkyl, haloalkoxy, heterocyclyl, A / -heterocyclyl, heterocyclylalkyl, heteroaryl, N- heteroaryl, phosphoalkoxy and / or heteroarylalkyl) wherein at least one hydrogen atom (e.g., 1 , 2, 3 or all hydrogen atoms) is replaced by a bond to a non-hydrogen atom such as, but not limited to: a halogen atom such as F, Cl, Br, and I; an oxygen atom in groups such as hydroxyl groups, alkoxy groups, and ester groups; a sulfur atom in groups such as thiol groups, thioalkyl groups, sulfone groups, sulfonyl groups, and sulfoxide groups; a nitrogen atom in groups such as amines, amides, alkylamines, dialkylamines, arylamines, alkylarylamines, diarylamines, N-oxides, imides, and enamines; a silicon atom in groups such as trialkylsilyl groups, dialkylarylsilyl groups, alkyldiarylsilyl groups, and triarylsilyl groups; and other heteroatoms in various other groups. “Substituted" also means any of the above groups in which one or more hydrogen atoms are replaced by a higher-order bond (e.g., a double- or triple-bond) to a heteroatom such as oxygen in oxo,carbonyl, carboxyl, and ester groups; and nitrogen in groups such as imines, oximes, hydrazones, and nitriles. For example, “substituted” includes any of the above groups in which one or more hydrogen atoms are replaced with -NRgRh, -NRgC(=O)Rh, -NRgC(=O)NRgRh, -NRgC(=O)ORh, -NRgSO2Rh, -OC(=O)NRgRh, -ORg, -SRg, -SORg, -SO2Rg, -OSO2Rg, -SO2ORg, =NSO2Rg, and -SO2NRgRh. “Substituted” also means any of the above groups in which one or more hydrogen atoms are replaced with -C(=O)Rg, -C(=O)ORg, -C(=O)NRgRh, -CH2SO2Rg, -CH2SO2NRgRh. In the foregoing, Rgand Rh are the same or different and independently hydrogen, alkyl, alkoxy, alkylaminyl, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, A / -heterocyclyl, heterocyclylalkyl, heteroaryl, A / -heteroaryl and / or heteroarylalkyl. “Substituted” further means any of the above groups in which one or more hydrogen atoms are replaced by a bond to an aminyl, cyano, hydroxyl, imino, nitro, oxo, thioxo, halo, alkyl, alkoxy, alkylaminyl, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, A / -heterocyclyl, heterocyclylalkyl, heteroaryl, A / -heteroaryl and / or heteroarylalkyl group. In addition, each of the foregoing substituents may also be optionally substituted with one or more of the above substituents.More preferably, substituents suitably include halogen atoms and halomethyl groups such as CF3 and CCH; oxygen containing groups such as oxo, hydroxy, carboxy, carboxyalkyl, alkoxy, alkoyl, alkoyloxy, aryloxy, aryloyl and aryloyloxy; nitrogen containing groups such as amino, alkylamino, dialkylamino, cyano, azide and nitro; sulfur containing groups such as thiol, alkylthiol, sulfonyl and sulfoxide; heterocyclic groups which may themselves be substituted; alkyl groups, which may themselves be substituted; and aryl groups, which may themselves be substituted, such as phenyl and substituted phenyl. Alkyl includes substituted and unsubstituted benzyl.Where two or more moieties are described as being "each independently" selected from a list of atoms or groups, this means that the moieties may be the same or different. The identity of each moiety is therefore independent of the identities of the one or more other moieties.Molecular weight. This term is used to refer to the mass of a given molecule and is expressed herein as “weight average molecular weight” or Mw. In the present disclosure, the molecular weight may be determined by mass spectrometry, preferably by an ESI quadrupole or Orbitrap instrument, more preferably with an Agilent 6100 Series Single Quadrupole MS instrument.Dissociation constant (Kd). This term refers to the equilibrium of ligand binding to a specific binding site, that is, the concentration of ligand at which 50% of the ligand is bound to the specific binding site. It is expressed in concentration units and particularly in nM. In this disclosure, and unless stated otherwise, the dissociation constant may be determined by Surface Plasmon Resonance (SPR). Preferably, a SPR measurement useful for determining Kd may be performed using a CM5 chip, e.g., with a Biacore X100 instrument. A suitable measurement protocol is as follows. ACP3 is immobilized on both flow cells of a CM5 chip (e.g., Cytiva, #BR100012), reaching 3500 to 4500 RUs, using the EDC / NHS protocol provided by the manufacturer. ACP3 immobilized on the reference flow cell is denatured (e.g., with a denaturing solution: 0.85% H3PO4, 10 mM NaOH, and 50 mM HCI). PBS (pH 7.4) can be used as running buffer. Test compounds are injected at different concentrations (e.g., 1 pM or 500 nM in running buffer), e.g., according to a multicycle analysis with the following settings: 120 seconds contact time and 15,000 seconds dissociation time at a flow rate of 10 μL / min. Sensograms may be plotted, e.g. with GraphPad Prism (version 8, GraphPad Software), and fitted, e.g., using the BIAcore Evaluation Software 3.2 RCI (GE Healthcare).Specific binding. As used herein, and unless specified otherwise, "specific binding to ACP3" refers to better ACP3 binding expressed by Kd as compared to binding to other proteins found in mammals, preferably humans, primates and / or rodents, e.g., albumin (e.g., HSA or MSA) and / or other phosphatase(s) (e.g., PLAP, ACPI, TCPTP, and / or TNAP).EXAMPLESExample 1 : Synthesis of derivatives1.1 General RemarksReversed-phase High-Pressure Liquid Chromatography (HPLC): Test compounds were purified by semipreparative reversed-phase HPLC (RP-HPLC) on an Agilent 1200 Series RP-HPLC with a PDA UV detector. The system was equipped with a Synergi 4 pm, Polar-RP 80 A 10 x 150 mm C18 column using a flow rate of 5 mL / min with the following gradient of eluent A (mQ millipore water 0.1 % TFA) and eluent B (acetonitrile with 0.1 % TFA): 0-15 min 90% to 0% A, 15-16 min 0% A, 16-17 min 0% to 90% A, 17-18 min 90% A.Reversed-phase Medium-Pressure Liquid Chromatography (MPLC): Small organic molecules that could be produced at higher quantities (i.e., >10 mg) were purified by reversed-phase MPLC (BUCHI) on a C18 40 pM irregular 12 g column using mQ millipore water 0.1% formic acid (FA) (eluent A) and acetonitrile 0.1% FA (eluent B) as mobile phase at following gradient: 0-5 min 98% A, 5-45 min 98% to 0% A, 45-50 min 0% A, 50-50.1 min 0% to 98% A and 50.1-55 min 98% A. The flow rate was set to 30 mL / min.Analytical LC-MS: Spectra were recorded on an Agilent 6100 Series Single Quadrupole MS system combined with an Agilent 1200 Series LC, using an InfinityLab Poroshell 120 EC-C18 Column, 2.7 pm, 4.6 x 50 mm, at a flow rate of 0.8 mL / min, acetonitrile:water with 0.1 % formic acid. The analysis was performed with the following gradient: 10% to 100% acetonitrile in 5 min.Liquid-Chromatography / Mass-Spectrometry (LC / MS) for oligonucleotides: Liquid-Chromatography / Mass- Spectrometry (LC / MS) spectra of oligonucleotides were performed on an Agilent 1260 Series LC coupled to an Agilent 6100 Series Single Quadrupole MS. The system was equipped with an ACQUITY UPLC Oligonucleotide BEH C18 column (130 A, 1.7 pm, 2.1 x 50 mm), using the following gradient of eluent A (15 mM TEA, 400 mM HFIP in mQ H2O) and eluent B (methanol) at a flow rate of 0.4 mL / min and 60°C column temperature: 0-0.2 min 95% A, 0.2-8.2 min 95% to 5% A, 8.2-8.7 min 5% A, 8.7-9.2 min 5 to 95% A, 9.2-13 min 95% A.Reversed-phase High-Pressure Liquid Chromatography (HPLC) for oligonucleotides: Preparative reversed- phase high-performance liquid chromatography (RP-HPLC) for the purification of oligonucleotides were performed on an Agilent 1200 Series equipped with a XTerra Shield RP18 preparative column (125 A, 10 x 150 mm). A gradient of eluent C (100 mM triethylammonium acetate pH 7 in mQ H2O) and eluent D (100 mM TEAA pH 7 in 80% acetonitrile) were applied at a flow rate of 4 mL / min. Product-containing fractions were dried in a SpeedVac vacuum concentrator (RVC 2-25CDplus, Martin Christ) and re-dissolved for ethanol precipitation.General solid-phase synthesis procedures (S 1 ): Solid-phase synthesis was performed with Wang resin (100- 200 mesh, 1.1 mmol / g). In brief, the resin was swollen for 15 min in dimethylformamide (DMF) before anyreaction steps. Incubations were performed in 10 mL reaction columns on a rotator mixer at room temperature.Fmoc deprotection (S2): Resin was incubated two times (15 min) with 20% piperidine in DMF. After deprotection, the resin was washed 5-10 times with DMF to remove residual piperidine.Mini cleavage test for LC-MS analysis (S3): A small portion of resin was transferred to an Eppendorf tube and incubated with 40 μL trifluoracetic acid (TFA) for 15 min at room temperature. The cleavage was quenched by addition of 80 μL DMF to centrifuge the suspension (1 min at 10’000 ref) before LC-MS analysis. This method was used to monitor the synthesis after each reaction step on resin.Amide coupling (S4): The carboxylic acids, O-(7-azabenzotriazol-1-yl)-A / ,A / ,A / ',A / '-tetramethyluronium hexafluorophosphate (HATU) and diisopropylethylamine (DIPEA) were dissolved in DMF (0.08 M) and added to the resin-bound free amino group. After incubation, the resin was subsequently washed five times with DMF. Coupling efficiency was monitored by LC-MS.Resin cleavage and purification (S5): Cleavage solution was prepared as follows: 95% trifluoracetic acid (TFA), 2.5% water, and 2.5% triisopropylsilane (TIPS). Two consecutive cleavages (1 h at room temperature each) were performed. Cleavage fractions were combined and either directly purified via RP HPLC or precipitated in diethyl ether for subsequent purification (see below).Peptide precipitation (S6): Peptides were precipitated from the cleavage solution by addition of 5-10 volumes of ice-cold diethyl ether after most of the TFA was removed under reduced pressure. Precipitation proceeded for 30 min at -20 °C to obtain the peptide as pellet by centrifugation (3200 ref, 5 min, 4 °C). The crude was dissolved in a mixture of watenacetonitrile (1 :1) and purified by reversed-phase chromatography.One-pot synthesis of a-Aminophosphonic acids (GP1):Aldehyde (1 equiv.) and amine (1 equiv.) were dissolved in dry acetonitrile (0.6 M) within a reaction vessel. Chlorotrimethylsilane (4 equiv.) was added dropwise and the cloudy solution was sonicated for 2h. P(OSiMe3)3 was added and the mixture was sonicated for an additional 2h. Lastly, methanol (2.5x volume of acetonitrile) and water (5 equiv.) were added and the clear solution was sonicated for 30 min. The solvents were removed under reduced pressure and the residue was resuspended in DMF or DMSO and purified via reversed-phase semi-preparative HPLC.Synthesis of ethyl-protected a-Aminophosphonic acids (GP2): 3 A molecular sieves (approx. 200 mg / mmol) were loaded into a round bottom flask with a magnetic stirring bar and further dried under high vacuum via heating with a heat gun. Aldehyde (1 equiv.), amine (1 equiv.), and dry dichloromethane (0.2 M) were loaded into the flask and the suspension was left to stir overnight. Diethyl phosphite (7 equiv.) was added and the mixture was cooled in an ice bath. Boron trifluoride etherate (3 equiv.) was added dropwise and the solution was left to warm up to room temperature and was stirred for an additional 2-4h. The suspension was then filtered into a separatory funnel and the organic phase was further diluted with dichloromethane and washed with water (1x), sat. aq. sodium bicarbonate (2x), and brine (1x), and was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified via silica gel flash column chromatography (0-70% EtOAc in DCM).Alkylation of propargyl bromide to phenols (GP3): Phenol (1 equiv.), potassium carbonate (3 equiv.), and potassium iodide (1 equiv.) were loaded into a round-bottom flask coupled with a magnetic stirring bar and suspended in dry acetone (0.13 M). The solution was stirred at room temperature for 30min - 1 h and propargyl bromide (1 .2 equiv.) was added. The mixture was heated to 50 °C and left to stir overnight. The solvent was removed under reduced pressure and the residue was redissolved in ethyl acetate and water and transferred into a separatory funnel. The phases were separated and the organic phase was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified via silica gel flash column chromatography (0-40% EtOAc in DCM).Phosphonate deprotection (GP4): Protected phosphonate (1 equiv.) was loaded into a round-bottom flask coupled with a magnetic stirring bar and was dissolved in dry acetonitrile (0.25 M) under argon. The solution was cooled in an ice bath and bromotrimethylsilane (5 equiv.) was added dropwise. The reaction was monitored by LC-MS. Upon complete conversion, the solvent was removed under reduced pressure and the residue was purified via reverse-phase semi-preparative HPLC.Catalytic Click reaction (GP5): Alkyne (1 equiv.) and Azide (1 equiv.) were loaded into a reaction vessel and dissolved in DMSO. Copper sulfate pentahydrate (0.2 equiv.) and sodium ascorbate (2 equiv.) were loaded into a separate container and dissolved in water. The two solutions were mixed (final DMSO:water ratio - 4:1 , 0.06M) and the reaction was monitored via LC-MS. Upon completion, the reaction mixture was diluted with 3 volumes of DMSO, filtered through a syringe frit, and purified directly via reversed-phase semipreparative HPLC.Stoichiometric Click reaction (GP6): This protocol was performed in crude mixtures of pre-formed azide (1 equiv.) and alkyne (1 equiv.) in either acetonitrile or DMSO (0.05-0.1 M). Copper Iodide (1 equiv.) was added to the mixture, followed by DIPEA (3 equiv.). The reaction was monitored by LC-MS and upon completion was diluted with DMSO (3-4x volume) and was filtered through a syringe frit before direct purification via reversed-phase semi-preparative HPLC.Nucleophilic substitution with DOTA-GA anhydride (GP7): Amine (1.0 equiv.), DOTA-GA anhydride (1.0 equiv.), and DMAP (0.1 equiv.) were weighed into an Eppendorf tube and dissolved in DMSO (0.01 M). DIPEA (3.0 equiv.) was added and the reaction was incubated in a Thermomixer at 24 °C overnight. The mixture was used as crude for click reaction or diluted with DMSO (3x volume) and was directly purified via reversed-phase semi-preparative HPLC.Esterification reaction (GP8): In a dry round-bottom flask carboxylic acid (1.0 equiv.) was suspended in dry MeOH (0.25 M) and HCI 4M in dioxane (4.0 equiv.) was added dropwise to the mixture. The reaction was heated to reflux for 16 h. The solvent was removed under reduced pressure and the crude was directly used in the next step.Sonogashira cross-coupling reaction (GP9): Functionalized 3-iodo-phenylalanine (1.0 equiv.), Cui (0.4 equiv.), and PdCl2(PPh3)2 (0.15 equiv.) were loaded into a round-bottom flask coupled with a magnetic stirring bar. The flask was put under argon and a stock solution of protected phosphonate 113 (1 .2 equiv.) in DMF (0.1 M) was added, followed by DIPEA (8.0 equiv.). The reaction was heated to 75 °C until completion (monitored by LC-MS). The solution was diluted with EtOAc and washed with sat. aq. ammonium chloride.The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.Sonogashira cross-coupling reaction with free phosphonates (GP10): Functionalized 3- / ocfo-phenylalanine (1 .0 equiv.), copper(l) iodide (Cui, 0.4 equiv.), bis(triphenylphosphine)palladium chloride (PdCl2(PPh3)2, 0.15 equiv.), phosphonate I6b (1 .2 equiv.) and DIPEA (8.0 equiv.) were dissolved in dry DMF (0.1 M) into a roundbottom flask with a magnetic stirring bar. The reaction was heated at 70 °C for 1 h. The reaction was cooled to room temperature and diluted with MeOH (6x volume). The solution was filtered through celite and solvents evaporated under reduced pressure. The crude was directly used for further reactions.Radiolabeling of DOTAGA compounds with Lutetium-177 (GP11): DOTAGA derivatives (30 nmol) were dissolved in 30 μL of PBS 2% DMSO and diluted with sodium acetate (198 μL, 1 M in water, pH 4.5). 24 MBq of177Lu solution (12 μL at an activity of 2 MBq / μL) were added and the mixture was heated at 90 °C for 10 min and passively cooled down to rt for 10 min. After cooling to room temperature, an aliquot was analyzed by RP-HPLC (XTerra C18, 5% MeCN in 0.1 % aq. TFA to 80% over 20 min on a Merck-Hitachi D- 7000 HPLC system equipped with a Raytest Gabi Star radiodetector).177Lu incorporations >95% were routinely achieved.Coupling of payloads to (4-nitrophenyl) carbonate derivatives (GP12): The respective (4-nitrophenyl) carbonate derivative (1 .0 equiv.) and HOAt (1 .0 equiv.) were weighed into an Eppendorf tube and dissolved in DMF (0.05 M). The solution was transferred to another Eppendorf tube containing the respective payload (1 .2 equiv.), which was weighed in under appropriate safety conditions. DIPEA (6.0 equiv.) was added, and the mixture was incubated in a shaker incubator overnight (16-24 h) at 25 °C. The reaction mixture was diluted with DMF (1 :3) and was directly purified via (Agilent 1200 series system equipped with Synergi 4pm Polar-RP 80A 10 x 150 mm C18 column using a gradient of 90:10 to 0:100 in 14 min water / ACN + 0.1 % TFA).One-pot Michael addition + Click reaction for final step ofACP3 SMDC synthesis (GP13): The maleimido- containing linker-payload derivative (1 equiv.) and the cysteine-containing compound (1 .0 equiv.) were loaded into an Eppendorf tube and dissolved in a 1 :1 mixture of PBS and DMF (0.01 M). DIPEA (8.0 equiv.) was added and the reaction was incubated in a ThermoMixer at 37 °C for 1 h. Intermediate I6c (1 .2 equiv.) was then added to the solution, followed by copper iodide (1.2 equiv.) and sodium ascorbate (1.0 equiv.), and the mixture was incubated at 37 °C until completion by LC-MS was observed (2 h). The reaction mixture was diluted with DMF (1 :3) and was directly purified via (Agilent 1200 series system equipped with Synergi 4pm Polar-RP 80A 10 x 150 mm C18 column using a gradient of 90:10 to 0:100 in 14 min water / ACN + 0.1 % TFA).Two step one pot amidation and click reaction (GP14): Azide (1 equiv.) and HATU (1 .0 equiv.) were weighed into an Eppendorf tube and dissolved in acetonitrile (0.08 M). Tert-butyl (6-aminohexyl)carbamate (1.5 equiv.) and DIPEA (4.0 equiv.) were added and the reaction was incubated in a ThermoMixer at 37 °C for 2 h. Alkyne (1 .2 equiv.) was then added to the solution, followed by copper iodide (1 .0 equiv.), and the mixture was incubated at 37 °C until completion by LC-MS was observed (around 30 min to 1 h). The solution was diluted with DMSO (3x volume), filtered through a syringe frit, and directly purified via reversed-phase semipreparative HPLC.Nucleophilic substitution with DOTA-NHS ester(GP15): Amine (1 .0 equiv.) and DOTA-NHS ester (2.0 equiv.) were weighed into an Eppendorf tube and dissolved in DMSO (0.05 M). DIPEA (8.0 equiv.) was added, and the reaction was incubated in a Thermomixer at 40 °C for 30 mins. The mixture was diluted with DMSO or DMF (3x volume) and was directly purified via reverse-phase semi-preparative HPLC.1.2 Synthesis of CompoundsSynthesis of Compound 1 (Benchmark)Compound 1 was prepared via GP1 (1 mmol scale) from benzaldehyde and benzylamine. The product was a white solid after lyophilization (100 mg, 0.36 mmol, 36% yield), m / z calculated for C14H15NO3P [M - H]_276.08; observed 276.1.11 was prepared via GP2 (1 mmol scale) from benzaldehyde and 3-hydroxybenzylamine. The product after column chromatography was a yellow oil (295 mg, 0.84 mmol, 84% yield), m / z calculated for C18H25NO4P[M + H]+350.15; observed 350.2.I2 was prepared via GP3 (0.84 mmol scale) from 11. The product after column chromatography was a clear oil (215 mg, 0.55 mmol, 66% yield), m / z calculated for C21H27NO4P [M + H]+388.17; observed 388.2.Compound 2 was obtained via GP4 (0.5 mmol scale) from I2. The product was a white solid after lyophilization (120 mg, 0.36 mmol, 72% yield), m / z calculated for C17H17NO4P [M - H]_330.09; observed 330.1.Synthesis of Compound 3Amino PEG2 Azide (1 .05 mg, 0.006 mmol, 1 .00 equiv) was loaded into an Eppendorf tube and was dissolved in DMSO (100 μL, 0.06 M). Acetic anhydride (0.6 μL, 0.0066 mmol, 1.1 equiv.) was added and the reaction was incubated in a ThermoMixer at room temperature overnight. Compound 2 was added to the mixture and GP5 was followed for the click reaction. The product was a white solid after lyophilization (1.3 mg, 0.0024 mmol, 40% yield), m / z calculated for C25H33N5O7P [M - H]_546.21 ; observed 546.2.Synthesis of compound 4Compound 4 was prepared via GP5 (1 .0 μmol scale) from azido-PEG2 fluoresceine thiourea and compound 2. The product was an orange solid after lyophilization (0.6 mg, 0.67 μmol, 67% yield), m / z calculated for C44H42N6O11PS [M - H]- 893.24; observed 893.2.Synthesis of intermediate 14Compound 2 (6.6 mg, 0.02 mmol, 1.0 equiv.) was loaded into an Eppendorf tube and was dissolved in acetonitrile (0.2 mL, 0.1 M). BOC2O (5.5 μL, 0.024 mmol, 1.2 equiv.) was added followed by DIPEA (7 μL, 0.04 mmol, 2.0 equiv.). The reaction was incubated in a ThermoMixer at room temperature overnight to obtain I3 and click-protocol GP6 was directly followed with the crude mixture. I4 was obtained as a white solid after lyophilization (1 mg, 1 .6 μmol, 8% yield), m / z calculated for C28H39N5O8P [M - H]- 604.25; observed 604.3.Synthesis of Compound 5DOTA-GA Anhydride was reacted with I4 according to GP7 (1 .6 μmol scale). The reaction was incubated in a ThermoMixer at room temperature overnight and the cleavage solution from S5 (200 μL) was added and the mixture was further incubated until completion by LC-MS. The solution was then further diluted with DMSO (3x volume) and directly purified via reversed-phase semi-preparative HPLC to obtain compound 5 as a white solid after lyophilization (1 .0 mg, 1 μmol, 65% yield).Synthesis of intermediates I6a-cIntermediates I5a-c were synthesized according to GP3 (1 mmol scale) from the respective phenols: a = ortho-, b = meta-, c = para-substituted. Products were obtained as oils after silica gel flash column chromatography:15a (80 mg, 0.5 mmol, 50% yield), 15b (93 mg, 0.58 mmol, 58% yield), 15c (108 mg, 0.67 mmol, 67% yield).Intermediates I6a-c were prepared according to GP1 (0.25 mmol scale) from I5a-c and benzyl amine. The products were white solids after lyophilization:I6a (25 mg, 0.07 mmol, 30% yield), m / z calculated for C17H17NO4P [M - H]_330.09; observed 330.1.I6b (38 mg, 0.11 mmol, 46% yield), m / z calculated for C17H17NO4P [M - H]- 330.09; observed 330.1 .I6c (52 mg, 0.16 mmol, 63% yield), m / z calculated for C17H17NO4P [M - H]_330.09; observed 330.1.Synthesis of Intermediates 18a, bIntermediates I7a,b were synthesized according to GP3 (1 mmol scale) from the respective phenols: a = ortho-, b = para-substituted. Boc-protected products were obtained as oils after silica gel flash column chromatography:I7a-Boc (211 mg, 0.81 mmol, 81 % yield), I7b-Boc (259 mg, 0.99 mmol, 99% yield)The Boc group was deprotected by dissolving the purified material in a DCM:TFA (1 :1 , 10 mL) mixture and stirring for 2 hours at room temperature. The solvent was removed under reduced pressure and the crude was directly used in the next step.Intermediates I8a,b were prepared according to GP1 (0.25 mmol scale) from I7a,b and benzaldehyde. The products were white solids after lyophilization:I8a (21 mg, 0.06 mmol, 25% yield), m / z calculated for C17H17NO4P [M - H]_330.09; observed 330.1 .I8b (42 mg, 0.13 mmol, 51 % yield), m / z calculated for C17H17NO4P [M - H]_330.09; observed 330.1.Synthesis of Compounds 6a-c1) DMAP, DIPEA, DMSODOTA-GA Anhydride was reacted with amino PEG2 Azide according to GP7 (0.004 mmol scale). Intermediates I6a-c were added to the respective mixtures and GP6 was followed for the click reaction, ensuring that the reaction could proceed while copper was completely incorporated into the DOTA-GA cage. The products were blue solids after lyophilization6a (2 mg, 0.0019 mmol, 49% yield), m / z calculated for C42H61CUN9O15P [M - H]- 1025.33; observed 1025.3.6b (2.1 mg, 0.002 mmol, 51.1 % yield), m / z calculated for C42H61CUN9O15P [M - H]- 1025.33; observed1025.3.6c (2.3 mg, 0.0022 mmol, 56% yield), m / z calculated for C42H61CUN9O15P [M - H]_1025.33; observed 1025.3.Synthesis of Compounds 7a-cDOTA-GA Anhydride was reacted with amino PEG2 Azide according to GP7 (0.004 mmol scale). Intermediates I8a,b,c were added to the respective mixtures and GP6 was followed for the click reaction, insuring that the reaction could proceed while copper was completely incorporated into the DOTA-GA cage. The products were blue solids after lyophilization7a (1 .9 mg, 0.0019 mmol, 46% yield), m / z calculated for C42H61CUN9O15P [M - H]_1025.33; observed 1025.3.7b (2.2 mg, 0.0021 mmol, 54% yield), m / z calculated for C42H61CUN9O15P [M - H]- 1025.33; observed 1025.3.7c (2.2 mg, 0.0021 mmol, 54% yield), m / z calculated for C42H62CUN9O15P [M]2+513.16940; observed 513.16843.Compound 8 was prepared via GP6 (1.5 μmol scale) from azido-PEG4 fluoresceine thiourea and intermediate I6c. The product was an orange solid after lyophilization (1.0 mg, 0.95 μmol, 63% yield), m / z calculated for C51H55N7O14PS [M - H]_1052.33; observed 1052.3.Compound 9 was prepared via GP1 (4 μmol scale) from compound 2 and a racemic mixture of the O-Me, A / -Boc protected 4-azido proline derivative. The product was a white solid after lyophilization (0.6 mg, 1 μmol, 25% yield), m / z calculated for C28H35N5O8P [M - H]- 600.22; observed 600.3.Synthesis of Compound 10Compound 9 was prepared via GP1 (4 μmol scale) from compound 2 and a racemic mixture of the O-Me, A / -Boc protected 4-azido proline derivative. The product was a white solid after lyophilization (1 mg, 1 .7 μmol, 42% yield), m / z calculated for C28H35N5O8P [M - H]- 600.22; observed 600.2.Synthesis of Intermediate 19Commercially available Wang resin (120 mg, 0.125 mmol, 1.00 equiv.) was coupled to Fmoc-(2S,4S)-4- azidoproline or Fmoc-(2 / ?,4 / ?)-4-azidoproline (118 mg, 0.313 mmol, 2.50 equiv.) as described in S4 (2.4 equiv. HATU, 5 equiv. DIPEA, overnight). After Fmoc deprotection (as described in S2) the resin was swollen in DMF and 2-(dibenzylamino)acetic acid (128 mg, 0.500 mmol, 2.50 equiv.) was coupled as described in S4 (3.8 equiv. HATU, 8 equiv. DIPEA, 2 hours). After washing, the resin was cleaved according to S5. The cleavage solution was concentrated under reduced pressure and the crude mixture was diluted with DMSO and purified via reversed-phase semi-preparative HPLC.I9a (SS) was obtained as a white solid after lyophilization (22 mg, 0.06 mmol, 45% yield), m / z calculated for C21 H22N5O3 [M - H]- 392.17; observed 392.2.I9b (RR) was obtained as a white solid after lyophilization (10 mg, 0.06 mmol, 20% yield), m / z calculated for C21 H22N5O3 [M - H]- 392.17; observed 392.2.Synthesis of Compound 11I9a (3.9 mg, 0.01 mmol, 1 .0 equiv.) and HATU (3.8 mg, 0.01 mmol, 1 .0 equiv.) were loaded into an Eppendorf tube and dissolved in acetonitrile (0.125 mL, 0.08 M). Tert-butyl (6-aminohexyl)carbamate (3.4 μL, 0.015 mmol, 1 .5 equiv.) and DIPEA (7.0 μL, 0.04 mmol, 4.0 equiv.) were added and the reaction was incubated in a ThermoMixer at 37 °C for 2h. TFA (200 μL) was added and the reaction was further incubated for 1 h (until complete deprotection was observed by LC-MS). The mixture was diluted with DMSO (3x volume) and directly purified via reversed-phase semi-preparative HPLC to yield 110a as a white solid after lyophilization (2.8 mg, 0.006 mmol, 57% yield), m / z calculated for C27H38N7O2 [M + H]+492.31 ; observed 492.4. 110a (1.2 mg, 2.5 μmol, 1.0 equiv.), DOTA-GA anhydride (1.1 mg, 2.5 μmol, 1.0 equiv.), and DMAP (0.03 mg, 0.25 μmol, 0.1 equiv.) were weighed into an Eppendorf tube and dissolved in DMSO (125 μL, 0.02 M). DIPEA (1.3 μL, 7.5 μmol, 3.0 equiv.) was added and the reaction was incubated in a ThermoMixer at 24°C overnight. The mixture was diluted with DMSO (3x volume) and was directly purified via reversed-phase semi-preparative HPLC. Compound 11 was obtained as a white solid after lyophilization (1.8 mg, 1.9 μmol, 76% yield), m / z calculated for C46H66N11O11 [M - H]- 948.49; observed 948.5.I9a or b (3.9 mg, 0.01 mmol, 1.0 equiv.) and HATU (3.8 mg, 0.01 mmol, 1.0 equiv.) were loaded into an Eppendorf tube and dissolved in acetonitrile (0.125 mL, 0.08 M). Tert-butyl (6-aminohexyl)carbamate (3.4 μL, 0.015 mmol, 1.5 equiv.) and DIPEA (7.0 μL, 0.04 mmol, 4.0 equiv.) were added and the reaction was incubated in a ThermoMixer at 37 °C for 2h. Intermediate I6c (4.0 mg, 0.012 mmol, 1.2 equiv.) was then added to the solution followed by copper iodide (1.9 mg, 0.01 mmol, 1.0 equiv.) and the mixture was incubated at 37°C until completion by LC-MS was observed (around 30min - 1 h). The solution was diluted with DMSO (3x volume), was filtered through a syringe frit, and directly purified via reverse d-phase semipreparative HPLC. Upon completion of the purification, the fractions were combined and concentrated under reduced pressure. TFA was added and the purified solution was incubated until complete deprotection of the Boc group was noted by LC-MS. The residue was then lyophilized.111a was obtained as a white solid (4.0 mg, 0.0049 mmol, 49% yield), m / z calculated for C44H54N8O6P [M - H]- 821.39; observed 821.4.111 b was obtained as a white solid (4.0 mg, 0.0065 mmol, 65% yield), m / z calculated for C44H54N8O6P [M - H]- 821.39; observed 821.4.DOTA-GA Anhydride was reacted with 111 according to GP7 (1 .5 μmol scale).Compound 12a was obtained as a white solid after lyophilization (1.2 mg, 0.9 μmol, 62% yield), m / z calculated for C63H84N12O15P [M - H]- 1279.59; observed 1279.5.Compound 12b was obtained as a white solid after lyophilization (1.2 mg, 0.45 μmol, 31% yield), m / z calculated for C63H84N12O15P [M - H]- 1279.59; observed 1279.5.I9a (3.9 mg, 0.01 mmol, 1.0 equiv.), HATU (3.8 mg, 0.01 mmol, 1.0 equiv.), and 6-aminohexyl fluoresceine thiourea (5.9 mg, 0.012 mmol, 1.2 equiv.) were loaded into an Eppendorf tube and dissolved in acetonitrile (0.125 mL, 0.08 M). DIPEA (7.0 μL, 0.04 mmol, 4.0 equiv.) was added and the reaction was incubated in a ThermoMixer at 37 °C for 2h. Intermediate I6c (4.0 mg, 0.012 mmol, 1.2 equiv.) was then added to the solution followed by copper iodide (1.9 mg, 0.01 mmol, 1.0 equiv.) and the mixture was incubated at 37°C until completion by LC-MS was observed (around 30min - 1 h). The solution was diluted with DMSO (3x volume), was filtered through a syringe frit, and directly purified via reversed-phase semi-preparative HPLC.Compound 13 was obtained as an orange solid after lyophilization (2.0 mg, 0.0017 mmol, 17% yield), m / z calculated for C65H65N9O11PS [M - H]_1210.43; observed 1210.4.Synthesis of Intermediate 114113 was prepared via GP2 (10 mmol scale) from 3-hydroxybenzaldehyde and benzylamine. The product after column chromatography was a yellow oil (1.05 g, 3.00 mmol, 30% yield), m / z calculated for C18H25NO4P [M + H]+350.14; observed 350.2.114 was prepared via GP3 (2.46 mmol scale) from 113. The product after column chromatography was a clear oil (600 mg, 1 .55 mmol, 63% yield), m / z calculated for C21H27NO4P [M + H]+388.16; observed 388.2.Intermediates I15a,b were synthesized according to GP8 (3.4 mmol scale) from the respective 3-lodo- phenylalanine: a =3-lodo-L-phenylalanine, b = 3-lodo-D-phenylalanine.115a, b m / z calculated for C10H13INO2 [M + H]+305.99; observed 306.0.Intermediates 115a, b (500 mg, 1.64 mmol, 1.0 equiv.) were loaded into the respective reaction vessel and dissolved in DMF (5 mL). HATU (623 mg, 1.64 mmol, 1.0 equiv.) were), 3-chloro-4-fluorobenzoic acid (342 mg, 1.97 mmol, 1.2 equiv.) and DIPEA (822 μL, 4.92 mmol, 3.0 equiv.) were added and the mixture was stirred at r.t. for 30 min. The reaction was concentrated under reduced pressure. The resulting residue was diluted in EtOAc (30 mL) and washed with sat. aq. sodium bicarbonate (2 x 15 mL) and brine (20 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reversed-phase MPLC to obtain the products as pale-yellow solids after lyophilization:116a (550 mg, 1 .20 mmol, 73% yield), m / z calculated for C17H15CIFINO3 [M + H]+461 .97; observed 462.0.116b (520 mg, 1.13 mmol, 69% yield), m / z calculated for C17H15CIFINO3 [M + H]+461.97; observed 462.0.I17a,b were synthesized according to GP9 (0.22 mmol scale) from the respective functionalized 3-lodo- phenylalanines 116a, b. and 114.I17a,b m / z calculated for C38H40CIFN2O7P [M + H]+721 .22; observed 721 .2.The crudes were redissolved in THF (2 mL) and hydrolyzed with 2M NaOH (220 μL, 0.44 mmol, 2 equiv.) for 1 h at room temperature. The THF was removed under reduced pressure and the aqueous layer was further diluted with HCI 1 N (5 mL) and extracted with EtOAc (2 x 10 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude residues were purified reversed-phase semi-preparative HPLC. The products were obtained as pale-yellow solids after lyophilization:118a (76 mg, 0.11 mmol, 49% yield), m / z calculated for C37H38CIFN2O7P [M + H]+707.20; observed 707.2.118b (84 mg, 0.12 mmol, 53% yield), m / z calculated for C37H38CIFN2O7P [M + H]+707.20; observed 707.2.Intermediates 118a, b (21 mg, 0.03 mmol, 1.0 equiv.) were loaded into the respective reaction vessel and dissolved in DMF (0.5 mL). HATU (11.4 mg, 0.03, 1.0 equiv.), tert-butyl (6-aminohexyl)carbamate (10.2 μL, 0.045 mmol, 1 .5 equiv.) and DIPEA (21 μL, 0.12 mmol, 4.0 equiv.) were added to the mixture and the reaction was stirred at r.t. for 30 min. The solution was diluted with EtOAc and washed with sat. aq. ammonium chloride. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residues were directly used for the next step.119a, b m / z calculated for C48H60CIFN4O8P [M + H]+905.37; observed 903.4.Intermediates l20a,b were prepared according to the procedure GP4 (0.03 mmol scale) from I19a,b. The products were white solids after lyophilization:120a (1 1 mg, 15 μmol, 50% yield), m / z calculated for C39H42CIFN4O6P [M - H]_747.26; observed 747.3.120b (10 mg, 14 μmol, 45% yield), m / z calculated for C39H42CIFN4O6P [M - H]_747.26; observed 747.3.14a, b were prepared via GP7 (1.5 μmol scale) from the respective amines l20a,b. The final compounds were purified by reversed-phase semi-preparative HPLC and obtained as white solid after lyophilization:14a (1.6 mg, 1.4 μmol, 90% yield), m / z calculated for C58H72CIFN8O15P [M - H]_1205.46; observed 1203.4.14b (1 .6 mg, 1 .4 μmol, 90% yield), m / z calculated for C58H72CIFN8O15P [M - H]- 1205.46; observed 1203.4.Intermediates l20a,b (1 mg, 1.3 μmol, 1.0 equiv.) were loaded into the respective Eppendorf tube and dissolved in DMSO (100 μL, 0.01 M). DIPEA (4.5 μL, 26.0 μmol, 20 equiv.) and a stock solution of 5- carboxyfluorescein-N-hydroxysuccinimide ester 0.1 mM in DMSO (16 μL, 1.6 μmol, 1 .2 equiv.) were added to the mixture. The reaction was incubated in a ThermoMixer at r.t. for 10 min. The crude was filtered and directly purified via reversed-phase semi-preparative HPLC. The products were obtained as yellow solid after lyophilization:15a (1 .3 mg, 1.2 μmol, 90% yield), m / z calculated for C60H54CIFN4O12P [M + H]+1107.31 ; observed 1106.2.15b (1 .4 mg, 1 .2 μmol, 95% yield), m / z calculated for C60H54CIFN4O12P [M + H]+1107.31 ; observed 1106.2.Synthesis of Intermediates 121 a, bIntermediates I15a,b were synthesized according to GP8 (3.4 mmol scale) from the respective 3-lodo- phenylalanine: a =3-lodo-L-phenylalanine, b = 3-lodo-D-phenylalanine.115a, b m / z calculated for C10H13I NO2 [M + H]+305.99; observed 306.0.Intermediates 115a, b (500 mg, 1 .64 mmol, 1.0 equiv.) were loaded into the respective reaction vessel and dissolved in DMF (5 mL). 4-Fluorophenyl isocyanate (225 mg, 1.64 mmol, 1.0 equiv.) and DIPEA (855 μL, 4.92 mmol, 3.0 equiv.) were added and the mixture was stirred at r.t. for 30 min. The reaction was concentrated under reduced pressure. The resulting residue was diluted in EtOAc (30 mL) and washed with sat. aq. sodium bicarbonate (2 x 15 mL) and brine (20 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reversed- phase MPLC to obtain the products as pale-yellow solids after lyophilization:121a (254 mg, 0.57 mmol, 35% yield), m / z calculated for C17H17FI N2O3 [M + H]+443.02; observed 443.1 .121 b (297 mg, 0.67 mmol, 41 % yield), m / z calculated for C17H17FI N2O3 [M + H]+443.02; observed 443.1 .I22a,b were synthesized according to GP9 (0.22 mmol scale) from the respective functionalized 3-lodo- phenylalanines 121a, b. and 114.122a, b m / z calculated for C38H42FN3O7P [M + H]+702.27; observed 702.3.The crudes were redissolved in THF (2 mL) and hydrolyzed with 2M NaOH (220 μL, 0.44 mmol, 2 equiv.) for 1 h at room temperature. The THF was removed under reduced pressure and the aqueous layer was further diluted with HCI 1 N (5 mL) and extracted with EtOAc (2 x 10 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude residues were purified reversed-phase semi-preparative HPLC. The products were obtained as pale-yellow after lyophilization:I23a (76 mg, 0.11 mmol, 50% yield), m / z calculated for C37H40FN3O7P [M + H]+688.25; observed 688.3.I23b (76 mg, 0.1 1 mmol, 50% yield), m / z calculated for C37H40FN3O7P [M + H]+688.25; observed 688.3.Intermediates I23a,b (21 mg, 0.03 mmol, 1.0 equiv.) were loaded into the respective reaction vessel and dissolved in DMF (0.5 mL). HATU (11.4 mg, 0.03, 1.0 equiv.), tert-butyl (6-aminohexyl)carbamate (10.2 μL, 0.045 mmol, 1 .5 equiv.) and DIPEA (21 μL, 0.12 mmol, 4.0 equiv.) were added to the mixture and the reaction was stirred at r.t. for 30 min. The solution was diluted with EtOAc and washed with sat. aq. ammonium chloride. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residues were directly used for the next step.I24a,b m / z calculated for C48H62FN5O8P [M + H]+886.42; observed 886.4.Intermediates I25a,b were prepared according to the procedure GP4 (0.03 mmol scale) from I24a,b. The products were white solids after lyophilization:I25a (mg, 10 μmol, 35% yield), m / z calculated for C39H44FN5O6P [M - H]_728.31 ; observed 728.3.I25b (mg, 1 1 μmol, 37% yield), m / z calculated for C39H44FN5O6P [M - H]_728.31 ; observed 728.3.16a,b were prepared via GP7 (1.5 μmol scale) from the respective amines I25a,b. The final compounds were purified by reversed-phase semi-preparative HPLC and obtained as white solid after lyophilization:16a (1 .3 mg, 1 .1 μmol, 71% yield), m / z calculated for C58H74FN9O15P [M - H]_1186.51 ; observed 1186.4.16b (1.2 mg, 1.0 μmol, 68% yield), m / z calculated for C58H74FN9O15P [M - H]- 1186.51 ; observed 1186.4.Intermediates I25a,b (1 mg, 1.3 μmol, 1.0 equiv.) were loaded into the respective Eppendorf tube and dissolved in DMSO (100 μL, 0.01 M). DIPEA (4.5 μL, 26.0 μmol, 20 equiv.) and a stock solution of 5- carboxyfluorescein-N-hydroxysuccinimide ester 0.1 mM in DMSO (16 μL, 1.6 μmol, 1.2 equiv.) were added to the mixture. The reaction was incubated in a ThermoMixer at r.t. (24°C) for 10 min. The crude was filtered and directly purified via reversed-phase semi-preparative HPLC. The products were obtained as yellow solid after lyophilization:17a (0.7 mg, 0.7 μmol, 55% yield), m / z calculated for C60H56FN5O12P [M + H]+1088.36; observed 1088.3. 17b (0.7 mg, 0.7 μmol, 55% yield), m / z calculated for C60H56FN5O12P [M + H]+1088.36; observedl 088.3.Amino PEG2 Azide (1.7 mg, 0.01 mmol, 1.0 equiv.) was loaded into an Eppendorf tube and dissolved in acetonitrile (0.2 mL, 0.05 M). BOC2O (2.4 mg, 0.011 mmol, 1.1 equiv.) and DIPEA (7.0 μL, 0.04 mmol, 4.0 equiv.) were added and the reaction was incubated in a ThermoMixer at 24 °C overnight. Intermediate I6c (4.0 mg, 0.012 mmol, 1.2 equiv.) was then added to the solution followed by copper iodide (1.9 mg, 0.01 mmol, 1 .0 equiv.) and the mixture was incubated at 37°C until completion by LC-MS was observed (around 30min - 1 h). The solution was diluted with DMSO (3x volume), was filtered through a syringe frit, and directly purified via reversed-phase semi-preparative HPLC. Upon completion of the purification, the fractions were combined and concentrated under reduced pressure. TFA was added and the purified solution was incubated until complete deprotection of the Boc group was noted by LC-MS. The residue was then lyophilized. I26a was obtained as a white solid (4.4 mg, 0.009 mmol, 87% yield), m / z calculated for C23H31N5O6P [M - H]- 504.20; observed 504.2.DOTA-GA Anhydride was reacted with 111 according to GP7 (3.6 μmol scale). Compound 18 was obtained as a white solid after lyophilization (3 mg, 3.1 μmol, 86% yield), m / z calculated for C42H61N9O15P [M - H]_962.40; observed 962.4.111a,b (1.2 mg, 2.5 μmol, 1.0 equiv.), (R)-DOTAGA-NHS ester (1.4 mg, 2.4 μmol, 1.0 equiv.), and DMAP (0.03 mg, 0.25 μmol, 0.1 equiv.) were weighed into an Eppendorf tube and dissolved in DMSO (125 μL, 0.02 M). DIPEA (1.3 μL, 7.5 μmol, 3.0 equiv.) was added and the reaction was incubated in a ThermoMixer at 24°C overnight. The mixture was diluted with DMSO (3x volume) and was directly purified via reversed- phase semi-preparative HPLC. Products were isolated as white solids after lyophilization.25a (1.7 mg, 1.38 μmol, 55% yield), m / z calculated for C63H84N12O-|5P [M - H]- 1279.60; observed 1279.5.Compounds 25a, b are also referred to as ProX1-(SS)-DOTAGA_R and ProX1 -(RR)-DOTAGA_R, respectively. In names of these compounds and all other compounds referred according to this naming scheme herein, “(SS)” or“(RR)" refer to the configuration of the stereogenic centers on the central pyrrolidine moiety; “_R” refers to the configuration of the stereogenic center on the DOTAGA moiety, if present.111a, b (1.2 mg, 2.5 μmol, 1.0 equiv.), DOTA-NHS ester (1.9 mg, 2.5 μmol, 1.0 equiv.), and DMAP (0.03 mg, 0.25 μmol, 0.1 equiv.) were weighed into an Eppendorf tube and dissolved in DMSO (125 μL, 0.02 M). DIPEA (1 .3 μL, 7.5 μmol, 3.0 equiv.) was added and the reaction was incubated in a ThermoMixer at 24°C overnight.The mixture was diluted with DMSO (3x volume) and was directly purified via reversed-phase semipreparative HPLC. Products were isolated as white solids after lyophilization.27a (2.0 mg, 1 .63 μmol, 65% yield), m / z calculated for C60H8[lN12O13P [M - H]_1207.58; observed 1207.5.Synthesis of compounds 29a, bma,b 29a, bIntermediate 111a or 111 b (0.8 mg, 1 .0 μmol, 1 .0 equiv.) and AF488 NHS-ester (1 .1 mg, 1 .5 μmol, 1 .5 equiv.) were loaded into an Eppendorf tube and dissolved in DMSO (50 μL, final concentration 0.02 M). DIPEA (0.6 μL, 3.5 μmol, 3.5 equiv.) was added to the mixture and the reaction was shaken in a ThermoMixer at 24 °C for 30 min. The crude was filtered and directly purified via RP-HPLC. The product 29a (ProX1 -(SS)-AF488) was obtained as a red solid after lyophilization (1 .0 mg, 0.75 μmol,75% yield), m / z calculated for C65H66N10O16PS2 [M - H]- 1337.38; observed 1337.3.Intermediate I25a or I25b (0.7 mg, 1 .0 μmol, 1 .0 equiv.) and AF488 NHS-ester (1 .1 mg, 1 .5 μmol, 1 .5 equiv.) were loaded into an Eppendorf tube and dissolved in DMSO (50 μL, final concentration 0.02 M). DIPEA (0.65 μL, 3.5 μmol, 3.5 equiv.) was added to the mixture and the reaction was shaken in a ThermoMixer at 24 °C for 30 min. The crude was filtered and directly purified via RP-HPLC.The product 30a was obtained as a red solid after lyophilization (1.0 mg, 0.84 μmol, 84% yield), m / z calculated for C60H57FN7O13PS2 [M - H]_1196.32; observed 1196.2.Alternative synthetic route for the intermediates 120 a,bIntermediates 116a, b (265 mg, 0.58mmol, 1.0 equiv.) were loaded into the respective reaction vessel, dissolved in THF (2 mL) and hydrolyzed with LiOH (574 μL, 2 M in water, 1.15 mmol, 2 equiv.) for 1 h at room temperature. The THF was removed under reduced pressure. The aqueous layer was diluted with HCI 1 N (10 mL) and extracted with EtOAc (2 x 20 mL). The combined organic phases were separately dried15 over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The products were purified by reversed-phase MPLC. The compounds were obtained as white solids after lyophilization:127a (200 mg, 0.44 mmol, 77% yield), m / z calculated for Ci6Hi2CIFINO3[M + H]+447.95; observed 448.0.I27b (180 mg, 0.40 mmol, 70% yield), m / z calculated for Ci6Hi2CIFINO3[M + H]+447.95; observed 448.0.Intermediates I27a,b (180 mg, 0.4 mmol, 1.0 equiv.) were loaded into the respective reaction vessel, and dissolved in dry DMF (2 mL). HATU (152 mg, 0.4 mmol, 1 .0 equiv.) and DIPEA (210 μL, 1 .2 mmol, 3.0 equiv.) were added in both round-bottom flasks equipped with a magnetic stirring bar. The reactions were allowed to proceed at room temperature for 10 minutes. N-Boc-1 ,6-hexandiamin (95.2 mg, 0.44 mmol, 1.1 equiv.) was added to the mixtures and the reactions were stirred at room temperature for additional 50 minutes. The mixtures were diluted with 10 mL of EtOAc and washed with water (1 x 8 mL), sat. aq. ammonium chloride (2 x 8 mL), and brine (1 x 8 mL). Each organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crudes were purified via silica gel flash column chromatography (0-30% EtOAc in DCM) obtaining the products as a pale-yellow solid after removal of the solvents:I28a (200 mg, 0.31 mmol, 77% yield), m / z calculated for C27H34CIFIN3O4 [M + H]+646.13; observed 646.1.I28b (181 mg, 0.28 mmol, 70% yield), m / z calculated for C27H34CIFIN3O4 [M + H]+646.13; observed 646.1 .I29a,b were synthetized according to GP10 (0.23nmol scale) from the respective functionalized 3-iodo- phenylalanines I28a,b and I6b. The crudes were directly used in the next step.I29a,b m / z calculated for C44H51CIFN4O8P [M + H]+849.32; observed 849.3.The crudes were suspended in DCM (2 mL) and TFA (176 μL, 2.3 mmol, 10 equiv.) was added. The reactions were stirred for 30 minutes at room temperature and then concentrated under reduced pressure. The crude products were dissolved in DMSO and purified via reversed-phase MPLC. The compounds were obtained as white solids after lyophilization: l20a(31 mg, 0.04 mmol, 17% yield), m / z calculated for C39H43CIFN4O6P [M + H]+749.22; observed 749.2120b (40mg, 0.05 mmol, 22% yield), m / z calculated for C39H43CIFN4O6P [M + H]+749.22; observed 749.2Alternative synthetic pathway for the intermediate 125 a,bI32 a,b I25 a,bIntermediates 121a, b (254 mg, 0.58mmol, 1.0 equiv.) were loaded into the respective reaction vessel, dissolved in THF (2 mL) and hydrolyzed with LiOH (574μL, 2 M in water, 1 .15 mmol, 2 equiv.) for 1 h at room temperature. The THF was removed under reduced pressure. The aqueous layer was further diluted with HC1 1 N (10 mL) and extracted with EtOAc (2 x 20 mL). The combined organic phases were separately dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude products were purified by reversed-phase MPLC. The compounds were obtained as white solids after lyophilization:130a (230 mg, 0.53 mmol, 92% yield), m / z calculated for CieHi4CIFIN2O3 [M + H]+429.00; observed 429.0.130b (210 mg, 0.42 mmol, 90% yield), m / z calculated for CieHi4CIFIN2O3 [M + H]+429.00; observed 429.0.Intermediates l30a,b (170 mg, 0.4 mmol, 1.0 equiv.) were loaded into the respective reaction vessel, and dissolved in dry DMF (2 mL). HATU (152 mg, 0.4 mmol, 1 .0 equiv.) and DIPEA (210 μL, 1 .2 mmol, 3.0 equiv.) were added in both round-bottom flasks equipped with a magnetic stirring bar. The reactions were allowed to proceed at room temperature for 10 minutes. N-Boc-1 ,6-hexandiamin (95.2 mg, 0.44 mmol, 1.1 equiv.) was added to the mixtures and the reactions were stirred at room temperature for additional 50 minutes. The crudes were diluted with 10 mL of EtOAc and washed with water (1x 8 mL), sat. aq. ammonium chloride (2 x 8 mL), and brine (1 x 8 mL). Each organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residues were purified via silica gel flash column chromatography (0-30% EtOAc in DCM) to obtain the products as a pale-yellow solid after removal of the solvents:131a (187 mg, 0.30 mmol, 75% yield), m / z calculated for C27H36FIN4O4 [M + H]+627.18; observed 627.2.131 b (169 mg, 0.27 mmol, 68 % yield), m / z calculated for C27H36FIN4O4 [M + H]+627.18; observed 627.2.I32a,b were synthetized according to GP10 (0.25 nmol scale) from the respective functionalized 3-iodo- phenylalanines 131a, b and I6b. The crude was directly used in the next step.I32a,b m / z calculated for C44H53FN5O8P [M + H]+829.21 ; observed 829.2.The crudes were suspended in DCM (2 mL) and TFA (191 μL, 2.5 mmol, 10 equiv.) was added. The reactions were stirred for 30 minutes at room temperature and then concentrated under reduced pressure. The crudes were dissolved in DMSO and purified via reversed-phase MPLC. The compounds were obtained as white solids after lyophilization:I25a (43 mg, 0.06 mmol, 24% yield), m / z calculated for C39H45FIN5O6P [M + H]+729.31 ; observed 729.3.I25b (36 mg, 0.05 mmol, 20% yield), m / z calculated for C39H45FIN5O6P [M + H]+729.31 ; observed 729.3.Alternative synthesis of Compounds 27a (ProX1 -(SS)-DOTA)4-hydroxybenzaldehyde (1 .00 eq, 0.025 mol, 3.05 g), K2CO3 (3.00 eq., 0.075 mol, 10.37 g) and KI (1 .00 eq., 0.025 mol, 4.15 g) are dissolved in Acetone (120 mL) (T s 37 °C). The reaction mixture is then stirred at T = 50±5 °C for 1 h. Propargyl bromide solution (80 % in toluene) (1 .50 eq., 0.038 mol, 4.18 mL) is added at T= 60±5 °C. The reaction mixture is then stirred at T = 60±5 °C, and the reaction conversion is checked (HPLC-MS, 4-hydroxybenzaldehyde s 5.0%-a / a).The reaction mixture is worked up by evaporating the solvents at T ≤ 50 °C under vacuum. The crude was redissolved in EtOAc (50 mL) and washed with water (3 x 50 mL). The organic phase is evaporated at T s 50 °C under vacuum. The product 15c is obtained as a pale-yellow powder.15c (3.00 g, 0.019 mol, 75% yield).I5c (1.00 eq., 0.018 mol, 2.88 g) is dissolved in ACN (25 mL). Chlorotrimethylsilane (2.00 eq., 0.036 mol, 4.57 mL) and benzylamine (1.00 eq., 0.018 mol, 1.97 mL) are added (T S 37 °C). The reaction mixture is then sonicated at T S 50 °C for 1 h (±10 min). Tris(trimethylsilyl)phosphite (1.50 eq., 0.027 mol, 9.50 mL) and chlorotrimethylsilane (2.00 eq., 0.036 mol, 4.57 mL) are added. The reaction mixture is then sonicated at T ≤ 50 °C for ~ 2 h (+10 min), and the reaction conversion is checked (HPLC - MS, I5c ≤ 5.0%-a / a). Thereaction mixture is worked up by evaporating the solvents at T s 50 °C under vacuum. The crude product is purified via preparative RP-HPLC. Fractions containing I6c are combined and lyophilized overnight, and the product is obtained as white powder.I6c (2.98 g, 0.009 mol, 50% yield) m / z calculated for C17H17NO4P [M - Hp 330.09; observed 330.1 .(2S,4S)-4-azido-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (1 .00 eq., 0.012 mol, 3.00 g) and HATU (1 .00 eq., 0.012 mol, 4.45 g) are dissolved in DMF (50 mL). DIPEA (4.00 eq., 0.048 mol, 8.20 mL) is added at T ≤ 37 °C. The reaction mixture is stirred at T ≤ 37 °C for ~10 minutes. (9 / - / -fluoren-9-yl)methyl (6- aminohexyl)carbamate chlorohydrate (1.10 eq., 0.0132 mol, 4.95 g) is added at T 5 37 °C. The reaction mixture is then stirred at T s 37 °C, and the reaction conversion is checked (HPLC-MS, (2S,4S)-4-azido-1- (tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid S 5.0%-a / a). The reaction mixture is acidified to pH ~ 6 with HCI 2N and worked up by extraction with EtOAc (50 mL). The organic phase is washed with water (3 x 50 mL), saturated solution of ammonium chloride (3 x 50 mL) and water (3 x 50 mL). The washed organic phase is evaporated atT ≤ 50 °C under vacuum. The crude product is dissolved in DCM (30 mL). TFA (20.00 eq., 0.24 mol, 18.36 mL) is added (T ≤ 37 °C) to remove the Boc group from Boc-protected I69. The reaction mixture is stirred at T ≤ 37 °C, and the conversion is checked (HPLC-MS, Boc-protected I69 5 5.0%-a / a). The reaction mixture is worked up by evaporating the solvents at T s 50 °C under vacuum. The crude product is purified via preparative RP-HPLC. Fractions containing I69 are combined and lyophilized overnight. The product is obtained as a pale-yellow powder.169 (3.15 g, 6.60 mmol, 55% yield), m / z calculated for C26H33N6O3 [M + H]+477.25; observed 477.3.Dibenzylglycine (1.00 eq., 0.006 mol, 1.5 g) and HATU (1.00 eq, 0.006 mol, 2.28 g) are dissolved in DMF (12 mL). DIPEA (4.00 eq., 0.024 mol, 4.20 mL) is added at T ≤ 37 °C. The reaction mixture is stirred at T < 37 °C for at least 20 minutes. 169 (1.00 eq., 0.006 mol, 2.85 g) is added at T ≤ 37 °C. The reaction mixture is then stirred at T ≤ 37 °C, and the conversion is checked by HPLC-MS (Dibenzylglycine ≤ 5.0%-a / a). The reaction mixture is worked up by extraction with EtOAc (25 mL). The organic phase is washed with water (3 x 50 mL). The washed organic phase is evaporated at T ≤ 50 °C under vacuum. The crude product is redissolved in DMF (12 mL) to install I6c by click reaction. I6c (1.20 eq., 0.007 mol, 2.38 g), Cui (1.00 eq., 0.006 mol, 1.14 g), and DIPEA (4.00 eq., 0.024 mol, 4.20 mL) are added (T 2 37 °C). The reaction mixture is then stirred at T s 37 °C, and the conversion is checked by HPLC-MS (conversion of Dibenzylglycine- I6c intermediate: s 30.0%-a / a). The reaction mixture is filtered through celite, and the crude product is purified via preparative RP-HPLC. Fractions containing 170 are combined and lyophilized overnight. 170 is obtained as a white powder.170 (1.60 g, 1.50 mmol, 25% yield), m / z calculated for CsgHeeNsOsP [M + H]+1045.47; observed 1045.5.170 (1 .00 eq., 0.957 mmol, 1 .00 g) is dissolved in DMF (8 mL) at T ≤ 37 °C. Piperidine (4.00 eq, 3.83 mmol, 0.38 mL) is added at T ≤ 37 °C, and the reaction is stirred at T ≤ 37 °C. The reaction conversion is checked (HPLC-MS, I70 < 5.0%-a / a). The reaction flask is placed in an ice bath (ice and water) and the reaction mixture is cooled to T < 10 °C. HCI (2N in water) is added dropwise until pH s 3 is reached. Water (25 mL) is added and the aqueous phase is washed with DCM (3 x 25 mL). The water phase is evaporated at T £ 50 °C under vacuum. The crude product is purified via preparative RP-HPLC. Fractions containing 111a are combined and lyophilized overnight. 111a is obtained as a white powder.111a (511.91 mg, 0.62 mmol, 65% yield), m / z calculated for C44H54N8O6P [M - H]- 821.39; observed 821.4.111a (1.00 eq., 0.49 mmol, 0.40 g) and 2',2”-(10-(2-((2,5-dioxopyrrolidin-1-yl)oxy)-2-oxoethyl)-1 ,4,7,10- tetraazacyclododecane-1 ,4,7-triyl)triacetic acid (1.30 eq., 0.64 mmol, 485.06 mg) are dissolved in dry DMF (5 mL). DIPEA (10.00 eq., 4.90 mmol, 858.49 μL) is added at T S 37 °C. The reaction mixture is then stirred at T 37 °C, and the conversion to Prox1-(SS)-DOTA (27a) is checked by HPLC-MS (111a s 5.0%-a / a). The crude product was diluted with ~ 1 mL DMF and purified via preparative RP-HPLC. Fractions containing 27a with purity > 98.0% (a / a) are combined and lyophilized overnight. The product 27a is obtained as a white powder.27a (355.55 mg, 0.294 mmol, 60 % yield), m / z calculated for C60H8[lN12O13P [M - H]_1207.58; observed 1207.5.Commercially available Wang resin (22.1 mg, 0.024 mmol, 1 .00 equiv.) was coupled to Fmoc-Lys(Alloc)-OH (43.4 mg, 0.072 mmol, 3.00 equiv.) as described in S4 to afford s34. After Fmoc deprotection of s34 (S2), the resin was swollen in DCM, the solvent was removed, and a solution of 4-nitrophenyl chloroformate (9.7 mg, 0.048 mmol, 2.00 equiv.) and DIPEA (16.7 μL, 0.096 mmol, 4.00 equiv.) in DCM (0.3 mL) was added to the resin. After 1 h, the resin was washed five times with DCM. A solution of L-glutamic acid d\-tert- butyl ester hydrochloride (14.2 mg, 0.048 mmol, 2.00 equiv.) and DIPEA (16.7 μL, 0.096 mmol, 4.00 equiv.) in DCM (0.3 mL) was added to the resin and the mixture was incubated for 1 h to obtain the urea s35. Theresin was washed with DCM (5x), and Alloc deprotection was initiated by the addition of Pd(PhsP)4 (0.23 equiv.) and PhSihh (10 equiv.) dissolved in DCM (0.3 mL). The suspension was incubated for 1 h at rt with controlled pressure release. The solvent was removed, and the resin was thoroughly washed with DCM (5x) and DMF (5x). Fmoc-3-(2-naphthyl)-L-alanine (21.0 mg, 0.048 mmol, 2.00 equiv.) was coupled to the resin (S4, using 2 equiv. HATU and 2 equiv. DIPEA) to afford compound s36. Compound s36 was Fmoc deprotected (S2) and coupled to 6-(Fmoc-amino)caproic acid (33.9 mg, 0.096 mmol, 4.00 equiv.), following S4, to obtain compound s37. After Fmoc removal (S2), 2-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1 ,4,7,10- tetraazacyclododecan-1-yl)acetic acid (43.9 mg, 0.072 mmol, 3.00 equiv.) was coupled to the resin (S4, 2.8 equiv. HATU and 6 equiv. DIPEA, 3 h). After washing steps in DMF and DCM, the resin was cleaved using a solution of 95:2.5:2.5 TFA:H2O:TIPS. Cleavage fractions were pooled and dried under reduced pressure for subsequent purification by RP-HPLC (S5). After lyophilization, PSMA-617 (s38) was obtained as a white solid (3.0 mg, 0.003 mmol, 12% yield).Radiosynthesis of177Lu-labelled s38 (177Lu-PSMA-617, i.e.,177Lu vipivotide tetraxetan) was performed via GP11 from s38. Labelling was performed at the molar activity of 20 MBq / nmol. The HPLC chromatogram of177Lu-PSMA-617 as recorded with a radio-detector showed a peak at 12 min. The products were used in autoradiography experiments.Synthesis of ProX1-(SS)-MMAEI. Synthesis of ProX1-(SS)-CysII. Synthesis of MMAE conjugates (Michael addition and amide formation)Ila. ProX1-(SS)-GlyPro-MMAE (OncoACP3-Gly-Pro-MMAE (variant 1))5 lib. ProX1-(SS)-GlyPro-MMAE (OncoACP3-Gly-Pro-MMAE (variant 2))5 lie. ProX1-(SS)-ValCit-MMAE (OncoACP3-Val-Cit-MMAE)5 Synthesis of Intermediate 135I34 !356-maleimidohexanoic acid (52.8 mg, 0.25 mmol, 1.00 equiv.) was loaded into a 5 mL round-bottom flask coupled with a magnetic stirring bar. The solid was dissolved in DMF (1 .0 mL, 0.25 M) and HATU (95.1 mg, 0.25 mmol, 1.00 equiv.) and DIPEA (87.1 μL, 0.50 mmol, 2.00 equiv.) were added to the solution. The mixture was stirred for 30 min at room temperature before the addition of solid Gly-Pro (86.1 mg, 0.50 mmol, 2.00 equiv.). The reaction was further stirred for 2-4 hours (until completion was noted by LC-MS). The crude mixture was directly loaded onto the column of the RP-MPLC and purified with the described gradient conditions to yield I33 after lyophilization as a white solid (62 mg, 0.17 mmol, 68% yield), m / z calculated for C17H22N3O6 [M-H]-: 364.15, detected: 364.1.Intermediate I33 (62.1 mg, 0.17 mmol, 1.00 equiv.), 4-aminobenzyl alcohol (31.3 mg, 0.25 mmol, 1.50 equiv.) and PyBOP (133 mg, 0.255 mmol, 1.5 equiv.) were loaded into a 5 mL round-bottom flask coupled with a magnetic stirring bar and were dissolved in DCM (1 mL, 0.17 M) and cooled to 0°C. DIPEA (59.2 μL, 0.34 mmol, 2.00 equiv.) was added dropwise to the reaction mixture, which was allowed to warm up to room temperature and was stirred overnight (16 h). The solution was diluted with DCM, transferred into a separatory funnel, and washed with a sat. aq. solution of NaHCOs, 1 M HCI, and brine. The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford a yellow oil. The crude was purified via flash column chromatography (95:5 DCM / MeOH) to afford I34 as a yellow solid (14 mg, 0.03 mmol, 17% yield), m / z calculated for C24H30N4O5 [M-OH]+: 453.22, detected: 453.3.Intermediate I34 (14.1 mg, 0.03 mmol, 1.00 equiv.) was dissolved in a mixture of dry pyridine (3.6 μL, 0.04 mmol, 1.5 equiv.) and dry DCM (0.3 mL, 0.1 M). The solution was cooled at 0°C, then 4-nitrophenyl chloroformate (13.3 mg, 0.066 mmol, 2.20 equiv.) was added as a solution in dry DCM (0.1 mL). The reaction was stirred at room temperature for 1 h then directly purified via column chromatography (95:5 DCM / MeOH) to afford compound I35 as a white solid (17 mg, 0.027 mmol, 89% yield), m / z calculated for C31 H34N5O10 [M+H]+636.23; observed 636.2.Synthesis of MC-GlyPro-PAB-MMAE (136)Compound 136 was prepared via GP12 (5 μmol scale) from compound I35 and MMAE as the respective payload. The product was a white solid after lyophilization (3.2 mg, 2.6 μmol, 53% yield), m / z calculated for C64H96N9O14 [M+H]+1214.71 ; observed 1214.7.Synthesis of MC-GlyPro-PAB-MMAF (137)Compound I37 was prepared via GP12 (on a 3 μmol scale) from compound I35 and MMAF as the payload.After lyophilization, the product was obtained as a white solid (2.0 mg, 1 .6 μmol, 54% yield), m / z calculated for C64H92N9O15 [M-H]- 1226.67; m / z observed 1226.6.Synthesis of MC-ValCit-MMAF (138)Compound I38 was prepared via GP12 (on a 10 μmol scale) from MC-Val-Cit-PNP and MMAF as the payload. After lyophilization, the product was obtained as a white solid (7.2 mg, 5.4 μmol, 54% yield), m / z calculated for C68H104N11O16 [M+H]+1330.77; m / z observed 1330.7.Synthesis of MC-MMAE (139)6-maleimidohexanoic acid (1.3 mg, 6.0 μmol, 1.2 equiv.) and HATU (1 .9 mg, 5 μmol, I .O equiv.) were weighed into an Eppendorftube and dissolved in DMF (0.1 mL, 0.05 M). DIPEA (1 .7 μL, 10 μmol, 2.0 equiv.) was added, and the solution was incubated in a shaker incubator for 20 min at room temperature. MMAE (3.6 mg, 5.0 μmol, 1.00 equiv.) was loaded into a separate Eppendorf tube, with the necessary precaution, and the pre-activated carboxylic acid mixture was added to it. The reaction was further incubated overnight at room temperature (16 h). The crude solution was diluted with DMF (200 μL) and was purified by RP-HPLC to yield I39 as a white solid after lyophilization (4 mg, 4.4 μmol, 88% yield), m / z calculated for C49H79N6O10 [M+H]+: 91 1 .58, detected: 911 .5.s40 140Commercially available Wang-Cys-Trt resin (362 mg, 0.250 mmol, 1 .00 equiv.) was coupled to Fmoc-6-Ahx-OH (265 mg, 0.750 mmol, 3.00 equiv) as described in S4 (2.9 equiv. HATU, 6 equiv. DIPEA, 2 h). After Fmoc deprotection (as described in S2), intermediate s39 and Fmoc-(2S,4S)-4-azidoproline (189 mg, 0.500 mmol, 2.00 equiv.) were amide bonded according to S4 (1.9 equiv. HATU, 4 equiv DIPEA, 16h). The intermediate was Fmoc deprotected (S2) to afford s40, which was further reacted with 2-(dibenzylamino)acetic acid (191 mg, 0.750 mmol, 3.00 equiv.) as described in S4 (2.9 equiv. HATU, 6 equiv. DIPEA, 2 h). After washing, the resin was cleaved according to a modified version of S5, using the following cleavage cocktail is: 50% TFA, 45% DCM, 2.5% TIPS, and 2.5% thioanisole. The cleavage solution was concentrated under reducedpressure, and the crude mixture was precipitated according to S6. The precipitate was diluted with DMF and purified via reversed-phase semi-preparative HPLC to yield 140 as a white solid (21 mg, 0.03 mmol, 14% yield), m / z calculated for C30H38N7O5S [M-Hp: 608.27, detected: 608.3.SMDC 31 was prepared via GP13 (on a 3 μmol scale) using I40, 136 and I6c. After lyophilization, the product was obtained as a white solid (1 .00 mg, 0.46 μmol, 15% yield), m / z calculated for C111H154N17O23PS [M+2H]2+1078.54; m / z observed 1078.6.SMDC 45 was prepared via GP13 (on a 0.4 μmol scale) using I40, I37 and I6c. After lyophilization, the product was obtained as a white solid (0.50 mg, 0.23 μmol, 58% yield), m / z calculated for C1 11 H152N17O24PS [M+2H]2+1085.53; m / z observed 1085.6.Synthesis of ProX1-(SS)-ValCit-MMAE (33)SMDC 33 was prepared via GP13 (on a 2 μmol scale) using I40, Vedotin and I6c. After lyophilization, the product was obtained as a white solid (1 .20 mg, 0.53 μmol, 27% yield), m / z calculated for C115H164N19O24PS [M+2H]2+1129.58; m / z observed 1129.6.SMDC 46 was prepared via GP13 (on a 2.1 μmol scale) using I40, I38 and I6c. After lyophilization, the product was obtained as a white solid (0.90 mg, 0.40 μmol, 19% yield), m / z calculated for C115H162N19O25PS [M+2H]2+1136.57; m / z observed 1136.6.SMDC 34 was prepared via GP13 (on a 3.0 μmol scale) using I40, I39 and I6c. After lyophilization, the product was obtained as a white solid (1 .00 mg, 0.54 μmol, 18% yield), m / z calculated for C96H137N14O19PS[M+2H]2+926.98; m / z observed 926.7.Synthesis of Intermediate 1441-(6-aminohexyl)-1 H-pyrrole-2, 5-dione (233 mg, 1.00 mmol, 1.00 equiv.) and 5-formyl-2-hydroxybenzoic acid (332 mg, 2.00 mmol, 2.00 equiv.) were loaded into a 25 mL round-bottom flask coupled to a magnetic stirring bar and were dissolved in N-Methyl-2-pyrrolidone (5.0 mL, 0.2 M). HATU (456 mg, 1.20 mmol, 1.20 equiv.) was added, followed by DI PEA (348 μL, 2.00 mmol, 2.00 equiv.) and the mixture was left to stir overnight (16h). The solution was diluted with ethyl acetate and transferred into a separatory funnel. The organic layer was washed with 1 M HCI (x2), sat. aq. NaHCO3 (x2), and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to yield 141 as a white solid (66 mg, 0.19 mmol, 19% yield), which was used in the next step without further purification, m / z calculated for C18H19N2O5 [M-H]- 323.13; m / z observed 343.2.Crude 141 (62 mg, 0.18 mmol, 1.0 equiv.) was loaded into a 10 mL round-bottom flask coupled with a magnetic stirring bar and was dissolved in anhydrous MeCN (3.6 mL, 0.05M) by carefully heating the mixture with a heat gun. The resulting solution was then cooled in an ice bath and CCI4 (87 μL, 0.9 mmol, 5.0 equiv.), DIPEA (66 μL, 0.38 mmol, 2.1 equiv.) and DMAP (2.2 mg, 0.02 mmol, 0.1 equiv.) were successively added. One minute later, dibenzylphosphite (48 μL, 0.2 mmol, 1 .2 equiv.) was added and the reaction was stirred for 30 min at 0 °C. Then, the mixture was diluted with ethyl acetate and washed successively with sat. aq. NaHCO3 (x3), 1 M HCL (x3) and brine, dried over Na2SO4, and concentrated under reduced pressure. The product was purified by flash column chromatography (eluent: 70:30 DCM / Ethyl Acetate) affording I42 a white solid (46 mg, 0.08 mmol, 42% yield), m / z calculated for C32H34N2O8P [M+H]+605.20; m / z observed 605.3.Intermediate I42 (46 mg, 0.08 mmol, 1 .00 equiv.) was loaded into a 10 mL round-bottom flask coupled with a magnetic stirring bar and was dissolved in a 1 :1 mixture of DCM:MeOH (3.2 mL, 0.024M). The solution was cooled down to -78 °C, sodium borohydride (7.2 mg, 0.19 mmol, 2.5 equiv.) was added, and the reaction was stirred for 1 h. Acetone (~1 mL) was added, the mixture was left to warm up to room temperature and was further diluted with DCM. The organic layer was washed with 1 M HCI (x2), sat. aq. NaHCOs (x2), and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to yield I43 as a clear oil (36 mg, 0.06 mmol, 78% yield), which was used in the next step without further purification, m / z calculated for C32H36N2O8P [M+H]+607.22; m / z observed 607.3.Intermediate I43 (18 mg, 0.03 mmol, 1.00 equiv.) was dissolved in a mixture of dry pyridine (4.8 μL, 0.06 mmol, 2.0 equiv.) and dry DCM (0.3 mL, 0.1 M). The solution was cooled at 0 °C, then 4-nitrophenyl chloroformate (18 mg, 0.09 mmol, 3.0 equiv.) was added as a solution in dry DCM (0.1 mL). The reaction was stirred at room temperature for 1 h then directly purified via column chromatography (95:5 DCM / MeOH) to afford intermediate I44 as a white solid (5 mg, 0.006 mmol, 22% yield), m / z calculated for C39H39N3O12P [M+H]+772.23; observed 772.3.Synthesis of MC-PhoCI1-MMAE (145)I44 I45Compound 145 was prepared via GP12 (15 μmol scale) from compound I44 and MMAE as the respective payload. After purification, the solvent was removed under reduced pressure and the residue was treated with TFA (2 mL). The acid was removed under reduced pressure, and the product was lyophilized to yield a white solid (2.8 mg, 2.4 μmol, 16% yield), m / z calculated for C58H89N7O16P [M+H]+1170.61 ; observed 1170.6.SMDC 36 was prepared via GP13 (on a 1.2 μmol scale) using I40, I45 and I6c. After lyophilization, the product was obtained as a white solid (0.20 mg, 0.09 μmol, 8% yield), m / z calculated for C105H147N15O25P2S2 [M+2H]2+1056.49; m / z observed 1056.6.1.3 On-DNA synthesisEthanol precipitationPrecipitation of the DNA from aqueous phase was achieved by addition of 10% v / v 5 M NaCI or 3 M acetic acid buffer (pH 5). Then, 3 volumes of EtOH were added and the mixture was vortexed and left at -20°C overnight. The DNA was obtained as a pellet Fiby centrifugation (16,100 ref, 4°C, 1 h), the supernatant was discarded, and the pellet dried in a SpeedVac vacuum concentrator.1.2.1 Synthesis of O1 a-d and O2a-dThe four stereo-defined isomers (2S, 4S), (2R, 4R), (2S, 4 / ?) and (2R, 4S) of 1-(((9 / 7-fluoren-9- yl)methoxy)carbonyl)-4-azidopyrrolidine-2-carboxylic acid (200 mM in DMSO, 187.5 μL, 150 equiv.) were separately activated by the addition of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC, 200 mM in DMSO, 150 μL, 120 equiv.) and N-hydroxysulfosuccinimide (sNHS, 200mM in DMSO:water (2:1), 125 μL, 100 equiv.). After 20 min, the pre-activation mixture was added to a 5’-amino modified 12-mer oligonucleotide (5’ Ce-amino-TAGTAGCCATCC, 250 nmol in 200 μL MOPS buffer (100 mM MOPS, 1 M NaCI, pH 8). The reaction proceeded for 2 h at room temperature and was stopped by ethanol precipitation. The DNA-pellet was redissolved in H2O (300 μL) to which piperidine (35 μL) was added. The deprotection was complete after 1 h at 40 °C and quenched by the addition of 53 μL 3 M acetic acid buffer. The oligonucleotide was precipitated by the addition of ethanol for subsequent by RP-HPLC.Acetic acid (24 μL, 200 mM in DMSO, 160 equiv.) was pre-activated with 4-(4,6-dimethoxy-1 ,3,5-triazin-2- yl)-4-methyl-morpholinium chloride (DMT-MM, 16 μL, 200 mM in H2O, 107 equiv.) in 60 μL DMSO for 30 min at room temperature. The solution was added to the stereo-defined 4-amino-proline-modified oligonucleotides (30 nmol in 40 μL 250 mM borate buffer, pH 9.4) and the coupling proceeded for 3 h atroom temperature. The reaction was stopped by EtOH precipitation, and the oligonucleotides were purified by RP-HPLC.The modified oligonucleotides (15 nmol each) were dissolved in 50 μL 250 mM borate buffer, pH 9.4 and CuSO4 (6 μL, 50 mM in H2O, 20 equiv.), 50 μL 20 mM intermediate I6c (67 equiv.) and sodium ascorbate (6 μL, 50 mM in H2O, 20 equiv.) were added. The copper(l)-catalyzed alkyne-azide cycloaddition (CuAAC) proceeded for 30 min at 60 °C and was stopped by the addition of 20 μL 3 M acetic acid buffer pH 5 for subsequent ethanol precipitation. The crudes were purified by RP-HPLC.The four stereo-defined isomers (2S, 4S), (2R, 4R), (2S, 4R) and (2R, 4S) of 1-(((9 / 7-fluoren-9- yl)methoxy)carbonyl)-4-azidopyrrolidine-2-carboxylic acid (200 mM in DMSO, 187.5 μL, 150 equiv.) were coupled to a 5’-amino modified 12-mer oligonucleotide as described above.2-(dibenzylamino)acetic acid (24 μL, 200 mM in DMSO, 160 equiv.) was pre-activated with 4-(4,6-dimethoxy- 1 ,3,5-triazin-2-yl)-4-methyl-morpholinium chloride (DMT-MM, 16 μL, 200 mM in H2O, 107 equiv.) in 60 μL DMSO for 30 min at room temperature. The solution was added to the stereo-defined 4-amino-proline- modified oligonucleotides (30 nmol in 40 μL 250 mM borate buffer, pH 9.4) and the coupling proceeded for 3 h at room temperature. The reaction was stopped by EtOH precipitation and the oligonucleotides were purified by RP-HPLC.The modified oligonucleotides (15 nmol each) were dissolved in 50 μL 250 mM borate buffer, pH 9.4 and CuSO4 (6 μL, 50 mM in H2O, 20 equiv.), 50 μL 20 mM intermediate I6c (67 equiv.) and sodium ascorbate (6 μL, 50 mM in H2O, 20 equiv.) were added. The copper(l)-catalyzed alkyne-azide cycloaddition (CuAAC) proceeded for 30 min at 60 °C and was stopped by the addition of 20 μL 3 M acetic acid buffer pH 5 for subsequent ethanol precipitation. The crudes were purified by RP-HPLC.1.2.2 Synthesis of O3a-b, O4a-b, O5a-bThe 2 stereo-defined isomers (S) and (R)-2-((((9 / 7-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(3- iodophenyl)propanoic acid (200 mM in DMSO, 187.5 μL, 150 equiv.) were separately activated by the addition of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC, 200 mM in DMSO, 150 μL, 120 equiv.) and N-hydroxysulfosuccinimide (sNHS, 200mM in DMSO:water (2:1), 125 μL, 100 equiv.). After 20 min, the preactivation mixture was added to a 5’-amino modified 12-mer oligonucleotide (5’ Ce-amino- TAGTAGCCATCC, 250 nmol in 200 μL 100 mM MOPS buffer pH 8). The reaction proceeded for 2 h at r.t. and was stopped by EtOH precipitation. The DNA-pellet was redissolved in H2O (300 μL) to which piperidine (30 μL) was added. The deprotection was complete after 2h at r.t. and quenched by the addition of 255 μL 3 M acetic acid buffer pH 4.7. The oligonucleotide was precipitated by the addition of ethanol for subsequent by RP-HPLC.The stereo-defined 3-lodo-phenylalanine-modified oligonucleotides (30 nmol each) were dissolved in 40 μL 250 mM borate buffer, pH 9.4 and acetic anhydride (200 mM in DMSO, 6 μL, 40 equiv.) was added. The reaction proceeded for 1 h at r.t. The reaction was stopped by EtOH precipitation, and the oligonucleotides were purified by RP-HPLC.All solvents were degassed in argon atmosphere. The pre-catalyst solution was prepared by mixing 10mM palladium (II) acetate in DMA (100 μL), 100 mM TPPTS in water (100 μL), 20mM Copper (II) acetate in water (100 μL) and diluted up to 1 mL with mQ millipore water, resulting in a 1 mM solution of Pd(0)-TPPTS complex and 2 mM solution of Cu(ll). Each modified oligonucleotide (10 nmol scale) was dissolved in 100 μL 200 mM potassium carbonate, the pre-catalyst solution (20 μL of, 20 nmol in Pd) and alkyne I6b (100 mM in DMSO, 20 μL, 200 equiv.) were subsequently added. The copper was reduced by adding sodium L- ascorbate (10 mM in water, 50 μL, 50 equiv.) and the resulting solutions were heated at 65 °C for 1 h. The reactions were quenched by adding 100 mM DTT:3M acetate buffer pH 4.7 (1 :1 , 30 μL). The products O3a, b were precipitated by adding EtOH and purified by RP-HPLC.The 2 stereo-defined isomers (S) and (R)-2-((((9 / 7-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(3- iodophenyl)propanoic acid (200 mM in DMSO, 187.5 μL, 150 equiv.) were separately activated by the addition of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC, 200 mM in DMSO, 150 μL, 120 equiv.) and N-hydroxysulfosuccinimide (sNHS, 200mM in DMSO:water (2:1), 125 μL, 100 equiv.). After 20 min, the preactivation mixture was added to a 5’-amino modified 12-mer oligonucleotide (5’ Ce-amino- TAGTAGCCATCC, 250 nmol in 200 μL 100 mM MOPS buffer, pH 8). The reaction proceeded for 2 h at r.t. and was stopped by EtOH precipitation. The DNA-pellet was redissolved in H2O (300 μL) to which piperidine (30 μL) was added. The deprotection was complete after 2h at r.t. and quenched by the addition of 255 μL 3 M acetic acid buffer, pH 4.7. The oligonucleotide was precipitated by the addition of ethanol for subsequent by RP-HPLC.3-Chloro-4-fluorobenzoic acid (24 μL, 200 mM in DMSO, 160 equiv.) was pre-activated with 4-(4,6- dimethoxy-1 ,3,5-triazin-2-yl)-4-methyl-morpholinium chloride (DMT-MM, 16 μL, 200 mM in H2O, 107 equiv.) in 60 μL DMSO for 30 min at r.t. The solution was added to the stereo-defined 3-lodo-phenylalanine-modified oligonucleotides (30 nmol in 40 μL 250 mM borate buffer, pH 9.4) and the coupling proceeded for 1 h at room temperature. The reaction was stopped by EtOH precipitation, and the oligonucleotides were purified by RP-HPLC.All solvents were degassed in argon atmosphere. The pre-catalyst solution was prepared by mixing 10mM palladium (II) acetate in DMA (100 μL), 100 mM TPPTS in water (100 μL), 20mM Copper (II) acetate in water (100 μL) and diluted up to 1 mL with mQ millipore water, resulting in a 1 mM solution of Pd(0)-TPPTS complex and 2 mM solution of Cu(ll). Each modified oligonucleotide (10 nmol scale) was dissolved in 100 μL 200 mM potassium carbonate, the pre-catalyst solution (20 μL of, 20 nmol in Pd) and alkyne I6b (100 mM in DMSO, 20 μL, 200 equiv.) were subsequently added. The copper was reduced by adding sodium L- ascorbate (10 mM in water, 50 μL, 50 equiv.) and the resulting solutions were heated at 65 °C for 1 h. The reactions were quenched by adding 100 mM DTT:3M acetate buffer (1 :1 , 30 μL). The products were precipitated by adding EtOH and purified by RP-HPLC.The 2 stereo-defined isomers (S) and (R)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(3- iodophenyl)propanoic acid (200 mM in DMSO, 187.5 μL, 150 equiv.) were separately activated by the addition of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC, 200 mM in DMSO, 150 μL, 120 equiv.) and N-hydroxysulfosuccinimide (sNHS, 200mM in DMSO:water (2:1), 125 μL, 100 equiv.). After 20 min, the preactivation mixture was added to a 5’-amino modified 12-mer oligonucleotide (5’ Ce-amino- TAGTAGCCATCC, 250 nmol in 200 μL 100 mM MOPS buffer, pH 8). The reaction proceeded for 2 h at r.t. and was stopped by EtOH precipitation. The DNA-pellet was redissolved in H2O (300 μL) to which piperidine (30 μL) was added. The deprotection was complete after 2h at r.t. and quenched by the addition of 255 μL 3 M acetic acid buffer, pH 4.7. The oligonucleotide was precipitated by the addition of ethanol for subsequent by RP-HPLC.4-Fluorophenyl isocyanate (24 μL, 200 mM in DMSO, 160 equiv.) was pre-activated with 4-(4,6-dimethoxy- 1 ,3,5-triazin-2-yl)-4-methyl-morpholinium chloride (DMT-MM, 16 μL, 200 mM in H2O, 107 equiv.) in 60 μL DMSO for 30 min at r.t. The solution was added to the stereo-defined 3-lodo-phenylalanine-modified oligonucleotides (30 nmol in 40 μL 250 mM borate buffer, pH 9.4) and the coupling proceeded for 1 h at room temperature. The reaction was stopped by EtOH precipitation, and the oligonucleotides were purified by RP-HPLC.All solvents were degassed in argon atmosphere. The pre-catalyst solution was prepared by mixing 10mM palladium (II) acetate in DMA (100 μL), 100 mM TPPTS in water (100 μL), 20mM Copper (II) acetate in water (100 μL) and diluted up to 1 mL with mQ millipore water, resulting in a 1 mM solution of Pd(0)-TPPTS complex and 2 mM solution of Cu(ll). Each modified oligonucleotide (10 nmol scale) was dissolved in 100 μL 200 mM potassium carbonate, the pre-catalyst solution (20 μL of, 20 nmol in Pd) and alkyne I6b (100 mM in DMSO, 20 μL, 200 equiv.) were subsequently added. The copper was reduced by adding sodium L- ascorbate (10 mM in water, 50 μL, 50 equiv.) and the resulting solutions were heated at 65 °C for 1 h. The reactions were quenched by adding 100 mM DTT:3M acetate buffer (1 :1 , 30 μL). The products were precipitated by adding EtOH and purified by RP-HPLC.Example 2: Enzymatic Assay Studies (IC50 Determination) of different compoundsEnzymatic assay protocol 1 : Short assayGrenier 384 transparent, flat-bottom well plates were used. Each potential inhibitor was measured in triplicate. 16 μL of a solution of inhibitor (5% DMSO in PBS, pH = 7.4) was loaded into the first row. 8 μL of 5% DMSO in PBS were added in the rest of the wells. A serial dilution was performed vertically starting from the first row all through the end of the plate (16 points). 16 μL of an ACP3 solution (25 nM in PBS, pH = 7.4) were added to the respective wells. After 5 to 15 min of incubation, 16 μL of a solution of pNPP (12.5 mM in PBS, pH = 7.4) was added. The plate was left to develop in the dark for 15 to 20 min and was quenched by the addition of 50 μL of 2M NaOH to each of the wells. The readout was performed using a plate reader (Tecan) and measuring absorption at 405 vs 620 nm.Final concentration of ACP3: 10 nMFinal concentration of pNPP: 5 mMEnzymatic assay protocol 2: Long, sensitive assayGrenier 384 transparent, flat-bottom well plates were used. Each potential inhibitor was measured in triplicate. 16 μL of a solution of inhibitor (5% DMSO in PBS, pH = 7.4) was loaded into the first column. 8 μL of 5% DMSO in PBS were added in the rest of the wells. A serial dilution was performed horizontally starting from the first column all through the end of the plate (24 points). 16 μL of an ACP3 solution (2.5 nM in PBS, pH = 7.4) were added to the respective wells. After 5 to 15 min of incubation, 16 μL of a solution of pNPP (5 mM in PBS, pH = 7.4) was added. The plate was sealed and left to develop in the dark for 18 -20 hours and was quenched by the addition of 50 μL of 2M NaOH to each of the wells. The readout was performed using a plate reader (Tecan) and measuring absorption at 405 vs 620 nm.Final concentration of ACP3: 1 nMFinal concentration of pNPP: 2 mMResults are shown in FIGs. 1 to 5.The phosphonate-containing group (R1) is considered to be effectively positioned in the active site of the pocket of ACP3. Further surrounding binding sites on ACP3 may be utilized to further improve affinity and inhibitory potency by utilizing suitable groups Y. For instance, using a proline-type scaffold is a viable approach, as indicated by the results in FIGs. 3 and 4.We also studied a second scaffold based on the 2 stereoisomers of the 3-iodo-phenylalanine directly conjugated to the a-aminophosphonic acid moieties incorporating the meta-derivative I6b. The Iodo moiety was exploited as attachment point of phosphonates via Sonogashira cross-coupling while the amino moiety was modified by the insertion of different building blocks. Using such scaffold is a viable approach, as indicated by the results in FIG. 5.Example 3: Fluorescence polarization studiesFluorescence Polarisation (FP) measurements with FITC-labelled compoundsThe FITC-labelled compounds were diluted to a concentration between 10 and 50 nM (5 pl) and incubated for 15 min in a black 384-well plate (Greiner small volume and non-binding) with serial dilutions of protein (5 pl). The fluorophore was excited at 485 nm and the emission was measured at 535 nm on a Spectra Max Paradigm multimode plate reader (Tecan). The experiments were performed in triplicate.Results are shown in FIG. 6.Example 4: Cell binding experiments of ACP3 Ligands against newly-generated cell linesFlow Cytometry on ACP3-expressing stable cells (HT 1O8O.hACP3)HT1080.hACP3 and wild type HT1080 cells were detached with an Accutase® cell detachment solution, resuspended in a standard culture medium, and transferred to falcon tubes. The cells were counted and the mixtures were centrifuged at 400 ref for 3 min. The supernatant was removed and the cells were resuspended in FACS buffer (PBS 1x, 2% BSA, 2mM EDTA) at a dilution of approx. 300,000 cells / 100 μL; the suspensions were kept on ice. A 96-well plate was used and 100 μL of the cell solution was loaded in each well. The plate was left to incubate on ice for 30 min and was then centrifuged at 4 °C for 3 min (400 ref). The supernatant was removed and the cell pellets were resuspended in FACS buffer containing 50 nM concentrations of each of the compounds. The plate was further incubated in the dark at room temperature for 1 h, after which the plate was centrifuged at 4 °C for 3 min (400 ref). A washing step followed and a live / dead cell stain (Zombie NIR) was performed for 20 min at 4°C in the dark. The cells were washed and resuspended in 200 μL FACS buffer. Data was acquired on a Cytoflex S flow cytometer (Beckman Coulter) and analyzed using the FlowJo software v10 (BD Biosciences).ResultsTo demonstrate cell binding on ACP3+ cells, we pursued a stable viral transduction approach. FIG. 7 demonstrates that the FITC-labelled ACP3-binding compounds selectively stained the transfected HT1080.hACP3 cell line, while FIG. 8 shows that they do not bind to the wild type HT1080 cells. These results validate the ability of the ligands to bind to ACP3, expressed on the cell surface.Example 5: Surface Plasmon Resonance (SPR)SPR measurements were performed with a Biacore X100 instrument, using a CM5 chip (Cytiva, #BR100012). For the immobilization of ACP3, the CM5 chip was equilibrated with PBS pH 7.4 to follow the templated procedure (EDC / NHS) to reach a target level of 5000 RUs (typically reaching 3500-4500 RUs). ACP3 was immobilized on the reference cell line as well for subsequent by injecting 0.85% H3PO4, 10 mM NaOH, and 50 mM HCI. Using PBS pH 7.4 as running buffer, three concentrations of each compound (1 pM, 500 nM and 250 nM in PBS pH 7.4) were injected according to the multicycle analysis template at the following settings: 120 seconds contact time and 15000 seconds dissociation time ata flow rate of 10 μL / min. Sensograms were plotted with GraphPad Prism (version 8, GraphPad Software) and fitted using the BIAcore Evaluation Software 3.2 RCI (GE Healthcare).ResultsAffinity-matured compounds were compared with the benchmark starting point (6c) (FIG. 9). Compound 12a displayed the slowest dissociation (low kOff). Compounds 14 and 15 had a faster association (high kon). In general, compounds 12, 14, and 16 had improved binding kinetics in comparison to compound 6c.Example 6: In Vivo biodistribution studies with radiolabeled ligandsRadiolabeling of ProX-DOTAGA and ProX-DOTA compounds with Lutetium-177Radiolabeling of Compounds 18, 12a,b, 16a,b, 14a,b, 25a and 27a with Lutetium-177 (a theranostic radionuclide) was performed before biodistribution studies at the molar activity of 800 KBq / nmol.Before the biodistribution study, precursors (30 nmol) were dissolved in 30 μL of PBS 2% DMSO and diluted with 198 μL sodium acetate (1 M in milliQ water, pH = 4.5). 24 MBq of177Lu solution (12 μL at an activity of 2 MBq / μL) were added and the mixture was heated at 90°C for 10 minutes and passively cooled down to room temperature for 10 min. After cooling to room temperature, radiolabelled compounds were obtained as clear solution.177Lu incorporations of >95% were routinely achieved as confirmed by RP-HPLC analysis on a Merck-Hitachi D-7000 HPLC system equipped with a XTerra C18 column which was coupled to a Raytest Gabi Star radiodetector. 10 μL of the labeling solution corresponds to one dose (1.25 nmol labeled with 1 MBq). For direct injections of 1.25 nmol labeled with 1 MBq, 40 μL of the labeling solution was diluted with 560 μL PBS to inject 150 μL per mouse. Dose escalation studies were performed by the addition of unlabeled precursor to reach the desired amounts per 1 MBq (2.5, 5, 10, and 20 nmol).Particularly good labelling efficiency (conversion) was obtained when the compound, in particular a DOTA- based compound, was dissolved in a buffer or a solution at an alkaline pH (e.g., acetate buffer or mQ water adjusted to pH > 7, preferably > 8) and reacted with a solution of the lutetium source, especially for precursors compounds comprising a DOTA chelator moiety (e.g., compound 27a). The labelling efficiencies were better than those when the compound was dissolved in a buffer or a solution at an acidic pH. To illustrate this, compound 27a was reacted at various conditions with a “cold” nuclide (175Lu) source, and the conversion was measured, as shown below.Compound 27a (10 mg, 8.3 μmol, 1 equiv.) was dissolved in 830 pl of CHsCOONa aqueous solution (0.5 M, pH = 8) or mQ (pH = 8) and heated for 1 minute at 90 °C. LuCh 6 H2O (16 mg, 41.5 μmol, 5 equiv.) was dissolved in 415 μL of HCI (0.1 M) was added to the mixture. The reaction was shaken at 90 °C for 10 min, then the crude was cooled down to room temperature, filtered and purified via RP-HPLC. The product 28cwas obtained as a white solid after lyophilization (7.0 mg, 5.1 μmol, 61 % yield), m / z calculated forCRonUH7 / RoLuN1I9ZO„ I OP [LM + H]J+1381 .30; ’ observed 1382.50.Various advantageous reaction conditions for the synthesis of175Lu-ProX1 -(SS)-DOTA (28c) are summarized in the table below.Quantitative In Vivo Biodistribution in ACP3+ tumor-bearing miceFor tumor engraftment, HT1080.hACP3 cells and PC3.hACP3 cells, grown to 80% confluency, were detached with trypsin-EDTA, collected by centrifugation (5 min at 1 ,000g), and resuspended in sterile Hanks’ Balanced Salt Solution (Gibco, #14170-1 12). 100 μL comprising 5 million cells was injected subcutaneously in the right flank of athymic BALB / c AnNRj-Foxnl nude mice (age 4-8 weeks). Upon reaching a tumor size of 200-300 mm3, tumor-bearing mice were intravenously injected with [177Lu]-labeled compounds (if not stated otherwise: 1.25 nmol, 1 MBq in 150 μL sterile PBS). Mice were sacrificed at specified time points (e.g., 2 h, 6 h, 24 h, 48 h and 72 h post-injection) to isolate and measure radioactivity of the following organs: tumor, heart, lung, liver, spleen, kidney, blood, muscle, tail and salivary glands (for male mice also prostate, seminal vesicles, testicles, and bone were taken). Radioactivity was measured with a Packard Cobra Gamma Counter and calculated as %ID g1± standard error of the mean (n = 3 biologically independent animals). Measured values were normalized to the radioactive decay of [177Lu].ResultsCompound 20a was extensively studied in HT1080.hACP3 xenograft, in a dose escalation experiment in order to determine the optimal dose to perform further timecourse studies. As can be seen in FIG. 17, both 1 .25 nmol / mouse and 2.5 nmol / mouse seem to not be saturating doses, while a clear trend is observed at 5 nmol / mouse and above. We thus utilized the dose of 1.25 nmol / mouse for the following timecourse experiments. A comparative study was performed between the affinity-matured compound 20a (FIG. 18A) and the starting point benchmark compound 19 (FIG. 18B). A significant improvement in tumor accumulation was observed for compound 20a along with a stable retention of activity over long time points.A comparative study was also performed with the second class of affinity-matured molecules (21a, b and 22a, b). As can be seen in FIG. 19, compound 22a showed the cleanest profile at 2 hours. In contrast, the highest uptake in the tumor was observed with compound 21a; however, the profile in the healthy organs is not clean. A timecourse study at 1 .25 nmol / mouse was performed with the best compound 22a highlighting a good tumor accumulation with a retention of activity overtime (FIG. 20).Additionally, compound 20a, it’s least-inhibiting enantiomer 20b, compound 22a, and benchmark compound 19 were comparatively evaluated at a 24h time point (FIG. 21). The data highlights that 20a is the best performing compound in terms of tumor accumulation and tumor-to-organ ratios.Biodistribution analyses were also performed in PC3.hACP3 xenografts. In FIG. 22 selective tumor accumulation was observed for compound 20a, (FIG. 22A) and for compound 22a (FIG. 22B) with long tumor residence time (tumor half life > 72 hours) and low accumulation in healthy organs including prostate, salivary glands, seminal vesicles, bones, testicles.A comparative study in HT108O.hACP3 xenograft with compounds 20a, 28a, and 26a presented a selective accumulation in solid tumors expressing ACP3, with low healthy organ uptake (FIG. 23). The configuration of DOTAGA did not significantly impact the biodistribution of the radio-conjugates (see 20a vs 26a). The radio-conjugates efficiently target tumors even at ultra-low doses (see 26a administered at 4.5 nmol / kg).A confirmatory biodistribution study in HT1080.hACP3 xenograft was performed with compounds 19, 20a and 22a at short time point (2 hours) (FIG. 24). Selective tumor accumulation was observed for all compounds, with low accumulation in healthy organs including prostate, salivary glands, seminal vesicles, bones, testicles.Example 7: Structure-activity relationshipInhibition of tyrosyl protein phosphatase has been evaluated, as described by Beers, S.A. et al. Bioorganic & Medicinal Chemistry, Vol. 4, No. 10, 1996, pp. 1693-1701 t28l, by incubating an aliquot of purified human prostatic tyrosyl protein acid phosphatase with radiolabelled phosphotyrosine. The radiolabelled substrate, [14C]phosphotyrosine, is separated from the product, [14C]tyrosine by ion exchange chromatography and the production of radiolabelled tyrosine is quantified. Test compounds were incubated in the presence of tyrosyl acid phosphatase (Sigma Chemical Co.) and radiolabelled substrate ([14C]phosphotyrosine, (NEN Dupont Custom Synthesis)) plus cold O-phospho-L-tyrosine (10 pM) (Sigma Chemical Company) in a 50 mM sodium acetate buffer (pH 5.5) for 30 min at 37°C. The reaction was stopped by placing the assay on ice and the addition of a 100 μL aliquot of an enzyme inhibitor solution (1.1 mM sodium orthovanadate, Sigma Chemical Co.; 0.55 M sodium fluoride, Sigma Chemical Co.). The incubation mixture was passed through an ion exchange column ((Ag 1 -x8) (Bio-Rad Laboratories)) and washed with 2.5 mL of distilled deionized water. The total column effluent containing the radiolabelled product [14C]tyrosine) was collected and quantified by liquid scintillation spectroscopy. The test compound IC50 or the concentration of test compound necessary to inhibit 50% of the dephosphorylation was calculated using a quantal dose-response calculation and is reported as an average of at least duplicate determinations using several inhibitor concentrations.Results for test compounds of the below formula X-0 are shown in Table 5.X-0Table 5. Inhibition of prostatic acid phosphatase by various test compounds.In view of the above, and without wishing to be bound by any theory, it is contemplated that structural fragments corresponding to compounds X-1 to X-27 are particularly useful in groups R1of the compounds according to the present invention (e.g., where in group R1, a structure corresponding to the above general v _ & formula X-0 is bound the remainder of the molecule via group?as defined elsewhere herein, or where x _ i the substituent on one of the aryl rings functions as group?derived by removing one of the atoms on said substituent). A person skilled in the art will readily appreciate that the above structure-activity relationship may apply also to structural motifs similar to (even if different from) general formula X-0.Further without wishing to be bound by any theory, while both stereoisomers at the C atom to which the phosphonic acid (PO3H2), or a bioisostere thereof (e.g., a group Q), is bound exhibit good binding activity, the (Reconfiguration at that C atom is considered to provide a particularly high binding affinity and inhibitory activity towards prostatic acid phosphatase.1311Accordingly, while racemic mixtures and the individual diastereomers of all compounds described herein are contemplated as part of the subject-matter of the present invention, it is particularly preferred that the C atom to which the group Q (e.g., phosphonic acid (PO3H2) or an isostere thereof) is bound has an absolute configuration corresponding to the ones below;i.e., an (Reconfiguration, e.g. as shown in the structures below:Example 8: Therapy studiesTumor shrinkage analysisHT1080.hACP3 tumors were implanted into male Balb / c nu / nu mice (age 6-8 weeks) as described in Example 6 and allowed to grow for 7 days to an average volume of -170 mm3. Mice were randomly assigned to different therapy groups (n = 4 mice / group, biologically independent animals), and treated with a solution of the177Lu-labeled-targeted compounds or vehicle (PBS). Compound 20a (177Lu-ProX1-DOTAGA) or compound 22a (177Lu-ProX3-(S)-DOTAGA) were formulated in sterile PBS and systemically administered by tail vein injection (150 μL, 62.5 nmol / kg, 250 or 1000 MBq / kg). Animals were weighed, and tumor sizes were measured daily with an electronic caliper. The tumor volume was calculated according to the formula (long side) x (short side) x (short side) x 0.5. Animals were sacrificed when the termination criteria were reached.Prism 10 software (GraphPad Software) was used for data analysis (regular two-way ANOVA with the Bonferroni test).ResultsCompounds 20a and 22a mediated strong in vivo anti-cancer activity at the 1000 MBq / kg dose. Compound 20a induced cancer cures both at 250 and 1000 MBq / kg, with no signs of toxicity (FIG. 25).Example 9: Autoradiography studies with radiolabeled ligandsPreparation of tissue samplesCompounds were dissolved in DMSO (stock solutions at 1 mM) and diluted in acetate buffer (1 M, pH 4.5) to a final concentration of 200 pM. Compound solutions (5 μL) were mixed with177LuCh (10 μL, 2 MBq / μL) and with acetate buffer (5 μL, 1 M, pH 4.5). The mixture (20 μL) was heated at 90 °C for 10 min, left to equilibrate to rt, and diluted to 5 nM with 1 % bovine serum albumin (BSA) in PBS. OCT-embedded frozen tissue slices (10 pm) were thawed at rt and fixed in ice-cold acetone for 15 min. The tissue sections were washed two times with PBS (pH 7.4), dried at rt, and a hydrophobic circle was drawn around the tissue with a Dako Pen. The sections were blocked with 20% fetal calf serum and 3% BSA in PBS (pH 7.4) for 30 min and washed three times with PBS (pH 7.4). The tissue slices were separately incubated with177Lu-labeled compounds (500 μL, 5 nM, ~50 kBq) for 1 h at rt. Sections were subsequently washed three times with PBS (pH 7.4), dried at room temperature, and exposed to the phosphor screen overnight. I mages were recorded on a CR-35 Bio scanner and processed with the AIDA image analysis software.ResultsSelective binding on ACP3-positive tumors and human prostate cancer was observed compounds 19, 20a, and 22a, while a negligible uptake was observed on human salivary glands.177Lu-PSMA-617 (177Lu vipivotide tetraxetan), was used for direct comparison in the assay. Uptake on PSMA-positive tumors, human prostate cancer, and human salivary glands was observed with177Lu-PSMA-617 (FIG. 26).Example 10: Confocal microscopy studies of ProX1-(SS)-FITC (13), ProX2-(S)-Fluo (15a) and ProX2- (R)-Fluo (15b), ProX3-(S)-Fluo (17a) and ProX3-(R)-Fluo (17b)Confocal microscopy experimentsHT1080.hACP3, PC3.hACP3, and corresponding ACP3-negative wild-type cells were seeded into 4-well coverslip chamber plates at a density of 104cells per well in culture medium and allowed to grow for 24 hours at 37 °C (5% CO2). Hoechst 33342 nuclear dye was used to stain nuclear structures. Test compounds (100 nM) were incubated in fresh culture medium. Randomly selected colonies were imaged ~20 min after incubation on an SP8 confocal microscope equipped with an AOBS device (Leica Microsystems).ResultsThe results are shown in FIG. 27 for ProX1-(SS)-FITC (13), FIG. 28 for ProX2-(S)-Fluo (15a) and ProX2- (R)-Fluo (15b) and FIG. 29 for ProX3-(S)-Fluo (17a) and ProX3-(R)-Fluo (17b). Confocal microscopy studies confirmed membranous staining of ACP3-positive cell lines, while no interaction was detected with the wild-type cells (negative controls HT1080.wt and PC3.wt in FIGs. 27, 28 and 29). Internalization of ACP3 ligands was not observed in confocal microscopy studies.Example 11 : Ex vivo biodistribution studies of ProX1-(SS)-AF488 (29a) and ProX3-(S)-AF488 (30a)Ex Vivo Biodistribution in HT1080.hACP3 tumor-bearing miceTumor-bearing BALB / c nude mice (males, tumor model: HT1080.hACP3, tumor size of above 500 mm3) were intravenously injected with ProX1 -(SS)-AF488 (29a) and ProX3-(S)-AF488 (30a) (200 pM, 150 μL sterile PBS), respectively. Mice were sacrificed 2 h post-injection to isolate tumor, heart, lung, liver, spleen, intestine, kidney, muscle, and salivary glands. The tissues were embedded in Richard-Allan Scientific™ Neg-50™ Frozen Section Medium and cut (10 pm of thickness) with a cryostat microtome. Tissue sections were fixed using mounting medium with DAPI. Images were recorded on an Axioskop 2 fluorescence microscope (Zeiss; 20x / 0.7) and processed with lmageJ2 (version 2.14.0).The results are shown in FIG. 30 for ProX1-(SS)-AF488 (29a) and in FIG. 31 for ProX3-(S)-AF488 (30a). A homogeneous and selective diffusion in ACP3-positive tumor lesions was observed for AF488 analogues of ProX1-(SS) and ProX3-(S) by ex vivo biodistribution studies. Compound ProX3-(S)-AF488 (30a) showed very high accumulation in tumor tissue, and medium levels of accumulation in healthy liver, together with very low uptake in other normal tissues. Compound ProX1-(SS)-AF488 (29a) showed very high accumulation in tumor tissue, and very low accumulation in all healthy organs.Example 12: In Vivo biodistribution studies and PET-imaging with68Ga-ProX1-(SS)-DOTA (44)Radiosynthesis of68Ga-ProX1-(SS)-DOTA (44)Galli RD Gallium-68 Generator was used from IRE EliT Radiopharma. Standard elution protocol was followed, which typically yielded -380 MBq of68GaCh in ~1 .5 MBq / μL in 0.1 M HCI.ProX1-(SS)-DOTA (27a) (6 μL, 6 nmol, from 1 mM solution in PBS) was diluted with sodium acetate (34 μL, 1 M in water, pH 4.5). 24 MBq of68Ga solution (20 μL at an activity of 1.5 MBq / μL) were added and the mixture was heated at 90 °C for 10 min and passively cooled down to rt for 5 min. After cooling to room temperature, an aliquot was analyzed by RP-HPLC (XTerra C18, 5% MeCN in 0.1 % aq. TFA to 80% over 20 min on a Merck-Hitachi D-7000 HPLC system equipped with a Raytest Gabi Star radiodetector) (FIG. 34).In Vivo biodistribution studiesExperimental setup, including tumor xenografting, injection solution preparation, and organ radioactivity measurement for biodistribution studies were performed analogously to Example 6.PET-imagingFor the PET-CT study, the mouse was sacrificed 1 h after injection with a dose of 62.5 nmol / kg (600 MBq / kg) and the intact carcass was analysed using an imager (superArgus PET / CT scanner (Sedecal, Madrid, Spain, formerly Vista explore).ResultsA comparative study between177Lu-ProX1-(SS)-DOTA (28a) and68Ga-ProX1-(SS)-DOTA (44) revealed complete reproducibility between the two radionuclides (FIG. 35). The %ID / g in the tumors for both compounds was -50%, highlighting the excellent uptake. To highlight the cleanliness in healthy organs, the data are presented in a split graph format.Additional biodistribution studies were run with68Ga-ProX1-(SS)-DOTA (44) at a shorter time point (1 h), which demonstrated fast accumulation at the site of disease (-50 % ID / g) without a significant impact to the healthy organ uptake (FIG. 36a). Additional PET-CT images further showed that the molecule selectively accumulates at the tumor and off-target liabilities in organs that were not isolated in the previous experiments were not present (FIG. 36b).Blocking and negative model experiments were performed to prove that68Ga-ProX1-(SS)-DOTA (44) was selective for ACP3-expressing tumors (FIG. 37). When cold ProX1 -(SS)-DOTA (27a) was injected prior to injection of labelled molecule, the uptake in the tumor was significantly reduced from -50 to -13 %ID / g, proving that the cold compound was already saturating the antigen, preventing binding of the labelled compound thereafter. Additionally, when the experiment was run in SK-RC-52 tumor-bearing mice (ACP3 negative) no notable accumulation was observed at the site of disease.Example 13: In Vitro radioligand bead-based assay with177Lu-ProX1-(SS)-DOTA (28a) and177Lu- ProX3-(S)-DOTAGA (22a)RadiolabellingRadiolabelling of ligands was performed in accordance with Example 6. Specific activities of 20 MBq / nmol were used throughout all in vitro experiments.Radioligand bead-based assayMagnetic Streptavidin-coated DynabeadsTM M-280 (8 μL) were loaded into a 1 .5 mL Eppendorf tubes and washed with 390 μL of phosphate buffer saline solution containing 0.05% Tween-20 (PBS-T). Supernatant removal was performed when the Eppendorf tubes were loaded into a magnetic rack. The washed beads were resuspended in 390 μL of PBS-T and biotinylated recombinant ACP3 (10 μL of 3.6 pM solution) was added to the mixtures. After 30 min of incubation time, the supernatant was removed and the beads were washed with 400 μL PBS-T. The beads were resuspended with a solution of177Lu-ProX1 -(SS)-DOTA (28a) or177Lu-ProX3-(S)-DOTAGA (22a) (10 KBq, 1 μmol, 0.4 mL) in PBS-T and left to incubate for 30 min. A 5000-fold molar excess was added before adding the radioligand in the blocking arm. The supernatants were collected, the beads were washed with 400 μL PBS-T and then resuspended. The beads suspensions and the supernatants were measured with a Packard Cobra Gamma Counter.ResultsThe binding and specificity of 177-Lutetium labelled conjugates 28a and 22a was tested in vitro. The radioligand bead-based assay demonstrated that the molecules tightly bound ACP3-positive beads and thatpre-blocking with a large excess of unlabelled ligands, resulted in complete loss of binding (FIG. 38). These results showcase that the binding was specific to the antigen.Example 14: ProX1-(SS)-based Small Molecule-Drug Conjugates (SMDCs) - therapy studiesMethods for TherapyTumor xenografting was performed analogously to Example 6 and masses were allowed to grow to -100 mm3. Mice were randomly assigned to different therapy groups:For HT1080.hACP3 therapy: n = 4 mice for injections of SMDC 31 ; n = 3 mice for SMDC 36 and vehicle group.For PC3.hACP3 therapy: n = 6 mice for injections of SMDCs 31 ; n = 5 mice for vehicle group; n = 3 mice for injections with unlabelled ProX1-(SS)-DOTA (27a).All molecules were injected at a dose of 5 nmol / mouse (250 nmol / kg) or 100 μL of PBS (vehicle), according to the schedule illustrated in the figure with black arrows.Tumor shrinkage analysis was performed analogously to Example 8.ResultsThe HT1080.hACP3 model was used to assess the SMDCs of the invention in a therapeutic setting (FIG. 39). The best performing molecule was ProX1 -(SS)-GlyPro-MMAE (31) which resulted in notable tumor shrinkage in all treated animals. ProX1-(SS)-PhoCI1-MMAE (36) bearing the phosphatase cleavable linker also elicited tumor-growth retardation in all mice in the group.The therapy was repeated in a more relevant prostate cancer model PC3.hACP3 with larger groups of mice (FIG. 40). ProX1-(SS)-GlyPro-MMAE (31) mediated a therapeutic effect in all treated animals, causing significant tumor growth retardation. Additionally, unlabelled ProX1 -(SS)-DOTA (27a) didn’t elicit a therapeutic response in tumor bearing mice (FIG. 41) due to the lack of a cytotoxic moiety.Example 15: Fluorine-derivatives of a-Benzylaminobenzylphosphonic acid synthesis and in vitro characterization15.1 Fluorine-derivatives of a-benzylaminobenzylphosphonic acid synthesisGP1 synthesis is described in chapter 1.1.Synthesis of compound 47Compound 47 was prepared via GP1 (on a 0.25 mmol scale) from benzaldehyde and 3-fluorobenzylamine. After lyophilization, the product was obtained as a white solid (27.1 mg, 92 μmol, 37% yield), m / z calculated for C14H15FNO3P [M-H]- 294.25; m / z observed 294.1 .Synthesis of compound 48Compound 48 was prepared via GP1 (on a 0.25 mmol scale) from benzaldehyde and 4-fluorobenzylamine. After lyophilization, the product was obtained as a white solid (28.5 mg, 92 μmol, 39% yield), m / z calculated for C14H15FNO3P [M-H]- 294.25; m / z observed 294.1 .Synthesis of compound 49Compound 49 was prepared via GP1 (on a 0.25 mmol scale) from benzaldehyde and (2-Fluoropyridin-4- yl)methanamine hydrochloride. After lyophilization, the product was obtained as a white solid (2.2 mg, 7.4 μmol, 3% yield), m / z calculated for C13H14FN2O3P [M-H]- 294.24; m / z observed 294.1 .Synthesis of compound 50Compound 50 was prepared via GP1 (on a 0.25 mmol scale) from benzaldehyde and (6-Fluoropyridin-3- yl)methanamine. After lyophilization, the product was obtained as a white solid (1 .2 mg, 4.1 μmol, 2% yield). m / z calculated for C13H14FN2O3P [M-H]- 294.24; m / z observed 294.1 .15.2 Enzymatic inhibition measurements with compounds 1 , 47, 48, 49 and 50.Methods: The assay was performed according to protocol 2 in Example 2.Results: We studied four fluorine derivatives of a-aminophosphonic acid, and compounds 47, 48 and 49 retain the inhibitory potency of 1 , as indicated by the results in FIG. 42.Example 16: Synthesis and characterization of ProX1-(SS) and conjugates therof16.1 Synthesis of the new compoundsGP1 , GP14 and GP15 synthesis and S2, S4 and S5 procedures are described in chapter 1.1.I46 was prepared via GP1 (on a 0.25 mmol scale) from intermediate I5c and 2-Thiophenmethylamin. After lyophilization, the product was obtained as a white solid (31 .5 mg, 93 μmol, 37% yield), m / z calculated forC15H16NO4PS [M-H]- 336.33; m / z observed 336.0.I48 was prepared via GP14 (on a 20 μmol scale) from intermediates I9a and I46. The Boc group was deprotected by dissolving the purified material in a DCM:TFA (1 :1 , 5 mL) mixture and stirring for 2 hours at room temperature. The solvent was removed under reduced pressure and the crude was redissolved in acetonitrile:water (1 :1 , 10 mL) mixture. After lyophilization, the product was obtained as a white solid (5.6 mg, 7 μmol, 33% yield), m / z calculated for C42H53N8O6PS [M-Hp 827.97; m / z observed 827.4.51 was prepared via GP15 (on a 6 μmol scale) from intermediate I48. After lyophilization, the product was obtained as a white solid (0.7 mg, 0.6 μmol, 10% yield), m / z calculated for C58H79N12O13PS [M-H]- 1214.37; m / z observed 1214.5.Synthesis of intermediate 49149 was prepared via GP1 (on a 0.25 mmol scale) from intermediate I5c and 4-fluorobenzylamine. After lyophilization, the product was obtained as a white solid (25.6 mg, 73 μmol, 29% yield), m / z calculated for C17H17FNO4P [M-H]- 348.30; m / z observed 348.1 . Synthesis of intermediate 51151 was prepared via GP14 (on a 20 μmol scale) from intermediates I9a and I49. The Boc group was deprotected by dissolving the purified material in a DCM:TFA (1 :1 , 5 mL) mixture and stirring for 2 hours at room temperature. The solvent was removed under reduced pressure and the crude was redissolved in acetonitrile:water (1 :1 , 10 mL) mixture. After lyophilization, the product was obtained as a white solid (15.4 mg, 18 μmol, 92% yield), m / z calculated for C44H54FN8O6P [M-H]- 839.94; m / z observed 839.5.Synthesis of compound 5353 was prepared via GP15 (on a 8 μmol scale) from intermediate 151. After lyophilization, the product was obtained as a white solid (1.5 mg, 1.2 μmol, 16% yield), m / z calculated for C60H80FN12O13P [M-H]- 1225.57; m / z observed 1225.5.Synthesis of intermediate 52Commercially available Wang resin (100 mg, 0.10 mmol, 1.0 equiv.) was coupled to Fmoc-(2S,4S)-4- azidoproline (75.7 mg, 0.20 mmol, 2.0 equiv.) as described in S4 (1.9 equiv. HATU, 4.0 equiv. DIPEA, overnight) to afford s41. After Fmoc deprotection of s41 (S2), the resin was swollen in DMF and 3-[(2- oxopyrrolidin-1-yl)methyl]benzoic acid (65.8 mg, 0.30 mmol, 3.0 equiv.) was coupled as described in S4 (2.8 equiv. HATU, 8.0 equiv. DIPEA, 2 hours). After washing, the resin was cleaved according to S5. The cleavage solution was concentrated under reduced pressure and the crude mixture was diluted with DMF and purified via reversed-phase semi-preparative HPLC.I52a (S, S) was obtained as a white solid after lyophilization (4.4 mg, 12 μmol, 12% yield), m / z calculated for C17H19N5O4 [M-H]- 356.37; m / z observed 356.2.I52b (S, / ?) was obtained as a white solid after lyophilization (12.5 mg, 35 μmol, 35% yield), m / z calculated for C17H19N5O4 [M-H]- 356.37; m / z observed 356.2.I52c ( / ?, R) was obtained as a white solid after lyophilization (15.2 mg, 43 μmol, 43% yield), m / z calculated for C17H19N5O4 [M-H]- 356.37; m / z observed 356.2.I52d ( / ?, S) was obtained as a white solid after lyophilization (19.8 mg, 55 μmol, 55% yield), m / z calculated for C17H19N5O4 [M-H]- 356.37; m / z observed 356.2.I54 was prepared via GP14 (on a 12 μmol scale) from intermediate I52 and compound 2. The Boc group was deprotected by dissolving the purified material in a DCM:TFA (1 :1 , 5 mL) mixture and stirring for 2 hours at room temperature. The solvent was removed under reduced pressure and the crude was redissolved in acetonitrile:water (1 :1 , 10 mL) mixture.I54a (S, S) was obtained as a white solid after lyophilization (6.3 mg, 8.0 μmol, 66% yield), m / z calculated for C40H51N8O7P [M-H]- 785.36; m / z observed 785.4.I54b (S, R) was obtained as a white solid after lyophilization (5.3 mg, 6.7 μmol, 56% yield), m / z calculated for C40H51N8O7P [M-H]- 785.36; m / z observed 785.4.I54c (R, R) was obtained as a white solid after lyophilization (7.1 mg, 9.0 μmol, 75% yield), m / z calculated for C40H51N8O7P [M-H]- 785.36; m / z observed 785.4.I54d (R, S) was obtained as a white solid after lyophilization (7.4 mg, 9.4 μmol, 78% yield), m / z calculated for C40H51N8O7P [M-H]- 785.36; m / z observed 785.4.Synthesis of compound 5555 was prepared via GP15 (on a 6 μmol scale) from intermediate I54.55a (S, S) was obtained as a white solid after lyophilization (0.4 mg, 0.3 μmol, 5% yield), m / z calculated for C56H77N12O14P [M-H]- 1171 .54; m / z observed 1171 .5.55b (S, R) was obtained as a white solid after lyophilization (0.9 mg, 0.8 μmol, 12% yield), m / z calculated for C56H77N12O14P [M-H]- 1171 .54; m / z observed 1171 .5.55c (R, R) was obtained as a white solid after lyophilization (1.4 mg, 1.2 μmol, 19% yield), m / z calculated for C56H77N12O14P [M-H]- 1171 .54; m / z observed 1171 .5.55d (R, S) was obtained as a white solid after lyophilization (2.0 mg, 1.7 μmol, 27% yield), m / z calculated for C56H77N12O14P [M-H]- 1171 .54; m / z observed 1171 .5.Synthesis of intermediate 55Commercially available Wang resin (300 mg, 0.30 mmol, 1.0 equiv.) was coupled to Ns-L-Dap(Fmoc)-OH (211.4 mg, 0.60 mmol, 2.0 equiv.) as described in S4 (1.9 equiv. HATU, 4.0 equiv. DIPEA, overnight) toafford s42. After Fmoc deprotection of s42 (S2), the resin was swollen in DMF and 2-(dibenzylamino)acetic acid (229.8 mg, 0.90 mmol, 3.0 equiv.) was coupled as described in S4 (2.8 equiv. HATU, 8.0 equiv. DIPEA, 2 hours). After washing, the resin was cleaved according to S5. The cleavage solution was concentrated under reduced pressure and the crude mixture was diluted with DMF and purified via reversed-phase semipreparative HPLC.155a ( / ?) was obtained as a white solid after lyophilization (30 mg, 82 μmol, 14% yield), m / z calculated for C19H21 N5O3 [M-H]- 366.41 ; m / z observed 366.2.I55b (S) was obtained as a white solid after lyophilization (24 mg, 65 μmol, 11 % yield), m / z calculated for C19H21 N5O3 [M-H]- 366.41 ; m / z observed 366.2.I57 was prepared via GP14 (on a 20 μmol scale) from intermediates I55 and I6c. The Boc group was deprotected by dissolving the purified material in a DCM:TFA (1 :1 , 5 mL) mixture and stirring for 2 hours at room temperature. The solvent was removed under reduced pressure and the crude was redissolved in acetonitrile:water (1 :1 , 10 mL) mixture.I57a ( / ?) was obtained as a clear oil after lyophilization (6.5 mg, 8.0 μmol, 41 % yield), m / z calculated for C42H53N8O6P [M-H]- 795.91 ; m / z observed 795.5.I57b (S) was obtained as a clear oil after lyophilization (7.3 mg, 9.0 μmol, 46% yield), m / z calculated forC42H53N8O6P [M-H]- 795.91 ; m / z observed 795.5.Synthesis of compound 5656 was prepared via GP15 (on a 8 μmol scale) from intermediate I57.56a ( / ?) was obtained as a clear oil after lyophilization (0.8 mg, 0.7 μmol, 9% yield), m / z calculated for C58H79N12O13P [M-H]- 1181 .56; m / z observed 1181 .5.56b (S) was obtained as a clear oil after lyophilization (0.30 mg, 0.3 μmol, 3% yield), m / z calculated for C58H79N12O13P [M-H]- 1181 .56; m / z observed 1181 .5.Commercially available Wang resin (200 mg, 0.20 mmol, 1.0 equiv.) was coupled to N3-L-Aha(Fmoc)-OH (146.6 mg, 0.40 mmol, 2.0 equiv.) as described in S4 (1.9 equiv. HATU, 4.0 equiv. DIPEA, overnight) to afford s43. After Fmoc deprotection of s43 (S2), the resin was swollen in DMF and 2-(dibenzylamino)acetic acid (153.2 mg, 0.60 mmol, 3.0 equiv.) was coupled as described in S4 (2.8 equiv. HATU, 8.0 equiv. DIPEA, 2 hours). After washing, the resin was cleaved according to S5. The cleavage solution was concentrated under reduced pressure and the crude mixture was diluted with DMF and purified via reversed-phase semipreparative HPLC.I58a ( / ?) was obtained as a white solid after lyophilization (12.2 mg, 32 μmol, 8% yield), m / z calculated for C20H23N5O3 [M-H]- 380.18; m / z observed 380.2.I58b (S) was obtained as a white solid after lyophilization (9.6 mg, 25 μmol, 6% yield), m / z calculated for C20H23N5O3 [M-H]- 380.18; m / z observed 380.2.I60 was prepared via GP14 (on a 20 μmol scale) from intermediates I58 and I6c. The Boc group was deprotected by dissolving the purified material in a DCM:TFA (1 :1 , 5 mL) mixture and stirring for 2 hours at room temperature. The solvent was removed under reduced pressure and the crude was redissolved in acetonitrile:water (1 :1 , 10 mL) mixture.160a ( / ?) was obtained as a white solid after lyophilization (5.1 mg, 6 μmol, 31 % yield), m / z calculated for C43H55N8O6P [M-H]- 809.40; m / z observed 809.4.160b (S) was obtained as a white solid after lyophilization (7.1 mg, 9 μmol, 42% yield), m / z calculated for C43H55N8O6P [M-H]- 809.40; m / z observed 809.4.57 was prepared via GP15 (on a 6 μmol scale) from intermediate I60.57a ( / ?) was obtained as a clear oil after lyophilization (1.01 mg, 0.8 μmol, 14% yield), m / z calculated for C59H81N12O13P [M-H]- 1195.58; m / z observed 1195.5.57b (S) was obtained as a clear oil after lyophilization (0.89 mg, 0.7 μmol, 12% yield), m / z calculated for C59H81N12O13P [M-H]- 1195.58; m / z observed 1195.5.Synthesis of intermediate 61Commercially available Wang resin (100mg, 0.10 mmol, 1.0 equiv.) was coupled to Fmoc-(2S,4S)-4- azidoproline (75.7 mg, 0.20 mmol, 2.0 equiv.) as described in S4 (1.9 equiv. HATU, 4.0 equiv. DIPEA, overnight) to afford s44. After Fmoc deprotection of s44 (S2), the resin was swollen in DMF and Fmoc- glycine (89.2 mg, 0.30 mmol, 3.0 equiv.) was coupled as described in S4 (2.8 equiv. HATU, 8.0 equiv. DIPEA, 2 hours). After washing, the resin was cleaved according to S5. The cleavage solution was concentrated under reduced pressure and the crude mixture was diluted with DMF and purified via reversed -phase semipreparative HPLC. 161 was obtained as a white solid after lyophilization (30.8 mg, 71 μmol, 71 % yield), m / z calculated for C22H21N5O5 [M-H]- 434.15; m / z observed 434.1 .Synthesis of intermediate 63I63 was prepared via GP14 (on a 25 μmol scale) from intermediates 161 and I6c. The Boc group was deprotected by dissolving the purified material in a DCM:TFA (1 :1 , 5 mL) mixture and stirring for 2 hours at room temperature. The solvent was removed under reduced pressure and the crude was redissolved in acetonitrile:water (1 :1 , 10 mL) mixture. I63 was obtained as a white solid after lyophilization (3.3 mg, 4 μmol, 15% yield), m / z calculated for C45H53N8O8P [M-H]- 863.37; m / z observed 863.4.Synthesis of compound 5858 was prepared via GP15 (on a 4 μmol scale) from intermediate I63. The Fmoc group was deprotected by addition of 20% piperidine in DMF (0.3 mL). The mixture was incubated at 37 °C for 2 h (monitored by LC- MS). The resulting residue was partitioned between dichloromethane and water. The layers were separated, and the aqueous layer was diluted with DMF, filtered through a syringe frit, and directly purified via reversed- phase semi- preparative HPLC. 58 was obtained as a white solid after lyophilization (0.6 mg, 0.5 μmol, 12% yield), m / z calculated for C46H69N12O13P [M-H]- 1027.48; m / z observed 1027.6.Synthesis of intermediate 64(2S, 4S)-Boc-4-azidoproline (48.3 mg, 0.2 mmol, 1 equiv.) and HATU (76.0 mg, 0.2 mmol, 1.0 equiv.) were weighed into an Eppendorf tube and dissolved in acetonitrile (2.5 mL, 0.08 M). Fmoc-1 ,6-diaminohexane (101.5 mg, 0.3 mmol, 1.5 equiv.) and DIPEA (0.14 mL, 0.8 mmol, 4.0 equiv.) were added and the reaction was incubated in a ThermoMixer at 37 °C until completion by LC-MS was observed. The resulting residue was diluted in EtOAc (10 mL) and washed with 1 M HCI (10 mL), sat. aq. sodium bicarbonate (2 x 15 mL) and brine (20 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by normal-phase MPLC and I64 was obtained as a white solid after lyophilization (67 mg, 0.12 mmol, 58% yield), m / z calculated for C31H40N6O5 [M+H]+577.31 ; m / z observed 577.4.Synthesis of intermediate 65The Boc group was deprotected by dissolving the intermediate I64 (10 mg, 17 μmol, 1.0 equiv.) in a DCM:TFA (1 :1 , 5 mL) mixture and stirring for 1 hour at room temperature. The solvent was removed under reduced pressure and the crude was directly used in the next step.The crude was redissolved in DMF (0.22 mL, 0.08 M) and HATU (18.5 mg, 49 μmol, 2.8 equiv.) was added. A / -benzyl-A / -bocg lycine (13.8 mg, 52 μmol, 3.0 equiv.) and DIPEA (12 μL, 70 μmol, 4.0 equiv.) were added and the reaction was incubated in a ThermoMixer at 37 °C until completion by LC-MS was observed (around 2 h). The solution was diluted with DMSO (3x volume), filtered through a syringe frit, and directly purified via reversed-phase semi-preparative HPLC. I65 was obtained as a white solid after lyophilization (6.9 mg, 10 μmol, 55% yield), m / z calculated for C40H49N7O6 [M+H]+724.37; m / z observed 724.4.I65 (6.9 mg, 10 μmol, 1.0 equiv.) was dissolved in acetonitrile (0.12 mL, 0.08 M) and I6c (3.8 mg, 1 1 μmol,1 .2 equiv.), and copper iodide (1 .8 mg, 10 μmol, 1 .0 equiv.) were added to the solution. The resulting mixture was incubated in a ThermoMixer at 37 °C until completion by LC-MS was observed (around 30 min to 1 h). The Fmoc group was deprotected by addition of 20% piperidine in DMF (0.3 mL). The mixture was incubated at 37 °C for 2 h (monitored by LC-MS). The resulting residue was partitioned between dichloromethane and water. The layers were separated, and the aqueous layer was diluted with DMF, filtered through a syringe frit, and directly purified via reversed-phase semi- preparative HPLC. I66 was obtained as a white solid after lyophilization (6.3 mg, 6 μmol, 63% yield), m / z calculated for C42H57N8O8P [M-H]- 831.40; m / z observed 831.40.Synthesis of compound 5959 was prepared via GP15 (on a 4.7 μmol scale) from intermediate I66. The Boc group was deprotected by dissolving the purified material in a DCM:TFA (1 :1 , 5 mL) mixture and stirring for 2 hours at roomtemperature. The solvent was removed under reduced pressure and the crude was dissolved in acetonitrile:water (1 :1 , 5 mL) mixture. 59 was obtained as a white solid after lyophilization (1 .4 mg, 1 .3 μmol, 17% yield), m / z calculated for C53H75N12O13P [M-Hp 11 17.53; m / z observed 1117.6.Synthesis of intermediate 67The Boc group was deprotected by dissolving the intermediate I64 (20 mg, 35 μmol, 1.0 equiv.) in aDCM:TFA (1 :1 , 5 mL) mixture and stirring for 1 hour at room temperature. The solvent was removed under reduced pressure and the crude was directly used in the next step.The crude was redissolved in DMF (0.43 mL, 0.08 M) and HATU (36.9 mg, 97 μmol, 2.8 equiv.) was added. N, A / -dimethylglycine (10.7 mg, 0.10 mmol, 3.0 equiv.) and DIPEA (24 μL, 0.14 mmol, 4.0 equiv.) were added and the reaction was incubated in a ThermoMixer at 37 °C until completion by LC-MS was observed (around 2 h). The solution was diluted with DMSO (3x volume), filtered through a syringe frit, and directly purified via reversed-phase semi-preparative HPLC. I67 was obtained as a white solid after lyophilization (10.0 mg, 18 μmol, 51 % yield), m / z calculated for C30H39N7O4 [M+H]+562.31 ; m / z observed 562.4.Synthesis of intermediate 68I67 (10.0 mg, 18 μmol, 1 .0 equiv.) was dissolved in acetonitrile (0.22 mL, 0.08 M) and I6c (7.1 mg, 21 μmol, 1 .2 equiv.), and copper iodide (3.4 mg, 18 μmol, 1 .0 equiv.) were added to the solution. The resulting mixture was incubated in a ThermoMixer at 37 °C until completion by LC-MS was observed (around 30 min to 1 h). The Fmoc group was deprotected by addition of 20% piperidine in DMF (0.3 mL). The mixture was incubated at 37 °C for 2 h (monitored by LC-MS). The resulting residue was partitioned between dichloromethane and water. The layers were separated, and the aqueous layer was diluted with DMF, filtered through a syringe frit, and directly purified via reversed-phase semi- preparative HPLC. I68 was obtained as a white solid after lyophilization (4.3 mg, 6.4 μmol, 27% yield), m / z calculated for C32H47N8O6P [M-H]- 669.34; m / z observed 669.3.Synthesis of compound 6060 was prepared via GP15 (on a 6.4 μmol scale) from intermediate I68. 60 was obtained as a white solid after lyophilization (2.5 mg, 2 μmol, 37% yield), m / z calculated for C48H73N12O13P [M-H]- 1055.52; m / z observed 1055.6.16.2 Enzymatic inhibition measurementsMethods: The assay was performed according to protocol 2 in Example 2.16.2.1 Enzymatic inhibition measurements with compounds 27a, 51 , 53, 55a, 55b, 55c and 55d.Results: The compound 53 has similar high potency compared to compound 27a, while lower inhibitory potencies have been observed for compounds 53, 55a, 55b, 55c and 55d (FIG. 43).16.2.2 Enzymatic inhibition measurements with compounds 27a, 56a and 56b.Results: Incorporation of the open DAP scaffold (56a, b) resulted in similar potencies as compound 27a (FIG. 44).16.2.3 Enzymatic inhibition measurements with compounds 27a, 57a and 57b.Results: Incorporation of the linear Aha scaffold (57a, b) resulted in decreased potencies as compared to compound 27a (FIG. 45).16.2.4 Enzymatic inhibition measurements with compounds 27a, 58, 59 and 60.Results: Compounds 58 bearing a glycine, 59 bearing benzylgycine and 60 bearing dimethylglycine have a lower inhibitory potency compared to compound 27a bearing a benzylgycine, as indicated by the results in FIG. 46.16.3 In vivo biodistribution study with compounds 52, and 5416.3.1 Radiosynthesis of compounds 52 and 54The experiments were performed analogously to Example 6. The radiosynthesis of compounds 52 and 54 and HPLC chromatogram of the final products as recorded with a radio-detector are shown in FIG. 48 and FIG. 49 respectively.16.3.2 In vivo biodistribution study with compounds 52, and 54Methods: Experimental setup, including tumor xenografting, injection solution preparation, and organ radioactivity measurement for biodistribution studies were performed analogously to Example 6.Results: Compound 54 shows higher uptake in the tumor and lower uptake in healthy organs than compound 52 (FIG. 47).Example 17: Cross-reactivity study between human ACP3 and murine ACP317.1 Material & methodsThe assay was performed according to protocol 2 in Example 2.17.2 Results The cross-reactivity of both radioligand precursors 12a and 16a against human and murine ACP3 was compared. As shown in FIG. 50, the compounds displayed similar binding with both proteins, indicating that the tumor targeting performance could be translatable between mice and humans.References[1] J.-N. Rybak, E. Trachsel, J. Scheuermann, D. Neri, Ligand-Based Vascular Targeting of Disease, ChemMedChem 2007, 2, 22-40.[2] D. Schrama, R. A. Reisfeld, J. C. Becker, Antibody targeted drugs as cancer therapeutics, Nat. Rev. Drug Discovery 2006, 5, 147-159.[3] H. K. Binz, P. Amstutz, A. Pluckthun, Engineering novel binding proteins from nonimmunoglobulin domains, Nat. Biotechnol. 2005, 23, 1257-1268.[4] A. Sergeeva, M. G. Kolonin, J. J. Molldrem, R. Pasqualini, W. Arap, Display technologies: application for the discovery of drug and gene delivery agents, Adv. Drug Deliv. Rev. 2006, 58, 1622-1654.[5] P. S. Low, W. A. Henne, D. D. Doorneweerd, Discovery and Development of Folic-Acid-Based Receptor Targeting for Imaging and Therapy of Cancer and Inflammatory Diseases, Acc. Chem. Res. 2008, 41, 120-129.[6] M. Srinivasarao, C. V. Galliford, P. S. Low, Principles in the design of ligand-targeted cancer therapeutics and imaging agents, Nat. Rev. Drug Discov. 2015, 14, 203-219.[7] J. A. Reddy, R. Dorton, E. Westrick, A. Dawson, T. Smith, L.-C. Xu, M. Vetzel, P. Kleindl, I. R. Vlahov, C. P. Leamon, Preclinical Evaluation of EC145, a Folate-Vinca Alkaloid Conjugate, Cancer Res. 2007, 67, 4434-4442.[8] P. M. LoRusso, M. J. Edelman, S. L. Bever, K. M. Forman, M. Pilat, M. F. Quinn, J. Li, E. I. Heath, L. M. Malburg, P. J. Klein, et al., Phase I Study of Folate Conjugate EC145 (Vintafolide) in Patients With Refractory Solid Tumors, J. Clin. Oncol. 2012, 30, 4011-4016.[9] N. Krall, F. Pretto, W. Decurtins, G. J. L. Bernardes, C. T. Supuran, D. Neri, A Small-Molecule Drug Conjugate for the Treatment of Carbonic Anhydrase IX Expressing Tumors, Angew. Chem., Int. Ed. 2014, 53, 4231 -4235.

[0010] N. Krall, F. Pretto, D. Neri, A bivalent small molecule-drug conjugate directed against carbonic anhydrase IX can elicit complete tumour regression in mice, Chem. Sci. 2014, 5, 3640-3644.

[0011] E. Luchter-Wasyl, W. Ostrowski, Subunit structure of human prostatic acid phosphatase, Biochim. Biophys. Acta - Proteins Proteom. 1974, 365, 349-359.

[0012] D. W. Moss, F. D. Raymond, D. B. Wile, R. Rej, Clinical and Biological Aspects of Acid Phosphatase, Crit. Rev. Clin. Lab. Sci. 1995, 32, 431-467.

[0013] A. Anand, P. K. Srivastava, A Molecular Description of Acid Phosphatase, Appl. Biochem. Biotechnol. 2012, 167, 2174-2197.

[0014] A. B. Gutman, E. B. Gutman, An " acid " phosphatase occurring in the serum of patients with metastasizing carcinoma of the prostate gland, J. Clin. Invest. 1938, 17, 473-478.

[0015] S. Veeramani, T.-C. Yuan, S.-J. Chen, F.-F. Lin, J. E. Petersen, S. Shaheduzzaman, S. Srivastava, R. G. MacDonald, M.-F. Lin, Cellular prostatic acid phosphatase: a protein tyrosine phosphatase involved in androgenindependent proliferation of prostate cancer, Endocr.-Relat. Cancer 2005, 12, 805-822.

[0016] C. J. Ercole, P. H. Lange, M. Mathisen, R. K. Chiou, P. K. Reddy, R. L. Vessella, Prostatic Specific Antigen and Prostatic Acid Phosphatase in the Monitoring and Staging of Patients with Prostatic Cancer, J. Urol. 1987, 738, 1181-1184.

[0017] https: / / www.proteinatlas.org / ENSG00000014257-ACP3, accessed on the 07.08.2023.

[0018] I. B. Quintero, C. s. L. Araujo, A. E. Pulkka, R. S. Wirkkala, A. M. Herrala, E.-L. Eskelinen, E. Jokitalo, P. A. Hellstrom, H. J. Tuominen, P. P. Hirvikoski, et al., Prostatic Acid Phosphatase Is Not a Prostate Specific Target, Cancer Res. 2007, 67, 6549-6554.

[0019] R. J. Rebello, C. Oing, K. E. Knudsen, S. Loeb, D. C. Johnson, R. E. Reiter, S. Gillessen, T. Van der Kwast, R. G. Bristow, Prostate cancer, Nat. Rev. Dis. Primers 2021, 7, 9.

[0020] ClinicalTrials.gov Identifier: NCT03511664.

[0021] N. Heynickx, K. Herrmann, K. Vermeulen, S. Baatout, A. Aerts, The salivary glands as a dose limiting organ of PSMA- targeted radionuclide therapy: A review of the lessons learnt so far, Nucl. Med. Biol. 2021 , 98-99, 30-39.

[0022] E. J. Small, P. F. Schellhammer, C. S. Higano, C. H. Redfern, J. J. Nemunaitis, F. H. Valone, S. S. Verjee, L. A. Jones, R. M. Hershberg, Placebo-Controlled Phase III Trial of Immunologic Therapy with Sipuleucel-T (APC8015) in Patients with Metastatic, Asymptomatic Hormone Refractory Prostate Cancer, J. Clin. Oncol. 2006, 24, 3089- 3094.

[0023] M. Perala-Heape, P. Vihko, A. Laine, J. Heikkila, R. Vihko, Effects of tumour mass and circulating antigen on the biodistribution of111 In-labelled F(ab')2 fragments of human prostatic acid phosphatase monoclonal antibody in nude mice bearing PC-82 human prostatic tumour xenografts, Eur. J. Nucl. Med. 1991, 18, 339-345.

[0024] R. J. Babaian, J. L. Murray, L. M. Lamki, T. P. Haynie, E. M. Hersh, M. G. Rosenblum, H. J. Glenn, M. W. Unger,D. J. Carlo, A. C. von Eschenbach, Radioimmunological Imaging of Metastatic Prostatic Cancer with 111 Indium-Labeled Monoclonal Antibody Pay 276, J. Urol. 1987, 137, 439-443.

[0025] R. J. Babaian, L. M. Lamki, Radioimmunoscintigraphy of prostate cancer, Semin. Nucl. Med. 1989, 19, 309-321.

[0026] A. Ahonen, K. Kairemo, P. Karnani, J. Heikkila, M. Nurmi, M. Teras, O. Lukkarinen, Radioimmunodetection ofProstate Cancer by 1111n-Labeled Monoclonal Antibody Against Prostatic Acid Phosphatase, Acta Oncol. 1993, 32, 723-727.

[0027] G. S. Kilsheimer, B. Axelrod, Inhibition of prostatic acid phosphatase by alpha-hydroxycarboxylic acids, J. Biol. Chem. 1957, 227, 879-890.

[0028] S. A. Beers, C. F. Schwender, D. A. Loughney, E. Malloy, K. Demarest, J. Jordan, Phosphatase inhibitors — III. Benzylaminophosphonic acids as potent inhibitors of human prostatic acid phosphatase, Bioorg. Med. Chem. 1996, 4, 1693-1701.

[0029] C. F. Schwender, S. A. Beers, E. A. Malloy, J. J. Cinicola, D. J. Wustrow, K. D. Demarest, J. Jordan, Benzylphosphonic acid inhibitors of human prostatic acid phosphatase, Bioorg. Med. Chem. Lett. 1996, 6, 311- 314.

[0030] J. K. Myers, T. S. Widlanski, Mechanism-Based Inactivation of Prostatic Acid Phosphatase, Science 1993, 262, 1451-1453.

[0031] A. I. Vovk et al., Bioorg. Med. Chem. Lett. 18 (2008) 4620-4623.

[0032] Leamon, C.P. et al (2006) Bioconjugate Chem., 17, 1226.

[0033] Casi, G. et al (2012) J. Am. Chem. Soc., 134, 5887.

[0034] Bernardes, G.J. et al (2012) Angew. Chem. Int. Ed. Engl., 51 , 941.

[0035] Yang, J. et al (2006) Proc. Natl. Acad. Sci. USA, 103, 13872.

[0036] Doronina S.O. et al (2008) Bioconjugate Chem, 19, 1960.

[0037] Sutherland, M.S.K. (2006) J. Biol. Chem, 281. 10540

[0038] Carl et a.I (1981) J. Med. Chem. 24: 479-480.

[0039] Chakravarty et al (1983) J. Med. Chem. 26: 638-644.

[0040] de Groot, et al (2001) Journal of Organic Chemistry 66 (26): 8815-8830.

[0041] W02005 / 082023

[0042] Bosslet, K. et al. Cancer Res. 58, 1195-1201 (1998).

[0043] Berge et al., in J.Pharm.Sci., 66, 1-19 (1977).

[0044] Gennaro, A. R., ed. (1990) Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing Co.

[0045] Hardman, J. G., Limbird, L. E., and Gilman, A. G., eds. (2001) The Pharmacological Basis of Therapeutics, 10th ed., McGraw-Hill Co.

[0046] CoIowick, S. et al., eds., Methods In Enzymology, Academic Press, Inc.

[0047] Weir, D. M., and Blackwell, C. C., eds. (1986) Handbook of Experimental Immunology, Vols. I -IV, Blackwell Scientific Publications.

[0048] Maniatis, T. et al., eds. (1989) Molecular Cloning: A Laboratory Manual, 2nd edition, Vols. I-III, Cold Spring Harbor Laboratory Press.

[0049] Ausubel, F. M. et al., eds. (1999) Short Protocols in Molecular Biology, 4th edition, John Wiley & Sons.

[0050] Ream et al., eds. (1998) Molecular Biology Techniques: An Intensive Laboratory Course, Academic Press.

[0051] Newton, C. R., and Graham, A., eds. (1997) PCR (Introduction to Biotechniques Series), 2nd ed., Springer Verlag.

[0052] T W Greene and P G M Wuts, "Protective Groups in Organic Synthesis", John Wley and Sons Inc. (1991).

[0053] P.J. Kocienski, "Protecting Groups", Georg Thieme Verlag (1994).

[0054] Wurzer A, Di Carlo D, Schmidt A, et al. Radiohybrid Ligands: A Novel Tracer Concept Exemplified by18F- or 68Ga-Labeled rhPSMA Inhibitors. J NucI Med. 2020;61(5):735-742. doi:10.2967 / jnumed.119.234922

[0055] Wurzer A, Parzinger M, Konrad M, et al. Preclinical comparison of four [18F,natGa]rhPSMA-7 isomers: influence of the stereoconfiguration on pharmacokinetics. EJNMMI Res. 2020; 10(1): 149. Published 2020 Dec 7. doi: 10.1186 / sl 3550-020-00740-z

[0056] Heo YA. Flotufolastat F 18: Diagnostic First Approval. Mol Diagn Ther. 2023;27(5):631-636. doi: 10.1007 / S40291 -023-00665-y

[0057] Fleming MT, Hermsen R, Purysko AS, et al. True-Positive18F-Flotufolastat Lesions in Patients with Prostate Cancer Recurrence with Baseline-Negative Conventional Imaging: Results from the Prospective, Phase 3, Multicenter SPOTLIGHT Study. J Nucl Med. 2024;65(7): 1080-1086. Published 2024 Jul 1. doi:10.2967 / jnumed.123.267271

[0058] Sartor et al. N Engl J Med. 2021 Sep 16;385(12): 1091 -1103

[0059] Kratochwil et al., Journal of Nuclear Medicine December 2016, 57 (12) 1941 -1944

Claims

CLAIMS1. A compound specifically binding Acid Phosphatase 3 (ACP3), the compound having a molecular weight of 5000 Da or less and an ACP3 dissociation constant (K^) of 50 nM or less.

2. The compound according to claim 1 specifically binding to ACP3 on the membrane of tumor cells.

3. The compound according to claim 1 or 2 that is not substantially internalized.

4. The compound according to any one of claims 1 to 3 that shows a higher uptake in one or more tumor(s) than in one or more healthy organ(s) after administration.

5. The compound according to any one of claims 1 to 4 that does not substantially accumulate in kidneys or salivary glands or healthy prostate after administration.

6. The compound according to any one of claims 1 to 5, wherein the compound is as defined in any one of claims 7 to 92.

7. A compound, its individual diastereoisomers, its hydrates, its solvates, its crystal forms, its individual tautomers or a pharmaceutically acceptable salt thereof, wherein the compound structure comprises (i) at least one group R1and at least one group selected from R2and R3, or (ii) at least one group R1, wherein:R1is independently selected from:Q is independently selected from PO3H2, PO2N(R)2, PO2NH2, PO(OH)F, COOH, CON(R)2, SO2N(R)2, SO3H, and SO2NH2; preferably PO3H2, COOH or SO3H; more preferably PO3H2; most preferably PO3H2;A1is independently selected from aryl, heteroaryl, heterocyclyl, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, carbocyclyl, and heterocyclyl; preferably from 6- to 10-membered aryl, 5- to 10-membered heteroaryl, 5- to 10-membered heterocyclyl, C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, C3-5 carbocyclyl, C1-5 heteroalkyl, C2-5 heteroalkenyl, C2-5 heteroalkynyl, and C3-5 heterocyclyl; more preferably from 6- or 10-membered aryl, 5-, 6- or 10-membered heteroaryl containing at least one heteroatom selected from N, O and S, 4- or 5-membered heterocyclyl, C2, C3 or C4 alkyl, C2, C3 or C4 alkenyl, C2, C3 or C4 alkynyl, and C4 or C5 carbocyclyl; most preferably from phenyl, naphthyl, cyclopentyl, pyridyl, and thiophenyl;A2is independently selected from aryl, heteroaryl, heterocyclyl, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, carbocyclyl, and heterocyclyl; preferably from 6- to 10-membered aryl, 5- to 10-membered heteroaryl, 5- to 10-membered heterocyclyl, C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, C3-5 carbocyclyl, C1-5 heteroalkyl, C2-5heteroalkenyl, C2-5 heteroalkynyl, and C3-5 heterocyclyl; more preferably from 6- or 10-membered aryl, 5-, 6- or 10-membered heteroaryl containing at least one heteroatom selected from N, O and S, 4- or 5-membered heterocyclyl, C2, C3 or C4 alkyl, C2, C3 or C4 alkenyl, C2, C3 or C4 alkynyl, and C4 or C5 carbocyclyl; most preferably from phenyl, naphthyl, cyclopentyl, pyridyl, and thiophenyl;X is independently selected from O, -CR(R)-, -CH2-, -CH(Hal)-, -C(Hal)2-, -OCearyl-, -OCi-6alkyl-, -OC2^alenkyl-, -OC2-6alynkyl-, S, -S(O) -, -S(O)2-, -N(R)S(O)2-, -S(O)2(R)-, -N(R)-, -N(R)C(O)-, -C(O)N(R)-, -N(R)C(S)-, -C(S)N(R)-, -C(O)O-, -OC(O)-, -C(S)O-, -OC(S)-, -C(O)S-, -SC(O)-, -C(S)S-, -SC(S)-, -N(R)C(O)O-, -OC(O)N(R)-, -OC(S)N(R)-, -SC(O)N(R)-, -SC(S)N(R)-, - N(R)C(S)O-, -N(R)C(O)S-, -N(R)C(S)S-, -N(R)C(O)N(R)-, and -N(R)C(S)N(R)-, or is absent; preferably from O, -CR(R)-, -C(Hal)2-, -OCearyl-, or is absent; more preferably from O, CH2 and CF2; most preferably O; a1is 0, 1 , 2, 3, 4 or 5; preferably 0, 1 , or 2; more preferably 0 or 1 ; most preferably 0; a2is 0, 1 2, 3, 4 or 5; preferably 0, 1 or 2; more preferably 0 or 1 ; most preferably 1 ; preferably with the proviso that a1+ a2> 1 ; a3is 0, 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10; p is independently 0 or an integer of 1 or more; preferably 0, 1 , 2, 3 or 4; more preferably 0, 1 or 2; most preferably 0; q is independently 0 or an integer of 1 or more; preferably 0, 1 , 2, 3 or 4; more preferably 0, 1 or 2; most preferably 0; each of R1aand R1bis independently selected from OH, halogen, nitro, alkyl, haloalkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heteroaryl, alkyloxy, haloalkyloxy, alkenyloxy, alkynyloxy, heteroalkyloxy, heteroalkenyloxy, heteroalkynyloxy, aryloxy, heteroaryloxy, CN, -C(O)OH, -C(O)Oalkyl, -C(O)N(R)aryl, -C(O)N(R)heteroaryl, -N(R)C(O)aryl, -N(R)C(O)hetero- aryl, -(C(O)N(R))a3R, -(N(R)C(O))a3R, amino, ammonium, dialkylamino, and trialkylammonium, each of which may be optionally substituted, and wherein two or more of R1aor R1bmay be joined together to form a ring; preferably from OH, halogen, nitro, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C2-6 heteroalkyl, C2-6 heteroalkenyl, C2-6 heteroalkynyl, Cearyl, C1-6 alkyloxy, C2-6 alkenyloxy, C2- ealkynyloxy, C1-6 heteroalkyloxy, C1-6 heteroalkenyloxy, C1-6 heteroalkynyloxy, Ce aryloxy, heteroaryloxy, CN, -C(O)OH, -C(O)OCi-6alkyl, -C(O)N(R) Cearyl, -C(O)N(R) heteroaryl, -N(R)C(O)Cearyl, -N(R)C(O)heteroaryl, amino, ammonium, (C1-6alkyl)amino, di(Ci- ealkyljamino, and tri( C1-6alkyl)alkylammonium, each of which may be optionally substituted, and wherein the heteroaryl is a 5- or 6-membered heteroaryl containing at least one heteroatom selected from N, O and S; more preferably from OH, F, Cl, Br, I, nitro, Ci, C2, C3 or C4alkoxy, Ci, C2, C3 or C4haloalkoxy, Cearyloxy, CN, -C(O)OH, -C(O)OCialkyl, -C(O)OC2alkyl, -C(O)OC3alkyl, -C(O)N(R)aryl, -C(O)N(R)halo aryl, -C(O)N(R)(tri(Ci-3alkyl)ammonium)aryl, -C(O)N(R)C5heteroaryl, -C(O)N(R)C5(halo)heteroaryl,-N(R)C(O)aryl, -N(R)C(O)haloaryl, -N(R)C(O)C5heteroaryl, -N(R)C(O)C5(halo)heteroaryl, -N(R)C(O)(tri(Ci-3alkyl) ammonium)C5heteroaryl, and (Ci-3alkyl)3N+, , each of which may be optionally substituted; most preferably from OH, F,18F, Cl, nitro, CH3O-, EtO-, n-PrO-, / -PrO-, CyPrO-, CF3O-, -C(O)OH, -C(O)OCH3, PhO-, [18F]fluoropyridinylcarbonylamino, [18F]fluoropyridinylaminocarbonyl, and MesN+;R2is independently selected from -C(O)(CR(R))riN((CR(R))r2R2a)(CR(R))r3R2b, -C(O)R, -C(O)(CR(R))r4R2c, -C(O)R2d(CR(R))r5R2e, and -C(O)R2fS(O)2R2s;R3is independently selected from C(O)R3a, (CR(R))r6C(O)R3a, C(O)N(R)R3b, C(O)R3c, C(O)N(R)R3d, C(O)NR3eR3f, and NR3eR3f; and each of n , r2, and rs is independently selected from 0, 1 , 2 and 3; preferably from 0, 1 and 2; more preferably 0 or 1 ; most preferably 1 ; each of r4, rs, and re is independently selected from 0, 1 , 2 and 3; preferably from 0, 1 and 2; more preferably 0 or 1 ; most preferably 0; each of R2a, R2b, R2c, R2d, R2e, R2f, R2s, R3a, R3b, R3c, R3d, R3e, and R3fis independently selected from aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkyl and heteroalkyl; preferably from 6- to 10-membered aryl, 5- to 10-membered heteroaryl, (6- to 10-membered aryl)Ci-3alkyl, (5- to 10-membered heteroaryl)Ci-3alkyl, C1-10 alkyl and C1-10 heteroalkyl; more preferably from 6- or 10-membered aryl, and 5-, 6- or 10-membered heteroaryl containing at least one heteroatom selected from N, O and S, linear, branched and / or cyclic C1-6 alkyl, and linear, branched and / or cyclic C1-6 heteroalkyl; most preferably wherein:R2aand R2bare each independently phenyl;R2cis independently selected from phenyl, benzo[b]thiophen-3-yl, 3,4-dihydro-2H- benzo[b][1 ,4]oxazine-2-yl, 2,3-dihydro-4H-benzo[b][1 ,4]oxazine-4-yl, and pyrimidine-4-yl;R2dis independently phenyl;R2eis independently pyrrolidin-1 -yl;R2fis independently phenyl;R29 is independently pyrrolidin-2-yl;R3ais independently phenyl, quinolin-4-yl or isopentyl;R3bis independently phenyl;R3cis independently methyl ;R3dis independently methyl;NR3eR3fis independently selected from morpholine-4-yl, (3-aminooxetan-3-yl)methylamino, (thiazol-2-yl)methylamino, octahydrocyclopenta[c]pyrrole-2-yl, (3-phenyl)oxetan-3-yl)amino, 2,3- dihydrobenzo[f|[1 ,4]oxazepin-4(5 / 7)-yl, ((4 / 7-1 ,2,4-triazol-3-yl)methyl)amino, and bicyclo[1 .1 .1]pentan-1 -ylamino; wherein two or more of R1a, R1 b, R2a. R2b, R2c, R2d, R2e, R2f, R2s, R3a, R3b, R3c, R3d, R3e, and R3fmay be joined together to form a ring;wherein each of R2aand R2bis optionally substituted; preferably optionally substituted by one or more groups independently selected from oxo, OH, halogen, C1-4alkyl, C1-4haloalkyl, C1-4alkyloxy, Ce-ioaryloxy, Ci-eheterocyclyl, (amino)C1-4alkyl, Ci-5heteroaryl, or unsubstituted; more preferably optionally substituted by one or more groups independently selected from oxo, OH, Cl, F, Br, I, t-Bu, CH3, CF3, and CH3O or is unsubstituted; most preferably unsubstituted; wherein R2cis optionally substituted; preferably optionally substituted by one or more groups independently selected from oxo, OH, Halogen, C1-4alkyl, C1-4haloalkyl, C1-4alkyloxy, C1-4alkylthio, or is unsubstituted; more preferably optionally substituted by one or more groups independently selected from oxo, OH, Cl, F, Br, I, t-Bu, CH3, CF3, CH3O and CH3S, or is unsubstituted; most preferably substituted by oxo, Cl, or CH3S, or is unsubstituted; wherein R2dis optionally substituted; preferably optionally substituted by one or more groups independently selected from oxo, OH, halogen, C1-4alkyl, C1-4haloalkyl, C1-4alkyloxy, Ce-ioaryloxy, Ci-eheterocyclyl, 0X0C4- eheterocyclylCi-2alkyl, (amino)C1-4alkyl, Ci-sheteroaryl, or is unsubstituted; more preferably optionally substituted by one or more groups independently selected from oxo, OH, Cl, F, Br, I, t-Bu, CH3, CF3, and CH3O or is unsubstituted; most preferably is unsubstituted; wherein R2eis optionally substituted; preferably optionally substituted by one or more groups independently selected from oxo, OH, halogen, C1-4alkyl, C1-4haloalkyl, C1-4alkyloxy, Ce-ioaryloxy, Ci-eheterocyclyl, (amino)C1-4alkyl, Ci-sheteroaryl, or is unsubstituted; more preferably optionally substituted by one or more groups independently selected from oxo, OH, Cl, F, Br, I, t-Bu, CH3, CF3, and CH3O or is unsubstituted; most preferably substituted by oxo; wherein R2fis optionally substituted; preferably optionally substituted by one or more groups independently selected from oxo, OH, halogen, C1-4alkyl, C1-4haloalkyl, C1-4alkyloxy, Ce-ioaryloxy, Ci-eheterocyclyl, (amino)C1-4alkyl, Ci-sheteroaryl, or unsubstituted, more preferably optionally substituted by one or more groups independently selected from oxo, OH, Cl, F, Br, I, t-Bu, CH3, CF3, and CH3O or is unsubstituted; most preferably substituted by OH; wherein R3ais optionally substituted, preferably optionally substituted by one or more groups independently selected from OH, Halogen, C1-4alkyl, C1-4haloalkyl, C1-4alkyloxy, Ce-ioaryloxy, Ci-eheterocyclyl, (amino)C1-4alkyl, Ci- sheteroaryl, (C1-4alkyl)NRS(O)2-, (C1-4alkenyl)NRS(O)2-, or unsubstituted, more preferably optionally substituted by one or more groups from Cl, F, CH3, F and CH3, CF3, CH3O, PhO, tetrazolyl, and allylNHSO2-, or is unsubstituted,most preferably substituted by F, by Cl, by Cl and F, by 1 / 7-tetrazol-5-yl, by allylNHSO2-, or is unsubstituted; wherein R3bis optionally substituted, preferably optionally substituted by one or more groups independently selected from OH, Halogen, C1-4alkyl, C1-4haloalkyl, C1-4alkyloxy, Ce-ioaryloxy, Ci-eheterocyclyl, (amino)C1-4alkyl, Ci- sheteroaryl, (C1-4alkyl)NRS(O)2-, and (C1-4alkenyl)NRS(O)2-, or unsubstituted; more preferably optionally substituted by one or more groups from F, Cl, CH3, tetrazolyl, and allylNHSO2-, or unsubstituted; most preferably substituted by F, by F and CH3, by CH3 and CH3, by Cl, by Cl and F, by (1 H- tetrazol-5-yl), by allylNHSO2-, or is unsubstituted; wherein R3cis optionally substituted; preferably optionally substituted by one or more groups independently selected from OH, Halogen, C1-4alkyl, C1-4haloalkyl, C1-4alkyloxy, Ce-ioaryloxy, Ci-eheterocyclyl, (amino)C1-4alkyl, Ci-sheteroaryl, or unsubstituted; more preferably optionally substituted by one or more groups independently selected from OH, Halogen, C1-4alkyl, C1-4haloalkyl, C1-4alkyloxy, Ce-ioaryloxy, Ci-eheterocyclyl, (amino)C1-4alkyl, Ci-sheteroaryl, or unsubstituted; most preferably unsubstituted; wherein R3dis optionally substituted; preferably optionally substituted by one or more groups independently selected from OH, Halogen, C1-4alkyl, C1-4haloalkyl, C1-4alkyloxy, Ce-ioaryloxy, Ci-eheterocyclyl, (amino)C1-4alkyl, Ci-sheteroaryl, or unsubstituted; more preferably optionally substituted by one or more groups independently selected from OH, Halogen, C1-4alkyl, C1-4haloalkyl, C1-4alkyloxy, Ce-ioaryloxy, Ci-eheterocyclyl, (amino)C1-4alkyl, Ci-sheteroaryl, or unsubstituted; most preferably unsubstituted;NR3eR3fis optionally substituted; preferably optionally substituted by one or more groups independently selected from OH, Halogen, amino, C1-4alkyl, C1-4haloalkyl, C1-4alkyloxy, optionally substituted Ce-ioaryl, Ce-ioaryloxy, Ci-eheterocyclyl, (amino)C1-4alkyl, Ci-sheteroaryl, or unsubstituted; more preferably optionally substituted by one or more groups independently selected from oxo, OH, Cl, F, Br, I, NH2, NHBoc, phenyl, methylphenyl, benzo, methylbenzo, Ci alkyl, C2 alkyl, C3 alkyl, C4 alkyl, CF3, or is unsubstituted; most preferably substituted by NH2, NHBoc, (4-methyl)phenyl, (4-chloro)phenyl, (4-fluoro-3- methyl)phenyl, methylbenzo, CH3, CH3(CH2)3, or CF3; wherein each R is independently selected from H, OH, halogen, optionally substituted alkyl or optionally substituted alkyloxy; preferably H, OH, halogen, optionally substituted C1-4alkyl and optionally substituted C1-4alkyloxy; more preferably from H, OH, Cl, F, Br, I, t-Bu, CH3, CF3, and CH3O; most preferably H.

8. The compound of claim 7, wherein the shortest path separating the attachment points of R1and of the closest group selected from R2and R3has a length of up to 20 bonds; preferably 2 to 15 bonds; more preferably 6 to 13 bonds; more preferably 8 to 12 bonds most preferably 9 to 11 bonds.

9. The compound of claim 7 or 8, having a structure represented by one of the following formulae:R1- R2, R1- R3,R1- R2 - z , R2- R1- Z R1- R3- ZandR3- R1- Z wherein each J independently represents a moiety, preferably linear, branched or cyclic, comprising 1 to 40; preferably 4 to 30; more preferably 6 to 26; most preferably 8 to 15 non-hydrogen atoms; andZ represents attachment point to the remainder of the molecule.

10. The compound of any one of claims 7-9, wherein the compound structure comprises at least one group independently represented by the following structure:R1— Y— Z wherein:Y is independently selected from:-(CR(R))niCyc1Cyc2(R2)C(O)-,-(CR(R))niRACyc3(CR(R))n3C(R)(NR(R3))(CR(R))n4C(O)-,-(CR(R))niCyc1(CR(R))n2(C(O))0_-|-,-(CR(R))niCyc1(CR(R))b’C(R)(NR(R2))C(O)-,-(CR(R))niCyc1(CR(R))n4C(R)( (CR(R))n3NR(R2))C(O)-,-(CR(R))niCyc1(CR(R))n2-, -(CR(R))niCyc1(CR(R))n2C(O)-, -(CR(R))niCyc1(CR(R))n2(C(O))0_i-, -(CR(R))niCyc1Cyc2(C(O)R2)C(O)-,-(CR(R))niCyc1(CR(R))a’N(R2)CR(R)C(O)-,-(CR(R))niCyc1(C(R)2)i-3N(C(O)R2)C(R)2C(O)-,-(CR(R))niCyc1(C(R)2)i-3NR(C(O)R2)C(O)-,-(CR(R))niRACyc3(CR(R))n3C(R)((CR(R))n4R3)NR(C(0))o-i(CR(R))n5(C(0))o-i-j-(CR(R))niRACyc3(CR(R))n3C(R)((CR(R))n4R3)NR- -(CR(R))niRACyc3(CR(R))n3C(R)(C(O)R3)(CR(R))n4NRC(O)(CR(R))n5C(O)- -(CR(R))niCyc1Cyc3(CR(R))n3C(R)(NR(R3))(CR(R))n4C(O)-, and -(CR(R))niCyc1Cyc3(CR(R))n3C(R)((CR(R))n4R3)NR(C(0))o-i(CR(R))n5(C(0))o-i-;preferably selected from: -(CR(R))mCyc1Cyc2(R2)C(O)-, and -(CR(R))mRACyc3(CR(R))n3C(R)(NR(R3))(CR(R))n4C(O)-; more preferably selected from -(CR(R))niCyc1Cyc2(R2)C(O)- and -(CR(R))niRACyc3(CR(R))n3C(R)(NR(R3))(CR(R))n4C(O)-; most preferably -(CR(R))niCyc1Cyc2(R2)C(O)-; wherein each of Cyc1and Cyc2is independently selected from carbocyclyl, heterocyclyl, alkyl, oxoalkyl, heteroalkyl and oxoheteroalkyl; preferably wherein Cyc1is independently selected from C5-10 carbocyclyl, and 5- to 10- membered heterocyclyl, NRC(O), and C(O)NR; more preferably Cearyl, C10 aryl, 5-membered heteroaryl, 6-membered heteroaryl, NHC(O), and C(O)NH; most preferably tetrazolyl or triazolyl, preferably wherein Cyc2is selected from 4- to 6-membered heterocyclyl, NRC(O), and C(O)NR; more preferably 4-, 5- or 6-membered heterocyclyl comprising at least one N; most preferably pyrrolidinyl; wherein Cyc3is independently selected from carbocyclyl and heterocyclyl; preferably independently selected from C^io carbocyclyl, Ce-io aryl, 5- to 10-membered heterocyclyl, and 5- to 10-membered heteroaryl; more preferably Cearyl, C10 aryl, 5-membered heteroaryl, and 6-membered heteroaryl; most preferably phenyl; wherein RAis independently selected form -C=C-, -C(R)2, -C(R)2C(R)2-, -C(R)2C(O)-, -C(O)C(R)2-, - N=CR-, -CR=N-, -SC(R)2-, -C(R)2S-, -OC(R)2-, -C(R)2O-, -C(R)2CR(OH)-, -CR(OH)C(R)2-, - NHC(O)-, -NRC(O)-, -NHC(O)-, -NRC(O)-, C^io carbocyclyl, Ce-io aryl, 5- to 10-membered heterocyclyl, and 5- to 10-membered heteroaryl; preferably from -CEC-, Cearyl, Cioaryl, 5-membered heteroaryl, and 6-membered heteroaryl; more preferably from -CEC-, phenyl, and triazolyl; most preferably -CEC-; m is independently 0, 1 or 2; preferably 1 ; n2 is independently 0, 1 , 2, 3, 4, 5, 6, 7, or 8; preferably 0, 1 , 2, 3, 4, 5, or 6; more preferably 2; n3is independently 0, 1 or 2; preferably 0 or 1 ; more preferably 1 ; n4is independently 0, 1 or 2; preferably 0 or 1 ; more preferably 0; ns is independently 0, 1 , 2, 3, 4, 5, 6, 7 or 8; preferably 0, 1 , 2, 3, or 4; more preferably 4; each of a’ and b’ is independently 1 , 2 or 3; preferably 1 or 2; more preferably 1 ; andZ represents attachment point to the remainder of the molecule.11 . The compound of any one of claims 7-10, wherein R1-Y-Z is independently selected form the following structures:wherein: m is independently 0, 1 or 2; preferably 1 ; n2 is independently 0, 1 , 2, 3, 4, 5, 6, 7, or 8; preferably 0, 1 , 2, 3, 4, 5, or 6; more preferably 2; ns is independently 0, 1 or 2; preferably 0 or 1 ; more preferably 1 ; n4 is independently 0, 1 or 2; preferably 0 or 1 ; more preferably 0; ns is independently 0, 1 , 2, 3, 4, 5, 6, 7, or 8; preferably 0, 1 , 2, 3, or 4; more preferably 4; each of a and b is 0, 1 or 2; preferably with the proviso that a + b is s 1 and s 3; more preferably wherein each of a and b is 1 ; and wherein each of V1, V2, V3V4, and V5is independently selected from carbon and a heteroatom; preferably O, S or N, and wherein one of V1, V2, V3V4, and V5can be absent.

12. The compound of any one of claims 7-11 , wherein R1-Y-Z is independently represented by one of the following structures:

13. The compound of any one of claims 7-12, wherein R1-Y-Z is independently represented by the following structure:

14. The compound of any one of claims 7-13, wherein R1-Y-Z is independently represented by any of the following structures:p y15. The compound of any one of claims 7-14, wherein R1-Y-Z is independently represented by the following structures:

16. The compound of any one of claims 7-15, wherein R1-Y-Z is independently represented by any of the following structures:

17. The compound of any one of claims 7-16, wherein R1-Y-Z is independently represented by any of the following structures:

18. The compound of any one of claims 7-17, wherein R1is independently selected from:wherein each of V1, V2and V3is independently selected from CH and a heteroatom; preferably O, S or N; and wherein one of V1, V2and V3can be absent.

19. The compound of any one of claims 7-18, wherein R1is independently selected from:

20. The compound of any one of claims 7-19, wherein R1is independently selected from:wherein each A1’ and A2’ independently represents aryl; preferably Ce-ioaryl; more preferably phenyl or naphthyl; most preferably phenyl.21 . The compound of any one of claims 7-20, wherein R1is independently selected from:

22. The compound of any one of claims 7-21 , wherein R1is independently selected from:

23. The compound of any one of claims 7-22, wherein:(a) X is bound to A1or A1’ at a 4- or 3-position relative to the attachment point of the (CR(R))mor CH(PO3H2) group bound to A1or A1’; and / or(b) X is bound to A2or A2’ a 3-position relative to the attachment point of the (CR(R))nor CR(R) group bound to A2or A2’.

24. The compound of any one of claims 7-23, wherein R1is independently selected from:The compound of any one of claims 7-24, wherein R1is26. The compound of any one of claims 7-25, wherein R1is independently selected from:(27. The compound of any one of claims 7-26, wherein R1is28. The compound of any one of claims 7-27, wherein R1is selected from:

29. The compound of any one of claims 7-28, wherein R2is represented by:each of R^a, R2banc| R2C jsindependently defined as for R^a; each of Daand Dbis independently selected from 6-membered aryl, and 5- or 6-membered heteroaryl containing at least one heteroatom selected from N, O and S, preferably from pyrrole, furane, thiophene, phenyl, thiazolyl, and pyridinyl; each of s and t is independently 0, 1 , 2, 3, 4, or 5; preferably 0 or 1 ; more preferably 0; and each of n, r2, and ra is independently selected from 0, 1 , 2 and 3; preferably from 1 and 2; more preferably 1 .

30. The compound of any one of claims 7-29, wherein R2is represented by a structure selected from:optionally wherein at least one atom of the structure is a radioisotope; preferably a radioisotope selected from11C,11mN,16F,18F; more preferably18F.The compound of any one of claims 7-30, wherein R2is represented32. The compound of any one of claims 7-31 , wherein R3is represented by:wherein u is 0, 1 , 2, 3, 4 or 5; preferably 1 or 2; more preferably 2; each of R3a' and R3a" is independently as defined above for R3a.The compound of any one of claims 7-32, wherein R3is represented by:wherein v is 0, 1 , 2, 3, 4 or 5; preferably 0 or 1 ; more preferably 1 ; andR3b' is independently as defined for R3b.

34. The compound of any one of claims 7-33, wherein R3is represented by a structure selected from:optionally wherein at least one atom of the structure is a radioisotope; preferably a radioisotope selected from11C,11mN,16F,18F; more preferably18F; most preferably wherein the structure is selected from:

35. The compound of any one of claims 7-34, wherein R3is represented by:Cg alkyl) (C^Cg heteroalkyl); p y; more preferablywherein w is 0, or an integer equal to or smaller than the total number of H atoms in the C1 -6 alkyl or heteroalkyl group; preferably 0, 1 , 2, or 3; more preferably 0; andR3c’ is independently as defined for R3c.

36. The compound of any one of claims 7-35, wherein R3is represented by a structure selected from:optionally wherein at least one atom of the structure is a radioisotope; preferably a radioisotope selected from11C,11mN,16F,18F; more preferably18F; most preferably wherein the structure is selected from:optionally wherein at least one atom of the structure is a radioisotope; preferably a radioisotope selected from11C,11mN,16F,18F; more preferably18F.

39. The compound of claim 38, wherein R1-Y-Z is represented40. The compound of any one of claims 7-39, wherein R1-Y-Z is independently selected form the following structures:541 . The compound of any one of claims 7-40, wherein R1-Y-Z is independently selected form thestructures A-1 to A-30 or A-31 to A-42 as defined in the description.

42. A compound, its individual diastereoisomers, its hydrates, its solvates, its crystal forms, its individual tautomers or a pharmaceutically acceptable salt thereof, wherein the compound structure comprises at least one group independently represented by the following structure:R1— Y— Z wherein:Y is independently selected from:-(CR(R))niCyc1Cyc2(R2)C(O)-,-(CR(R))niRACyc3(CR(R))n3C(R)(NR(R3))(CR(R))n4C(O)-, and-(CR(R))niCyc1(CR(R))n2(C(O))0_i-,Cyc1is independently selected from C^io carbocyclyl, 5- to 10-membered heterocyclyl, NRC(O), and C(O)NR;Cyc2is independently selected from 4- to 6-membered heterocyclyl;Cyc3is independently selected from C5-10 carbocyclyl, C6-10 aryl, 5- to 10-membered heterocyclyl, and 5- to 10-membered heteroaryl;RAis independently selected form -C = C-, Cearyl, Cioaryl, 5-membered heteroaryl, and 6-membered heteroaryl; m is independently 0, 1 or 2; n2 is independently 0, 1 or 2; ns is independently 0, 1 or 2; n4 is independently 0, 1 or 2; ns is independently 0, 1 , 2, 3, 4, 5, 6, 7 or 8; each of a’ and b' is independently 1 , 2 or 3;R1is independently selected from:A1is independently selected from 6- to 10-membered aryl, 5- to 10-membered heteroaryl, 5- to 10- membered heterocyclyl, C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, C3-5 carbocyclyl, C1-5 heteroalkyl, C2-5 heteroalkenyl, C2-5 heteroalkynyl, and C3-5 heterocyclyl;A2is independently selected from 6- to 10-membered aryl, 5- to 10-membered heteroaryl, 5- to 10- membered heterocyclyl, C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, C3-5 carbocyclyl, C1-5 heteroalkyl,C2-5 heteroalkenyl, C2-5 heteroalkynyl, and C3-5 heterocyclyl;X is independently selected from O, -CR(R)-, -C(Hal)2-, -OCearyl-, or is absent; more preferably from O, CH2 and CF2; most preferably O; a1is independently 0, 1 , or 2; a2is independently 0, 1 or 2; with the proviso that a1+ a2> 1 ; p is independently 0, 1 , 2, 3 or 4; q is independently 0, 1 , 2, 3 or 4; each of R1aand R1 bis independently selected from OH, halogen, nitro, C1-6 alkyl, C1-6 haloalky I, C2-6 alkenyl, C2-6 alkynyl, C2-6 heteroalkyl, C2-6 heteroalkenyl, C2-6 heteroalkynyl, Cearyl, C1-6 alkyloxy, C2-6 alkenyloxy, C2-ealkynyloxy, C1-6 heteroalkyloxy, C1-6 heteroalkenyloxy, Ci-e heteroalkynyloxy, Ce aryloxy, heteroaryloxy, and CN, -C(O)OH, and -C(O)OCi-ealkyl, each of which may be optionally substituted, and wherein the heteroaryl is a 5- or 6-membered heteroaryl containing at least one heteroatom selected from N, O and S;R2is independently selected from -C(O)(CR(R))riN((CR(R))r2R2a)(CR(R))r3R2b, -C(O)R, -C(O)(CR(R))r4R2c, -C(O)R2d(CR(R))r5R2e, and -C(O)R2fS(O)2R29;R3is independently selected from C(O)R3a, (CR(R))r6C(O)R3a, C(O)N(R)R3b, C(O)R3c, C(O)N(R)R3d, C(O)NR3eR3f, and NR3eR3f; each of n , r2, and rs is independently selected from 0, 1 and 2; each of R, rs, and re is independently selected from 0, 1 and 2; each of R2a’ R2b, R2c, R2d, R2e, R2f, R2s, R3a, R3b, R3c, R3d, R3e, and R3fis independently selected from 6- to 10-membered aryl, 5- to 10-membered heteroaryl, (6- to 10-membered ary l)Ci-3alkyl, (5- to 10-membered heteroaryl)Ci-3alkyl, C1-10 alkyl and C1-10 heteroalkyl; wherein two or more of R1a. R1 b,R2a. R2b, R2c, R2d, R2e, R2f, R2s, R3a, R3b, R3c, R3d, R3a, and R3fmay be joined together to form a ring; wherein each of R2aand R2bis optionally substituted by one or more groups independently selected from oxo, OH, halogen, C1-4alkyl, C1-4haloalkyl, C1-4alkyloxy, Ce-ioaryloxy, Ci-eheterocyclyl, (amino)Ci^ialkyl, Ci-sheteroaryl, or unsubstituted; wherein R2cis optionally substituted by one or more groups independently selected from oxo, OH, Halogen, Chalky I, C1-4haloalkyl, C1-4alkyloxy, C1-4alkylthio, or is unsubstituted; wherein R2dis optionally substituted by one or more groups independently selected from oxo, OH, halogen, Ci-4alkyl, C1-4haloalkyl, C1-4alkyloxy, Ce-ioaryloxy, Ci-eheterocyclyl, oxoC4-eheterocyclylCi-2alkyl, (amino)C1-4alkyl, Ci-sheteroaryl, or is unsubstituted; wherein R2eis substituted by one or more groups independently selected from oxo, OH, halogen, C1-4alkyl, C1-4haloalkyl, C1-4alkyloxy, Ce-ioaryloxy, Ci-eheterocyclyl, (amino)C1-4alkyl, Ci-sheteroaryl, or is unsubstituted; wherein R2fis substituted by one or more groupsindependently selected from oxo, OH, halogen, C1-4alkyl, C1-4haloalkyl, C1-4alkyloxy, Ce-ioaryloxy, C1-6heterocyclyl, (amino)C1-4alkyl, Ci-5heteroaryl, or unsubstituted; wherein R3ais optionally substituted by one or more groups independently selected from OH, Halogen, C1-4alkyl, C1-4haloalkyl, C1-4alkyloxy, Ce-ioaryloxy, Ci-eheterocyclyl, (amino)C1-4alkyl, Ci-5heteroaryl, (C1-4alkyl)NRS(O)2-, (C1-4alkenyl)NRS(O)2-, or unsubstituted; wherein R3bis optionally substituted by one or more groups independently selected from OH, Halogen, C1-4alkyl, C1-4haloalkyl, C1-4alkyloxy, Ce-ioaryloxy, Ci-eheterocyclyl, (amino)C1-4alkyl, Ci-sheteroaryl, (C1-4alkyl)NRS(O)2-, and (C1-4alkenyl)NRS(O)2-, or unsubstituted; wherein R3cis optionally substituted by one or more groups independently selected from OH, Halogen, C1-4alkyl, C1-4haloalkyl, C1-4alkyloxy, Ce-ioaryloxy, Ci-eheterocyclyl, (amino)C1-4alkyl, Ci-sheteroaryl, or unsubstituted; most preferably unsubstituted; wherein R3dis optionally substituted by one or more groups independently selected from OH, Halogen, C1-4alkyl, C1-4haloalkyl, C1-4alkyloxy, Ce-ioaryloxy, Ci-eheterocyclyl, (amino)C1-4alkyl, Ci-sheteroaryl, or unsubstituted; most preferably unsubstituted;NR3eR3fis optionally substituted by one or more groups independently selected from OH, Halogen, amino, C1-4alkyl, C1-4haloalkyl, C1-4alkyloxy, optionally substituted Ce-ioaryl, Ce-ioaryloxy, Ci-eheterocyclyl, (amino)C1-4alkyl, Ci-sheteroaryl, or unsubstituted; wherein each R is independently selected from H, OH, halogen, optionally substituted C1-4alky I and optionally substituted C1-4alkyloxy; andZ represents attachment point to the remainder of the molecule.

43. The compound of any one of claims 7-42, wherein:Cyc1is independently selected from Cearyl, C10 aryl, 5-membered heteroaryl, 6-membered heteroaryl, NHC(O), and C(O)NH;Cyc2is independently selected from 4-, 5- or 6-membered heterocyclyl comprising at least one N;Cyc3is independently selected from Cearyl, C10 aryl, 5-membered heteroaryl, and 6-membered heteroaryl;RAis independently selected form -C = C-, phenyl, and triazolyl; m is 1 ; n2 is 2; ns is 1 ; m is 0; ns is 4; n’ is independently 0, 1 , 2, 3 or 4; n” is 2; X’ is independently selected from O, and C(O)NH; each of a’ and b’ is 1 ;A1is independently selected from 6- or 10-membered aryl, 5-, 6- or 10-membered heteroaryl containing at least one heteroatom selected from N, O and S, 4- or 5-membered heterocyclyl, C2, C3 or C4 alkyl, C2, C3 or C4 alkenyl, C2, C3 or C4 alkynyl, and C4 or Cs carbocyclyl;A2is independently selected from 6- or 10-membered aryl, 5-, 6- or 10-membered heteroaryl containing at least one heteroatom selected from N, O and S, 4- or 5-membered heterocyclyl, C2, C3 or C4 alkyl, C2, C3 or C4 alkenyl, C2, C3 or C4 alkynyl, and C4 or Cs carbocyclyl;X is independently selected from O, CH2 and CF2;a1is independently 0 or 1 ; a2is independently 0 or 1 ; with the proviso that a1+ a2S 1 ; p is independently 0, 1 or 2; q is independently 0, 1 or 2; each of R1aand R1 bis independently selected from OH, F, Cl, Br, I , nitro, Ci, C2, C3 or C4alkoxy, Ci, C2, C3 or C4 haloalkoxy, Cearyloxy, CN, -C(O)OH, -C(O)OCialkyl, -C(O)OC2alkyl and -C(O)OC3alkyl, each of which may be optionally substituted;R2is independently selected from -C(O)(CR(R))riN((CR(R))r2R2a)(CR(R))r3R2b, -C(O)R, -C(O)(CR(R))r4R2c, -C(O)R2d(CR(R))r5R2e, and -C(O)R2fS(O)2R29;R3is independently selected from C(O)R3a, (CR(R))r6C(O)R3a, C(O)N(R)R3b, C(O)R3c, C(O)N(R)R3d, C(O)NR3eR3f, and NR3eR3f; each of n , r2, and rs is independently 0 or 1 ; each of r4, rs, and re is independently 0 or 1 ; each of R2a’ R2b, R2c, R2d, R2e, R2f, R2s, R3a, R3b, R3c, R3d, R3e, and R3fis independently selected from 6- or 10-membered aryl, and 5-, 6- or 10-membered heteroaryl containing at least one heteroatom selected from N, O and S, linear, branched and / or cyclic C1-6 alkyl, and linear, branched and / or cyclic C1-6 heteroalkyl; wherein two or more of R1a. R1 b,R2a. R2b, R2c, R2d, R2e, R2f, R2s, R3a, R3b, R3c, R3d, R3a, and R3fmay be joined together to form a ring; wherein each of R2aand R2bis optionally substituted by one or more groups independently selected from oxo, OH, Cl, F, Br, I, t-Bu, CH3, CF3, and CH3O or is unsubstituted; wherein R2cis optionally substituted by one or more groups independently selected from oxo, OH, Cl, F, Br, I, t-Bu, CH3, CF3, CH3O and CH3S, or is unsubstituted; wherein R2dis optionally substituted by one or more groups independently selected from oxo, OH, Cl, F, Br, I, t-Bu, CH3, CF3, and CH3O or is unsubstituted; wherein R2eis substituted by one or more groups independently selected from oxo, OH, Cl, F, Br, I, t-Bu, CH3, CF3, and CH3O or is unsubstituted; wherein R2fis substituted by one or more groups independently selected from oxo, OH, Cl, F, Br, I, t-Bu, CH3, CF3, and CH3O or is unsubstituted; wherein R3ais optionally substituted by one or more groups independently selected from Cl, F, CH3, F and CH3, CF3, CH3O, PhO, tetrazolyl, and allylNHSO2-, or is unsubstituted; wherein R3bis optionally substituted by one or more groups independently selected from F, Cl, CH3 tetrazolyl, and allylNHSO2-, or unsubstituted; wherein R3cis optionally substituted by one or more groups independently selected from OH, Halogen, C1-4alkyl, C1-4haloalkyl, C1-4alkyloxy, Ce-ioaryloxy, Ci-eheterocyclyl, (amino)C1-4alkyl, Ci-5heteroaryl, or unsubstituted; wherein R3dis optionally substituted by one or more groups independently selected from OH, Halogen, C1-4alkyl, C1-4haloalkyl, C1-4alkyloxy, Ce-ioaryloxy, Ci-eheterocyclyl, (amino)C1-4alkyl, Ci-sheteroaryl, or unsubstituted;NR3eR3fis optionally substituted by one or more groups independently selected from oxo, OH, Cl, F, Br, I, NH2, NHBoc, phenyl, methylphenyl, benzo, methylbenzo, Ci alkyl, C2 alkyl, C3 alkyl, C4 alkyl, CF3, or is unsubstituted; and wherein each R is independently selected from H, OH, Cl, F, Br, I, t-Bu, CH3, CF3, and CH3O.

44. The compound of claim 42, wherein:Cyc1is independently selected from Cearyl, C10 aryl, 5-membered heteroaryl, 6-membered heteroaryl, NHC(O), and C(O)NH;Cyc2is independently selected from 4-, 5- or 6-membered heterocyclyl comprising at least one N;Cyc3is independently selected from Cearyl, C10 aryl, 5-membered heteroaryl, and 6-membered heteroaryl;RAis independently selected form -C = C-, phenyl, and triazolyl; m is 1 ; n2 is 2; ns is 1 ; m is 0; ne is 4; n’ is independently 0, 1 , 2, 3 or 4; n” is 2; X’ is independently selected from O, and C(O)NH; each of a’ and b’ is 1 ;A1is independently selected from 6- or 10-membered aryl, 5-, 6- or 10-membered heteroaryl containing at least one heteroatom selected from N, O and S, 4- or 5-membered heterocyclyl, C2, C3 or C4 alkyl, C2, C3 or C4 alkenyl, C2, C3 or C4 alkynyl, and C4 or C5 carbocyclyl;A2is independently selected from 6- or 10-membered aryl, 5-, 6- or 10-membered heteroaryl containing at least one heteroatom selected from N, O and S, 4- or 5-membered heterocyclyl, C2, C3 or C4 alkyl, C2, C3 or C4 alkenyl, C2, C3 or C4 alkynyl, and C4 or C5 carbocyclyl;X is independently selected from O, CH2 and CF2; a1is independently 0 or 1 ; a2is independently 0 or 1 ; with the proviso that a1+ a2S 1 ; p is independently 0, 1 or 2; q is independently 0, 1 or 2; each of R1aand R1bis independently selected from OH, F, Cl, Br, I, nitro, Ci, C2, C3 or C4alkoxy, Ci, C2, C3 or C4 haloalkoxy, Cearyloxy, CN, -C(O)OH, -C(O)OCialkyl, -C(O)OC2alkyl and -C(O)OC3alkyl, each of which may be optionally substituted;R2is independently selected from -C(O)(CR(R))riN((CR(R))r2R2a)(CR(R))r3R2b, -C(O)R, -C(O)(CR(R))r4R2c, -C(O)R2d(CR(R))r5R2e, and -C(O)R2fS(O)2R29;R3is independently selected from C(O)R3a, (CR(R))r6C(O)R3a, C(O)N(R)R3b, C(O)R3c, C(O)N(R)R3d, C(O)NR3eR3f, and NR3eR3f; each of n, r2, and rs is independently 0 or 1 ; each of r4, rs, and re is independently 0 or 1 ; each of R2a’ R2b, R2c, R2d, R2e, R2f, R2s, R3a, R3b, R3c, R3d, R3e, and R3fis independently selected from 6- or 10-membered aryl, and 5-, 6- or 10-membered heteroaryl containing at least one heteroatom selected from N, O and S, linear, branched and / or cyclic C1-6 alkyl, and linear, branched and / or cyclic C1-6 heteroalkyl; wherein two or more of R1a’ R1b,R2a’ R2b, R2c, R2d, R2e, R2f, R2s, R3a, R3b, R3c, R3d, R3e, and R3fmaybe joined together to form a ring; wherein each of R2aand R2bis optionally substituted by one or more groups independently selected from oxo, OH, Cl, F, Br, I, t-Bu, CH3, CF3, and CH3O or is unsubstituted; wherein R2cis optionally substituted by one or more groups independently selected from oxo, OH, Cl, F, Br, I, t-Bu, CH3, CF3, CH3O and CH3S, or is unsubstituted; wherein R2dis optionally substituted by one or more groups independently selected from oxo, OH, Cl, F, Br, I, t-Bu, CH3, CF3, and CH3O or is unsubstituted; wherein R2eis substituted by one or more groups independently selected from oxo, OH, Cl, F, Br, I, t-Bu, CH3, CF3, and CH3O or is unsubstituted; wherein R2fis substituted by one or more groups independently selected from oxo, OH, Cl, F, Br, I, t-Bu, CH3, CF3, and CH3O or is unsubstituted; wherein R3ais optionally substituted by one or more groups independently selected from Cl, F, CH3, F and CH3, CF3, CH3O, PhO, tetrazolyl, and allylNHSO2-, or is unsubstituted; wherein R3bis optionally substituted by one or more groups independently selected from F, Cl, CH3 tetrazolyl, and allylNHSO2-, or unsubstituted; wherein R3cis optionally substituted by one or more groups independently selected from OH, Halogen, C1-4alkyl, C1-4haloalkyl, C1-4alkyloxy, Ce-ioaryloxy, Ci-eheterocyclyl, (amino)C1-4alkyl, Ci-5heteroaryl, or unsubstituted; wherein R3dis optionally substituted by one or more groups independently selected from OH, Halogen, C1-4alkyl, C1-4haloalkyl, C1-4alkyloxy, Ce-ioaryloxy, Ci-eheterocyclyl, (amino)C1-4alkyl, Ci-sheteroaryl, or unsubstituted;NR3eR3fis optionally substituted by one or more groups independently selected from oxo, OH, Cl, F, Br, I, NH2, NHBoc, phenyl, methylphenyl, benzo, methylbenzo, Ci alkyl, C2 alkyl, C3 alkyl, C4 alkyl, CF3, or is unsubstituted; and wherein each R is independently selected from H, OH, Cl, F, Br, I, t-Bu, CH3, CF3, and CH3O.

45. The compound of any one of claims 7-44, wherein R1-Y-Z is independently selected form the following structures:wherein each of a and b is 0, 1 or 2, with the proviso that a + b is s 1 and £ 3.

46. The compound of any one of claims 7-45, wherein R1is independently selected from:wherein each of V1, V2and V3is independently selected from CH and a heteroatom,5 preferably O, S or N, and wherein one of V1, V2and V3can be absent;47. The compound of any one of claims 7-46, wherein R2is represented by:(a), wherein: each of R2a' and R2b' is independently defined as for R2a;each of s and t is independently 0, 1 , 2, 3, 4, or 5; preferably 0 or 1 ; more preferably 0; andeach of n, r2, and ra is independently selected from 0, 1 , 2 and 3; preferably from 1 and 2; more preferably 1 ; or48. The compound of any one of claims 7-47, wherein R3is represented by:wherein u is 0, 1 , 2, 3, 4 or 5; preferably 1 or 2; more preferably 2; and v is 0, 1 , 2, 3, 4 or 5; preferably 0 or 1 ; more preferably 1 ; orwherein each of R3a’ and R3a” is independently as defined for R3a; andR3b' is independently as defined for R3b; or49. The compound of any one of claims 7-48, wherein R1-Y-Z is independently selected form the following structures:

50. The compound of any one of claims 7-49, wherein R1-Y-Z is independently represented by A-7:51 . A compound, its individual diastereoisomers, its hydrates, its solvates, its crystal forms, its individual tautomers or a pharmaceutically acceptable salt thereof, wherein the compound has a structure represented by the following structure :R1— Y — B - C wherein R1is as defined in any one of the preceding claims;Y is as defined in any one of the preceding claims or is absent;B is a linker; and each C is an atom, a molecule or a particle, and / or is a therapeutic or diagnostic agent.

52. The compound of claim 51 , wherein R1is as defined in any one of claims 42to 50.

53. A compound, its individual diastereoisomers, its hydrates, its solvates, its crystal forms, its individual tautomers or a pharmaceutically acceptable salt thereof, wherein the compound has a structure c represented by the following structure:R1— B — cB is a linker; and each C is an atom, a molecule or a particle, and / or is a therapeutic or diagnostic agent.

54. The compound of any one of claims 51-53, wherein B is a single bond or an optionally substituted C-| -5Q aliphatic group, in which optionally one or more carbon atoms can be replaced by heteroatom, a C3_-|2 carbocyclic or a C 2 heterocyclic group, and which can be saturated or optionally contain one or more double or triple bonds.

55. The compound of any one of claims 51-54, wherein B is a single bond.

56. The compound of any one of claims 51 to 54, wherein B is represented by any of the following generalFormulae II— V:wherein each x is 0, 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10; each y is 0, 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10; each z is 0, 1 , 2, 3 or 4; preferably 1 ; preferably with the proviso that at least one of x and y is not 0;* represents a point of attachment to a moiety R1-Y- or R1-;• represents a point of attachment to a moiety C; and each of BSand B[_ is independently selected from alkylene, cycloalkylene, arylalkylene, heteroarylalkylene, heteroalkylene, heterocycloalkylene, alkenylene, cycloalkenylene, arylalkenylene, heteroarylalkenylene, heteroalkenylene, heterocycloalenkylene, alkynylene, heteroalkynylene, arylene, heteroarylene, aminoacyl, oxyalkylene, aminoalkylene, diacid ester, dialkylsiloxane, amide, thioamide, thioether, thioester, ester, carbamate, hydrazone, thiazolidine, methylene alkoxy carbamate, disulfide, vinylene, imine, imidamide, phosphoramide, saccharide, phosphate ester, phosphoramide, carbamate, dipeptide, tripeptide, tetrapeptide, hexapeptide, heptapeptide, octapeptide, nonapeptide, and decapeptide, wherein the peptides longer than a dipeptide may be cyclic, and wherein each of the preceding is optionally substituted.

57. The compound of any one of claims 51to 54, wherein B is represented by (Bs)xwherein: each x is selected from 0, 1 , 2, 3, 4, 5, 6, 7, 8, 9 and 10; each Bs is independently selected from the group consisting of alkylene, cycloalkylene, arylalkylene, heteroarylalkylene, heteroalkylene, heterocycloalkylene, alkenylene, cycloalkenylene, arylalkenylene, heteroarylalkenylene, heteroalkenylene, heterocycloalenkylene, alkynylene, heteroalkynylene, arylene, heteroarylene, aminoacyl, oxyalkylene, aminoalkylene, diacid ester, dialkylsiloxane, amide, thioamide, thioether, thioester, ester, carbamate, hydrazone, thiazolidine, methylene alkoxy carbamate, disulfide, vinylene, imine, imidamide, phosphoramide, saccharide, phosphate ester, phosphoramide, carbamate, dipeptide, tripeptide, tetrapeptide, hexapeptide, heptapeptide, octapeptide, nonapeptide, and decapeptide, wherein the peptides longer than a dipeptide may be cyclic.

58. The compound of claim 52, wherein B is:(a) a single bond or an optionally substituted C-| _5Q aliphatic group, in which optionally one ormore carbon atoms can be replaced by heteroatom, a carbocyclic or a C-|_-|2 heterocyclic group, and which can be saturated or optionally contain one or more double or triple bonds;(b) represented by any of the following general Formulae II— V:wherein each x is 0, 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10; each y is 0, 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10; each z is 0, 1 , 2, 3 or 4; preferably 1 ; preferably with the proviso that at least one of x and y is not 0;* represents a point of attachment to a moiety R1-Y- or R1-;• represents a point of attachment to a moiety C; and each of Bg and B|_ is independently selected from alkylene, cycloalkylene, arylalkylene, heteroarylalkylene, heteroalkylene, heterocycloalkylene, alkenylene, cycloalkenylene, arylalkenylene, heteroarylalkenylene, heteroalkenylene, heterocycloalenkylene, alkynylene, heteroalkynylene, arylene, heteroarylene, aminoacyl, oxyalkylene, aminoalkylene, diacid ester, dialkylsiloxane, amide, thioamide, thioether, thioester, ester, carbamate, hydrazone, thiazolidine, methylene alkoxy carbamate, disulfide, vinylene, imine, imidamide, phosphoramide, saccharide, phosphate ester, phosphoramide, carbamate, dipeptide, tripeptide, tetrapeptide, each of which is optionally substituted; or(c) represented by (Bs)xwherein: each x is selected from 0, 1 , 2, 3, 4, 5, 6, 7, 8, 9 and 10; each Bs is independently selected from the group consisting of alkylene, cycloalkylene, arylalkylene, heteroarylalkylene, heteroalkylene, heterocycloalkylene, alkenylene, cycloalkenylene, arylalkenylene, heteroarylalkenylene, heteroalkenylene, heterocycloalenkylene, alkynylene, heteroalkynylene, arylene, heteroarylene, aminoacyl, oxyalkylene, aminoalkylene, diacid ester, dialkylsiloxane, amide, thioamide, thioether, thioester, ester, carbamate, hydrazone, thiazolidine, methylene alkoxy carbamate, disulfide, vinylene, imine, imidamide, phosphoramide, saccharide, phosphate ester, phosphoramide, carbamate, dipeptide, tripeptide, tetrapeptide.

59. The compound of any one of claims 56 to 58, wherein each Bg and B[_ is independently selectedfrom:each n is independently 0, 1 , 2, 3, 4, 5, 6, 7, or 8; each m is independently 0, 1 , 2, 3, or 4; each Rc, R^, and Reis independently selected from H, optionally substituted C-| _g alkyl, (C3-1 Q carbocyclyl)C-|_g alkyl, (Cg_-|Q aryl)C-|_g alkyl, (C-|_-| Q heterocyclyl)C-|_g alkyl, C2~g alkenyl, C2-6 alkynyl, and Cg--| Q aryl, in each of which optionally one or more of the carbon atoms can be replaced by heteroatoms; preferably selected from side-chain residues of proteinogenic or a non- proteinogenic amino acids; each occurrence of R and R’ is independently H or selected from C-j _g-alky I, O(C-|_g alkyl), S(C-|.g- alkyl), Cg.-j Q cycloalkyl, 0(03.1 Q cycloalkyl), 8(03.1 Q cycloalkyl), C2~g alkenyl, C2~g alkynyl, C-|_g heteroalkenyl, C-|_g heteroalkynyl, 03.-1 Q cycloalkenyl, C-|_-| Q cycloheteroalkenyl, Cg_-| Q aryl, C-|_ -| Q heteroaryl, (Cg_-| Q ary l)C-|_g alkyl and (C-|_-| Q heteroaryl)C-|_g alkyl, each of which can be optionally substituted with from 1 to 3 substituents selected from C 1 _g-alkyl, OH, oxo and halogen, or from OH, oxo and halogen. each * represents a point of attachment for which the shortest path to a moiety R1-Y- or R1- comprises less atoms than that for •; and each • represents a point of attachment for which the shortest path to a moiety C comprises less atoms than that for *, with the proviso that when n is > 1 and a respective point of attachment is indicated on any one of Rc, R^ and Re, then it can be independently present in one or more of the peptide monomeric units; preferably in one peptidemonomeric unit most distant from the other point of attachment indicated in the respective structure.

60. The compound according to any one of claims 7-59, wherein moiety B has one of the following structures: single bond, (Bg)x>5each n is independently 0, 1 , 2, 3, 4, 5, 6, 7, or 8; each m is independently 0, 1 , 2, 3, or 4; each Rc, R^, and Reis independently selected from H, optionally substituted C-| _g alkyl, (C3-19 carbocyclyl)C-|_g alkyl, (Cg--|Q aryl)C-|_g alkyl, (C-|--| Q heterocyclyl)C-|_g alkyl, C2~g alkenyl, C2-6 alkynyl, and Cg-19 aryl, in each of which optionally one or more of the carbon atoms can be replaced by heteroatoms; preferably selected from side-chain residues of proteinogenic or a non- proteinogenic amino acids; each occurrence of R and R’ is independently H or selected from C-| _g-alky I, O(C-|_g alkyl), S(C-|_g- alkyl), Cg.-j Q cycloalkyl, 0(03.-19 cycloalkyl), S(C3_-| Q cycloalkyl), C2~g alkenyl, C2~g alkynyl, C-|_g heteroalkenyl, C-|_g heteroalkynyl, 03.-19 cycloalkenyl, C-|_-| Q cycloheteroalkenyl, Cg_-| Q aryl, C-|_ -| Q heteroaryl, (Cg_-| 9 aryl)C-|_g alkyl and (C-|_-| 9 heteroaryl)C-|_g alkyl, each of which can be optionally substituted with from 1 to 3 substituents selected from C -| _g-alkyl, OH, oxo and halogen, or from OH, oxo and halogen; wherein each of AA3, AA4, AA5, AAg, AA7, and AAg represents a proteinogenic or non- proteinogenic amino acid, or is absent;wherein preferably: each proteinogenic or non-proteinogenic amino acid is preferably independently represented by one of the following structures:and / or AA4 is an amino acid with a charged sidechain, and AA7 is an amino acid with an aliphatic sidechain; wherein more preferably:AA3 is selected from Asp, Glu, and Lys, or is absent; preferably Asp;AA4 is selected from Arg, HomoArg, Lys, Asp, and Glu, or is absent; preferably Lys or Arg;AA5 is selected from Asp, Glu, and Lys; preferably Asp;AAg is selected from Cys, Lys, Gly and Vai; preferably Cys or Lys;AA7 is selected from Gly, Ala, Vai, Arg, lie, Pro; preferably Gly or Vai; andAAg is selected from Pro and citrulline (Cit); preferably Pro even more preferably according to one of the sequences shown in the below table:

61. The compound according to any one of claims 7-60, wherein moiety B has one of the following structures: single bond,62. The compound according to any one of claims 7-61 , wherein B is independently selected form the structures B-1 to B-50 as defined in the description.

63. The compound according to any one of claims 7-62, wherein -B-C is independently represented by any one of the following structures:

64. The compound according to any one of claims 7-63, wherein B is selected from:10 wherein:each of AA3, AA4, AA5, AAg, AA7, and AAg represents a proteinogenic or non-proteinogenic amino acid, or is absent; preferably wherein AA3 is selected from Asp, Glu, and Lys, or is absent; more preferably Asp; preferably wherein AA4 is selected from Arg, HomoArg, Lys, Asp, and Glu, or is absent; more preferably Lys or Arg; preferably wherein AA5 is selected from Asp, Glu, and Lys; more preferably Asp; preferably wherein AAg is selected from Cys, Lys, Gly and Vai; more preferably Cys or Lys; preferably wherein AA7 is selected from Gly, Ala, Vai, Arg, lie, Pro; more preferably Gly or Vai; preferably wherein AAg is selected from Pro and Cit; more preferably Pro; each n is independently 0, 1 , 2, 3, 4, 5, 6, 7, or 8; and each m is independently 0, 1 , 2, 3, or 4.

65. The compound of claim 52or 58, wherein B is as defined in claim 64.

66. The compound of any one of claims 51-65, wherein B is a cleavable linker, preferably an enzymatically cleavable linker.

67. The compound of any one of claims 51 -66, wherein B comprises a cleavable peptide unit capable of being enzymatically cleaved by one or more proteases on the cell surface or the extracellular regions of the target tissue.

68. The compound of any one of claims 51-67, wherein B comprises a cleavable peptide unit selected from Gly-Pro, Ala-Pro, Val-Pro, Arg-Pro, lle-Pro, Pro-Pro, Gly-Cit, Ala-Cit, Val-Cit, Arg-Cit, lle-Cit, and Pro-Cit; preferably Gly-Pro or Val-Cit.

69. The compound of any one of claims 51-68, wherein B comprises a cleavable unit able of being enzymatically cleaved by one or more phosphatases, sulfatases or esterases.

70. The compound of any one of claims 51-69, wherein B comprises a cleavable unit selected from:wherein Q1is independently selected from OPO3H2, OPO2N(R)2, OPO2NH2, OPO(OH)F, OC(O)OR, OC(O)R, OSO3H, OSO2N(R)2, and OSO2NH2; preferably OPO3H2, OC(O)OH or OSO3H, more preferably OPO3H2; most preferably OPO3H2;R5 is independently selected from H an electron withdrawing group, preferably from H, NO2, CN, halogen, C(O)R, CF3, and SO3H, more preferably from H and NO2.71 . The compound of claim 70, wherein B comprises a cleavable unit selected from:

72. The compound according to any one of claims 7-71 , wherein the moiety C is a chelating agent groupsuitable for radiolabeling; a radioactive group comprising a radioisotope; a chelate of a radioactive isotope with a chelating agent; a fluorophore group; a cytotoxic and / or cytostatic agent; immunomodulator agent; or a protein, wherein preferably:(a) the chelating agent group suitable for radiolabeling is selected from sulfur colloid, diethylenetriaminepentaacetic acid (DTPA), ethylenediaminetetraacetic acid (EDTA), 1 ,4,7,10- tetraazacyclododecane-N,N',N",N"'-tetraacetic acid (DOTA), 1 ,4,7-triazacyclononane-N,N',N"- triacetic acid (NOTA), 1 ,4,8,11-tetraazacyclotetradecane-N,N',N",N"'-tetraacetic acid (TETA), iminodiacetic acid, bis(carboxymethylimidazole)glycine, 6-Hydrazinopyridine-3-carboxylic acidhas a structure according to the following formula:wherein: e is 0, 1 , 2, 3, 4 or 5; preferably 1 ;R^e is independently H, COOH, CONH2, aryl-COOH or heteroaryl-COOH; preferably COOH;R^e’ is independently H, COOH, CONH2, aryl-COOH or heteroaryl-COOH; preferably COOH; each R^eis independently H, CONH2, COOH, aryl-COOH or heteroaryl-COOH; preferably COOH;R^e’ is independently H, COOH, CONH2, aryl-COOH or heteroaryl-COOH; preferably COOH; andX is O, NH or S; preferably O; preferably having the configurationhas a structure according to the following formulae:wherein: f and g are each independently 0, 1 , 2, 3, 4 or 5; preferably 1 ;R^f is independently H, COOH, C(O)NH2, aryl-COOH or heteroaryl-COOH; preferably COOH; R2F is independently H, COOH, C(O)NH2, aryl-COOH or heteroaryl-COOH; preferably COOH;R^f is independently H, COOH, C(O)NH2, aryl-COOH or heteroaryl-COOH; preferably COOH; and R19’ is independently H, COOH, C(O)NH2, aryl-COOH or heteroaryl-COOH; preferably COOH;R29 is independently H, COOH, C(O)NH2, aryl-COOH or heteroaryl-COOH; preferably COOH;R39 is independently H, COOH, C(O)NH2, aryl-COOH or heteroaryl-COOH; preferably COOH; and X is O, NH or S; preferably O; or has a structure according to any of the following formulae:wherein:Ri h and R2*"1are each independently selected from COOH, CONH2, aryl-COOH, heteroaryl- COOH, heteroaryl-CFhCOOH, wherein the heteroaryl is preferably pyridinyl; and each X is independently O, NH or S; or(b) the radioactive group comprising a radioisotope is selected from223Ra,89Sr,94mTc,99mTc,186Re, 188Re,203Pb,212Pb,67Ga,68Ga,47Sc,111ln,97Ru,62Cu,64Cu,65Cu,67Cu,54Cu,86Y,88Y, "Y,121Sn, AI18F,149Tb,152Tb,155Tb,161Tb,153Sm,166Ho,105Rh,177Lu,123l,124l ,125l,131l ,16F,18F,211At,225Ac, 89Sr,225Ac,117mSn,169Er,227Th,3H,11C,11 mN,J3N,82Rb,89Zr and32P, or a nuclide selected from 139La,69Ga, and175Lu; or(c) the chelate of a radioactive isotope is a chelate of an isotope listed under (b) above and / or with a chelating agent listed under (a) above; or moiety C is a group selected from any of the following structures:wherein M is a radioactive isotope; preferably selected among the list under (b) above; more preferably:(d) the fluorophore group is selected from a xanthene dye, acridine dye, oxazine dye, cyanine dye, styryl dye, coumarine dye, porphine dye, fluorescent metal-ligand-complex, fluorescent protein, nanocrystals, perylene dye, boron-dipyrromethene dye and phtalocyanine dye; preferably selected from the following structures:(e) the cytotoxic and / or cytostatic agent is selected from chemotherapeutic agent selected from the group consisting of topoisomerase inhibitors, alkylating agents, antimetabolites, antibiotics, mitotic disrupters, DNA intercalating agents, DNA synthesis inhibitors, DNA-RNA transcription regulator, enzyme inhibitors, gene regulators, hormone response modifiers, hypoxia-selective cytotoxins, epidermal growth factor inhibitors, anti-vascular agents and a combination of two or more thereof; preferably selected from the following structures:5moiety C is an auristatin derivative; preferably having a structure according to the following formula:wherein: is independently H or C1-6 alkyl; preferably H or CH3;is independently C1-6 alkyl; preferably CH3 or iPr;Rd^ is independently H or C1-6 alkyl; preferably H or CH3;Rd^ is independently H, C1-6 alkyl, COO(C1-6 alkyl), CON(H or C1-6 alkyl), C3-C 10 aryl or C3-C 10 heteroaryl; preferably H, CH3, COOH, COOCH3 or thiazolyl;RdS is independently H, OH, C1-6 alkyl; preferably H or OH; andR^ is independently C3-C 10 aryl or C3-C 10 heteroaryl; preferably optionally substituted phenyl or pyridyl, wherein preferably, moiety C is derived from MMAE or MMAF; or a topoisomerase inhibitor; preferably camptothecin (CPT) or a derivative thereof; more preferably derived (e.g., by replacing a hydrogen atom) from topotecan, irinotecan, silatecan, cositecan, exatecan, lurtotecan, gimatecan, belotecan, rubitecan, deruxtecan, DXd; even more preferably exatecan; even more preferably(f) the immunomodulator agent is selected from molecules known to be able to modulate the immune system, such as ligands of CD3, CD25, TLRs, STING, 4-1 BBL, 4-1 BB, PD-1 , mTor, PDL-1 , NKG- 2D IMiDs, wherein ligands can be agonists and / or antagonist; or(g) the protein is selected from cytokines, such as IL2, IL10, IL12, IL15, TNF, Interferon Gamma, chemokines, antibodies, and antibody fragments.

73. The compound according to any one of claims 7-72, wherein C is represented by a structure selected from:wherein the combination of A-B and C is preferably selected such that the covalent bond — connecting B with C is represented by S — S, S — C, C — S, C(O) — Ra, C(O) — N, C(O) — O, C(O) — N, N— C(O), N— C(O)O, N— C(S) or OC(O)— N.

74. The compound according to any one of claims 7-73, wherein the moiety C is(a) a chelating agent group suitable for radiolabeling selected has a structure according to one of the following formulae:wherein: each e, f and g is independently 0, 1 , 2, 3, 4 or 5; preferably 1 ; each R1e , R^e, R3e , R4e , R4f ,R2fiR3f R1g , R2ganc| R3g is independently H, COOH, aryl-COOH or heteroaryl-COOH; preferably COOH; andX is O, NH or S; preferably O; or(b) a radioactive group comprising a radioisotope selected from223Ra,89Sr,94mTc,99mTc,186Re, 188Re,203Pb,67Ga,68Ga,47Sc,111ln,97Ru,62Cu,64Cu,65Cu,67Cu,54Cu,86Y,88Y, "Y,121Sn, AI18F,149Tb,152Tb,155Tb,161Tb,153Sm,166Ho,105Rh,177Lu,123l ,124l ,125l,131l,16F,18F,211At, 225Ac,89Sr,225Ac,117mSn,169Er,227Th,3H,11C,11mN,13N,82Rb,89Zr and32P; or(c) a chelate of an isotope listed under (b) above with a chelating agent listed under (a) above; or(d) an auristatin derivative having a structure according to the following formula:wherein:Rd1 is independently H or C1-6 alkyl; preferably H or CH3;Rd2 is independently C1-6 alkyl; preferably CH3 or iPr;Rd3 js independently H or C1-6 alkyl; preferably H or CH3;Rd4 is independently H, C1-6 alkyl, COO(C1-6 alkyl), CON(H or C1-6 alkyl), C3-C 10 aryl or C3-C 10 heteroaryl; preferably H, CH3, COOH, COOCH3 or thiazolyl;RdS is independently H, OH, C1-6 alkyl; preferably H or OH; andRd6 is independently C3-C 10 aryl or C3-C-1 Q heteroaryl; preferably optionally substituted phenyl or pyridyl;more preferably derived from MMAE or MMAF.

75. The compound of any one of claims 52, 58 and 65, wherein C is as defined in claim 74.

76. The compound according to any one of claims 7-75, wherein C is independently selected form the structures C-1 to C-55 as defined in the description.

77. The compound according to any one of claims 7-76, wherein C is independently selected form the structures C-1 to C-47 as defined in the description.

78. The compound according to any one of claims 7-77, wherein A is independently selected from the structures A-1 to A-42, B is independently selected form the structures B-1 to B-50, and C is independently selected form the structures C-1 to C-55 as defined in the description.

79. The compound according to any one of claims 7-78, wherein A is independently selected from the structures A-1 to A-30, B is independently selected form the structures B-1 to B-50, and C is independently selected form the structures C-1 to C-47, as defined in the description.

80. The compound according to any one of claims 7-79, having a structure selected from those listed in Table 1 in the description.81 . The compound according to any one of claims 7-80, having a structure selected from those listed in Tables 3.1 to 3.7 in the description.

82. The compound according to any one of claims 7-81 , having a structure selected from those listed in Tables 3.1 , 3.2, 3.3, 3.4, and 3.5 in the description.

83. The compound according to any one of claims 7-82, having a structure represented by a formula below, or a chelate thereof with a radioactive isotope; preferably a radioisotope as listed in claim 72 or 74; more preferably177Lu or68Ga:wherein n is 0, 1 , 2, 3, 4, 5, 6, 7, or 8.

84. The compound according to any one of claims 7-83, having a structure represented by the following formula 20a or 28a:28a85. The compound of any one of claims 7-84, having a molecular weight of 5000 Da or less; preferably 4000 Da or less; more preferably 3000 Da or less.

86. The compound of any one of claims 7-85, having a molecular weight of 500 Da or more; preferably 600 Da or more; more preferably 800 Da or more.

87. The compound of any one of claims 7-86, having a molecular weight of 500 to 5000 Da; preferably 600 to 4000 Da; more preferably 800 to 3000 Da.

88. The compound of any one of claims 7-87, wherein at least one atom of the structure represented by R1or R1-Y is a radioisotope.

89. The compound of claim 88, wherein the radioisotope is an isotope of an element selected from C, N, F, P, H and I; preferably selected from11C,11mN,16F,18F,32P,3H,123l,124l,125l, and131l.

90. A compound obtained by additionally functionalizing the compound of any one of claims 7-89 with a radioactive group comprising or consisting of a radioisotope.91 . The compound of claim 90, wherein the radioactive group comprises or consists of a radioisotope of an element selected from C, N, F, P, H and I; preferably selected from11C,11mN,16F,18F,32P, 3H,123l,124l,125l, and131l; more preferably wherein the radioactive group is selected from16F,3H, 123l, and125l; or a radioisotope selected from23Ra,89Sr,94mTc,99mTc,186Re,188Re,203Pb,212Pb, 67Ga,68Ga,47Sc,1111n,97Ru,62Cu,64Cu,65Cu,67Cu,54Cu,86Y,88Y, "Y,121Sn, AI18F,149Tb,152Tb, 155Tb,161Tb,153Sm,166Ho,105Rh,177Lu,123l,124l,125l,131l,16F,18F,211At,225Ac,89Sr,117mSn,169Er, 227Th,3H,11C,11mN,13N,82Rb,89Zr and32P; or a nuclide selected from139La,69Ga, and175Lu.

92. A compound having a structure selected from those listed in Tables 1 , 3.1 , 3.2, 3.3, 3.4, 3.5, 3.6, and 3.7, its individual diastereoisomers, its hydrates, its solvates, its crystal forms, its individual tautomers or a pharmaceutically acceptable salt thereof.

93. The of any one of claims 7-92, which is specifically binding Acid Phosphatase 3 (ACP3), has a molecular weight of 5000 Da or less and an ACP3 dissociation constant (K^) of 50 nM or less.

94. The compound according to claim 93 specifically binding to ACP3 on the membrane of tumor cells.

95. The compound according to claim 93 or 94 that is not substantially internalized.

96. The compound according to any one of claims 93 to 95 that shows a higher uptake in one or more tumor(s) than in one or more healthy organ(s) after administration.

97. The compound according to any one of claims 93 to 96 that does not substantially accumulate in kidneys or salivary glands or healthy prostate after administration.

98. The compound of any one of the preceding claims, wherein the compound structure comprises C, wherein C is therapeutic or diagnostic agent as defined in any one of the preceding claims.

99. The compound of any one of the preceding claims, wherein the compound structure comprises -B-C, wherein B is a linker as defined in any one of the preceding claims.

100. The compound of any one of claims 1-6, wherein the compound structure comprises C, wherein C is a therapeutic or diagnostic agent as defined in any one of the preceding claims.

101. The compound of any one of the claims 1-6 and 101 , wherein the compound structure comprises -B-C, wherein B is a linker as defined in any one of the preceding claims.

102. A pharmaceutical composition comprising the compound according to any one of the preceding claims, and a pharmaceutically acceptable excipient.

103. The compound or the pharmaceutical composition according to any one of the preceding claims for use in:(a) a method for treatment of the human or animal body by surgery or therapy or a diagnostic method practiced on the human or animal body; or(b) a method for therapy or prophylaxis of a subject suffering from or having risk for a disease or disorder; or(c) a method for guided surgery practiced on a subject suffering from or having risk for a disease or disorder; or(d) a method for diagnosis of a disease or disorder, the method being practiced on the human or animal body and involving a nuclear medicine imaging technique, such as Positron Emission Tomography (PET) or Single Photon Emission Computed Tomography (SPECT); or(e) a method for targeted delivery of a therapeutic or diagnostic agent to a subject suffering from or having risk for a disease or disorder.

104. The compound or the pharmaceutical composition for use according to claim 103, wherein the disease or disorder is cancer.

105. The compound or the pharmaceutical composition for use according to claim 104, wherein the cancer associated with ACPP expression.

106. The compound or the pharmaceutical composition for use according to claim 104 or 105, whereinthe cancer is prostate cancer.

107. The compound or the pharmaceutical composition for use according to any one of claims 104 to 106, wherein the cancer is selected from prostate adenocarcinoma, ductal prostate cancer, ductal adenocarcinoma, clear cell adenocarcinoma, acinar adenocarcinoma, urothelial cancer, neuroendocrine prostate cancer, small cell prostate cancer, multiple myeloma.

108. The compound or the pharmaceutical composition for use according to claim 103, wherein the disease or disorder is associated with ACPP expression.

109. The compound or the pharmaceutical composition for use according to claim 103 wherein the disease or disorder is selected from pancreatitis, Paget's disease, sickle-cell disease, lysosomal storage diseases, and Gaucher's disease.

110. The compound or the pharmaceutical composition for use according to any one of claims 103 to 109, wherein the compound comprises a radioactive group comprising a radioisotope; preferably wherein moiety C is a chelate of a radioactive isotope with a chelating agent; more preferably a betaemitter; most preferably177Lu.111 . The compound or the pharmaceutical composition for use according to claim 1 10, wherein the compound is administered to a subject at a dose of > 250 MBq / kg, expressed as a mouse dose, or an equivalent human dose, e.g., > 20.3 MBq / kg; preferably S 500 MBq / kg, expressed as a mouse dose, or an equivalent human dose, e.g., > 40.6 MBq / kg.

112. The compound or the pharmaceutical composition for use according to claim 111 , wherein R1-Y-Z is represented by a structure as defined in claim 13 or 14; preferably A-7 as defined in the description.

113. The compound or the pharmaceutical composition for use according to claim 111 or 112, wherein the compound is 20a or 28a.

114. The compound or the pharmaceutical composition for use according to any one of claims 110 to 113, wherein the compound is administered to a subject at a dose of S1 μmol / kg, preferably expressed as a mouse dose, or an equivalent human dose, e.g., ≤ 0.08 μmol / kg.

115. The compound or the pharmaceutical composition for use according to claim 1 10, wherein the compound is administered to a subject at a dose of > 500 MBq / kg, expressed as a mouse dose, or an equivalent human dose, e.g., > 40.6 MBq / kg; preferably > 1000 MBq / kg, expressed as a mouse dose, or an equivalent human dose, e.g., > 81 .3 MBq / kg.

116. The compound or the pharmaceutical composition for use according to claim 115, wherein R1-Y-Z is represented by a structure as defined in any one of claims 15, 16 and 17; preferably A-23 as defined in the description.

117. The compound or the pharmaceutical composition for use according to claim 115 or 116, wherein the compound is 22a.

118. The compound or the pharmaceutical composition for use according to any one of claims 115 to 117, wherein the compound is administered to a subject at a dose of <1 μmol / kg, preferably expressed as a mouse dose, or an equivalent human dose, e.g., ≤ 0.08 μmol / kg.

119. A compound having a structure selected form those below, its individual diastereoisomers, its hydrates, its solvates, its crystal forms, its individual tautomers or a pharmaceutically acceptable salt thereof:wherein R1a, R1b, Q are as defined in claim 7.

120. The compound of claim 119, having a structure selected from those listed in Table 2.1 or 2.2.121 . The compound of claim 119 or 120 for use in a method for diagnosis of a disease or disorder, the method being practiced on the human or animal body and involving a nuclear medicine imaging technique, such as Positron Emission Tomography (PET); or a method for targeted delivery of diagnostic agent to a subject suffering from or having risk for a disease or disorder.

122. The compound for use of claim 121 , wherein the disease or disorder is as defined in any one of claims 104 to 109.

123. A compound having a structure selected form those below, its individual diastereoisomers, its hydrates, its solvates, its crystal forms, its individual tautomers or a pharmaceutically acceptable salt thereof:wherein R1a, R1b, Q are as defined in claim 7, and each G is independently selected from NO2 and (Ci-3alkyl)3N+.

124. The compound of claim 123, having a structure selected from those listed in Table 2.3.

125. A method of manufacturing a diagnostic agent suitable for a nuclear medicine imaging technique, such as Positron Emission Tomography (PET), the method involving using a compound as defined in claim 123 or 124 as a starting material, precursor or intermediate.

126. The method of claim 125, wherein the diagnostic agent is a compound according to claim 119 or 120, or a composition comprising that compound.

Images