Linker Information

General Information of This Linker
Linker ID
LIN00042
Linker Name
rac-(R)-2-(2-aminoacetamido)-3-(4-(2-(((R)-1-carboxy-2-phenylethyl)amino)-2-oxoethoxy)phenyl)propanoic acid
Structure
Formula
C22H25N3O7
#Ro5 Violations (Lipinski): 1 Molecular Weight (mw) 443.456
Lipid-water partition coefficient (xlogp) -0.0519
Hydrogen Bond Donor Count (hbonddonor) 5
Hydrogen Bond Acceptor Count (hbondacc) 6
Rotatable Bond Count (rotbonds) 12
Canonical smiles
NCC(=O)NC(Cc1ccc(OCC(=O)NC(Cc2ccccc2)C(=O)O)cc1)C(=O)O
InChI
InChI=1S/C22H25N3O7/c23-12-19(26)24-17(21(28)29)11-15-6-8-16(9-7-15)32-13-20(27)25-18(22(30)31)10-14-4-2-1-3-5-14/h1-9,17-18H,10-13,23H2,(H,24,26)(H,25,27)(H,28,29)(H,30,31)/t17-,18-/m0/s1
InChIKey
APHMHHAVZZCCTE-ROUUACIJSA-N
Each Peptide-drug Conjugate Related to This Linker
Full Information of The Activity Data of The PDC(s) Related to This Linker
[177Lu]Lu-4 [Investigative]
 PDC Info 
Revealed Based on the Cell Line Data
Click To Hide/Show 1 Activity Data Related to This Level
Experiment 1 Reporting the Activity Data of This PDC [1]
Indication Metastatic castration-resistant prostate cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50)
18.7 ± 0.3 nM
Administration Time 1 h
Evaluation Method Gamma counter assay
MOA of PDC
Prostate-specific membrane antigen (PSMA) is a promising target for the diagnosis and radionuclide therapy of prostate cancer. This study reports conversion of a previously reported 68Ga-imaging agent, [68Ga]Ga-P16-093, to a Lu-177 radionuclide therapeutic agent. Substitution of the HBED-CC metal chelating group with DOTA(GA)2 led to P17-087 (4) and P17-088 (7). Both agents showed excellent PSMA binding affinity (IC50 = 10-30 nM) comparable to that of recently FDA-approved [177Lu]Lu-PSMA-617 (Pluvicto). Biodistribution studies in PSMA expressing tumor bearing mice showed that [177Lu]Lu-4 exhibited very high tumor uptake and a fast blood clearance similar to those of [177Lu]Lu-PSMA-617. Conversely, [177Lu]Lu-7, containing an albumin binder, extended its blood half-life and exhibited significantly higher uptake and longer tumor residence time than [177Lu]Lu-4 and [177Lu]Lu-PSMA-617. The switch from chelator HBED-CC to DOTA(GA)2 and the switch from the imaging isotope gallium-68 to the therapeutic isotope lutetium-177 have successfully transformed a PSMA-targeting agent from diagnosis to promising radionuclide therapeutic agents.

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Description
The PSMA binding affinities were determined by a competitive binding assay using PSMA-overexpressing LNCaP human prostate carcinoma cell homogenates and a known high affinity 125I-labeled PSMA ligand, [125I]MIP-1095, as the radioligand. The IC50 values for the metal-free PSMA-inhibiting compounds and metal complexes are summarized in Table 1. PSMA-617 and P16-093 were included in this study as reference compounds. The PSMA affinities of 4 and 7 as well as their natLu-labeled complexes were comparable to those of the reference compounds and displayed excellent binding affinities (IC50 = 28.7, 15.4, 18.7, and 20.2 nM, respectively). The addition of the p-iodophenylbutanoyl group in compound 7 did not change the PSMA binding affinity because of the small molecular size and remote position from the PSMA binding site.

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In Vitro Model Prostate carcinoma LNCaP cell CVCL_0395
Half life period 162 ± 4.86 h
[177Lu]Lu-7 [Investigative]
 PDC Info 
Revealed Based on the Cell Line Data
Click To Hide/Show 1 Activity Data Related to This Level
Experiment 1 Reporting the Activity Data of This PDC [1]
Indication Metastatic castration-resistant prostate cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50)
20.2 ± 4.6 nM
Administration Time 1 h
Evaluation Method Gamma counter assay
MOA of PDC
Prostate-specific membrane antigen (PSMA) is a promising target for the diagnosis and radionuclide therapy of prostate cancer. This study reports conversion of a previously reported 68Ga-imaging agent, [68Ga]Ga-P16-093, to a Lu-177 radionuclide therapeutic agent. Substitution of the HBED-CC metal chelating group with DOTA(GA)2 led to P17-087 (4) and P17-088 (7). Both agents showed excellent PSMA binding affinity (IC50 = 10-30 nM) comparable to that of recently FDA-approved [177Lu]Lu-PSMA-617 (Pluvicto). Biodistribution studies in PSMA expressing tumor bearing mice showed that [177Lu]Lu-4 exhibited very high tumor uptake and a fast blood clearance similar to those of [177Lu]Lu-PSMA-617. Conversely, [177Lu]Lu-7, containing an albumin binder, extended its blood half-life and exhibited significantly higher uptake and longer tumor residence time than [177Lu]Lu-4 and [177Lu]Lu-PSMA-617. The switch from chelator HBED-CC to DOTA(GA)2 and the switch from the imaging isotope gallium-68 to the therapeutic isotope lutetium-177 have successfully transformed a PSMA-targeting agent from diagnosis to promising radionuclide therapeutic agents.

   Click to Show/Hide
Description
The PSMA binding affinities were determined by a competitive binding assay using PSMA-overexpressing LNCaP human prostate carcinoma cell homogenates and a known high affinity 125I-labeled PSMA ligand, [125I]MIP-1095, as the radioligand. The IC50 values for the metal-free PSMA-inhibiting compounds and metal complexes are summarized in Table 1. PSMA-617 and P16-093 were included in this study as reference compounds. The PSMA affinities of 4 and 7 as well as their natLu-labeled complexes were comparable to those of the reference compounds and displayed excellent binding affinities (IC50 = 28.7, 15.4, 18.7, and 20.2 nM, respectively). The addition of the p-iodophenylbutanoyl group in compound 7 did not change the PSMA binding affinity because of the small molecular size and remote position from the PSMA binding site.

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In Vitro Model Prostate carcinoma LNCaP cell CVCL_0395
Half life period 165 ± 0.99 h
[177Lu]Lu-P17-081 [Investigative]
 PDC Info 
Revealed Based on the Cell Line Data
Click To Hide/Show 5 Activity Data Related to This Level
Experiment 1 Reporting the Activity Data of This PDC [2]
Indication Metastatic castration-resistant prostate cancer
Efficacy Data Cell uptake rate
3.50%
Administration Time 5 min
Administration Dosage 37 kBq
Evaluation Method Gamma counter assay
MOA of PDC
Prostate-specific membrane antigen (PSMA) is an excellent target for imaging and radionuclide therapy of prostate cancer. Recently, [177Lu]Lu-PSMA-617 (Pluvicto) was approved by the FDA for radionuclide therapy. To develop hetero-bivalent agents targeting both PSMA and bone metastasis, [177Lu]Lu-P17-079 ([177Lu]Lu-1) and [177Lu]Lu-P17-081 ([177Lu]Lu-2) were prepared. In vivo biodistribution studies of [177Lu]Lu-PSMA-617, [177Lu]Lu-1, and [177Lu]Lu-2 in mice bearing PC3-PIP (PSMA positive) tumor showed high uptake in PSMA-positive tumor (14.5, 14.7, and 11.3% ID/g at 1 h, respectively) and distinctively different bone uptakes (0.52, 6.52, and 5.82% ID/g at 1 h, respectively). PET imaging using [68Ga]Ga-P17-079 ([68Ga]Ga-1) in the same mouse model displayed excellent images confirming the expected dual-targeting to PSMA-positive tumor and bone. Results suggest that [177Lu]Lu-P17-079 ([177Lu]Lu-1) is a promising candidate for further development as a hetero-bivalent radionuclide therapy agent targeting both PSMA expression and bone metastases for the treatment of prostate cancer.

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Description
As expected, the PSMA-targeting hetero-bivalent agents, [177Lu]Lu-1 and [177Lu]Lu-2, displayed excellent cell uptake in PC3-PIP PSMA-positive cells. Furthermore, [177Lu]Lu-1 displayed a higher uptake (about 2 times higher, p < 0.05) as that of [177Lu]Lu-2. The higher uptake in PSMA-positive cells suggested that [177Lu]Lu-1 may more readily penetrate the cell membrane and may be more localized in the PSMA-positive tumor cells. The uptake was specifically inhibited by blocking study (in the presence of 1 uM cold PSMA-617). Both agents did not show any significant cell uptakes in PSMA-negative cells (PC3 cells). Cell uptake kinetics of [177Lu]Lu-1 and [177Lu]Lu-2 showed very rapid uptakes in PC3-PIP PSMA-positive cells (5, 15, 30, 60, and 120 min, respectively). As a positive control, [177Lu]Lu-PSMA-617 also showed excellent cell uptake under a similar condition. It is noted that [177Lu]Lu-2 showed a very similar uptake kinetics as that of [177Lu]Lu-PSMA-617, while [177Lu]Lu-1 displayed a significantly higher and faster uptake. Apparently, a small change in the chemical structure of the location of the bisphosphonate group between [177Lu]Lu-1 and [177Lu]Lu-2 may have contributed to this observation. No obvious reason could be contributed to the superior cell uptake of [177Lu]Lu-1. This distinctive difference in in vitro cell uptake may also be responsible for variations of PSMA-positive tumor uptakes in vivo.

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In Vitro Model Prostate carcinoma PC3-PIP PSMA-positive cell CVCL_0035
Experiment 2 Reporting the Activity Data of This PDC [2]
Indication Metastatic castration-resistant prostate cancer
Efficacy Data Cell uptake rate
5.50%
Administration Time 15 min
Administration Dosage 37 kBq
Evaluation Method Gamma counter assay
MOA of PDC
Prostate-specific membrane antigen (PSMA) is an excellent target for imaging and radionuclide therapy of prostate cancer. Recently, [177Lu]Lu-PSMA-617 (Pluvicto) was approved by the FDA for radionuclide therapy. To develop hetero-bivalent agents targeting both PSMA and bone metastasis, [177Lu]Lu-P17-079 ([177Lu]Lu-1) and [177Lu]Lu-P17-081 ([177Lu]Lu-2) were prepared. In vivo biodistribution studies of [177Lu]Lu-PSMA-617, [177Lu]Lu-1, and [177Lu]Lu-2 in mice bearing PC3-PIP (PSMA positive) tumor showed high uptake in PSMA-positive tumor (14.5, 14.7, and 11.3% ID/g at 1 h, respectively) and distinctively different bone uptakes (0.52, 6.52, and 5.82% ID/g at 1 h, respectively). PET imaging using [68Ga]Ga-P17-079 ([68Ga]Ga-1) in the same mouse model displayed excellent images confirming the expected dual-targeting to PSMA-positive tumor and bone. Results suggest that [177Lu]Lu-P17-079 ([177Lu]Lu-1) is a promising candidate for further development as a hetero-bivalent radionuclide therapy agent targeting both PSMA expression and bone metastases for the treatment of prostate cancer.

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Description
As expected, the PSMA-targeting hetero-bivalent agents, [177Lu]Lu-1 and [177Lu]Lu-2, displayed excellent cell uptake in PC3-PIP PSMA-positive cells. Furthermore, [177Lu]Lu-1 displayed a higher uptake (about 2 times higher, p < 0.05) as that of [177Lu]Lu-2. The higher uptake in PSMA-positive cells suggested that [177Lu]Lu-1 may more readily penetrate the cell membrane and may be more localized in the PSMA-positive tumor cells. The uptake was specifically inhibited by blocking study (in the presence of 1 uM cold PSMA-617). Both agents did not show any significant cell uptakes in PSMA-negative cells (PC3 cells). Cell uptake kinetics of [177Lu]Lu-1 and [177Lu]Lu-2 showed very rapid uptakes in PC3-PIP PSMA-positive cells (5, 15, 30, 60, and 120 min, respectively). As a positive control, [177Lu]Lu-PSMA-617 also showed excellent cell uptake under a similar condition. It is noted that [177Lu]Lu-2 showed a very similar uptake kinetics as that of [177Lu]Lu-PSMA-617, while [177Lu]Lu-1 displayed a significantly higher and faster uptake. Apparently, a small change in the chemical structure of the location of the bisphosphonate group between [177Lu]Lu-1 and [177Lu]Lu-2 may have contributed to this observation. No obvious reason could be contributed to the superior cell uptake of [177Lu]Lu-1. This distinctive difference in in vitro cell uptake may also be responsible for variations of PSMA-positive tumor uptakes in vivo.

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In Vitro Model Prostate carcinoma PC3-PIP PSMA-positive cell CVCL_0035
Experiment 3 Reporting the Activity Data of This PDC [2]
Indication Metastatic castration-resistant prostate cancer
Efficacy Data Cell uptake rate
7.50%
Administration Time 30 min
Administration Dosage 37 kBq
Evaluation Method Gamma counter assay
MOA of PDC
Prostate-specific membrane antigen (PSMA) is an excellent target for imaging and radionuclide therapy of prostate cancer. Recently, [177Lu]Lu-PSMA-617 (Pluvicto) was approved by the FDA for radionuclide therapy. To develop hetero-bivalent agents targeting both PSMA and bone metastasis, [177Lu]Lu-P17-079 ([177Lu]Lu-1) and [177Lu]Lu-P17-081 ([177Lu]Lu-2) were prepared. In vivo biodistribution studies of [177Lu]Lu-PSMA-617, [177Lu]Lu-1, and [177Lu]Lu-2 in mice bearing PC3-PIP (PSMA positive) tumor showed high uptake in PSMA-positive tumor (14.5, 14.7, and 11.3% ID/g at 1 h, respectively) and distinctively different bone uptakes (0.52, 6.52, and 5.82% ID/g at 1 h, respectively). PET imaging using [68Ga]Ga-P17-079 ([68Ga]Ga-1) in the same mouse model displayed excellent images confirming the expected dual-targeting to PSMA-positive tumor and bone. Results suggest that [177Lu]Lu-P17-079 ([177Lu]Lu-1) is a promising candidate for further development as a hetero-bivalent radionuclide therapy agent targeting both PSMA expression and bone metastases for the treatment of prostate cancer.

   Click to Show/Hide
Description
As expected, the PSMA-targeting hetero-bivalent agents, [177Lu]Lu-1 and [177Lu]Lu-2, displayed excellent cell uptake in PC3-PIP PSMA-positive cells. Furthermore, [177Lu]Lu-1 displayed a higher uptake (about 2 times higher, p < 0.05) as that of [177Lu]Lu-2. The higher uptake in PSMA-positive cells suggested that [177Lu]Lu-1 may more readily penetrate the cell membrane and may be more localized in the PSMA-positive tumor cells. The uptake was specifically inhibited by blocking study (in the presence of 1 uM cold PSMA-617). Both agents did not show any significant cell uptakes in PSMA-negative cells (PC3 cells). Cell uptake kinetics of [177Lu]Lu-1 and [177Lu]Lu-2 showed very rapid uptakes in PC3-PIP PSMA-positive cells (5, 15, 30, 60, and 120 min, respectively). As a positive control, [177Lu]Lu-PSMA-617 also showed excellent cell uptake under a similar condition. It is noted that [177Lu]Lu-2 showed a very similar uptake kinetics as that of [177Lu]Lu-PSMA-617, while [177Lu]Lu-1 displayed a significantly higher and faster uptake. Apparently, a small change in the chemical structure of the location of the bisphosphonate group between [177Lu]Lu-1 and [177Lu]Lu-2 may have contributed to this observation. No obvious reason could be contributed to the superior cell uptake of [177Lu]Lu-1. This distinctive difference in in vitro cell uptake may also be responsible for variations of PSMA-positive tumor uptakes in vivo.

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In Vitro Model Prostate carcinoma PC3-PIP PSMA-positive cell CVCL_0035
Experiment 4 Reporting the Activity Data of This PDC [2]
Indication Metastatic castration-resistant prostate cancer
Efficacy Data Cell uptake rate
8%
Administration Time 60 min
Administration Dosage 37 kBq
Evaluation Method Gamma counter assay
MOA of PDC
Prostate-specific membrane antigen (PSMA) is an excellent target for imaging and radionuclide therapy of prostate cancer. Recently, [177Lu]Lu-PSMA-617 (Pluvicto) was approved by the FDA for radionuclide therapy. To develop hetero-bivalent agents targeting both PSMA and bone metastasis, [177Lu]Lu-P17-079 ([177Lu]Lu-1) and [177Lu]Lu-P17-081 ([177Lu]Lu-2) were prepared. In vivo biodistribution studies of [177Lu]Lu-PSMA-617, [177Lu]Lu-1, and [177Lu]Lu-2 in mice bearing PC3-PIP (PSMA positive) tumor showed high uptake in PSMA-positive tumor (14.5, 14.7, and 11.3% ID/g at 1 h, respectively) and distinctively different bone uptakes (0.52, 6.52, and 5.82% ID/g at 1 h, respectively). PET imaging using [68Ga]Ga-P17-079 ([68Ga]Ga-1) in the same mouse model displayed excellent images confirming the expected dual-targeting to PSMA-positive tumor and bone. Results suggest that [177Lu]Lu-P17-079 ([177Lu]Lu-1) is a promising candidate for further development as a hetero-bivalent radionuclide therapy agent targeting both PSMA expression and bone metastases for the treatment of prostate cancer.

   Click to Show/Hide
Description
As expected, the PSMA-targeting hetero-bivalent agents, [177Lu]Lu-1 and [177Lu]Lu-2, displayed excellent cell uptake in PC3-PIP PSMA-positive cells. Furthermore, [177Lu]Lu-1 displayed a higher uptake (about 2 times higher, p < 0.05) as that of [177Lu]Lu-2. The higher uptake in PSMA-positive cells suggested that [177Lu]Lu-1 may more readily penetrate the cell membrane and may be more localized in the PSMA-positive tumor cells. The uptake was specifically inhibited by blocking study (in the presence of 1 uM cold PSMA-617). Both agents did not show any significant cell uptakes in PSMA-negative cells (PC3 cells). Cell uptake kinetics of [177Lu]Lu-1 and [177Lu]Lu-2 showed very rapid uptakes in PC3-PIP PSMA-positive cells (5, 15, 30, 60, and 120 min, respectively). As a positive control, [177Lu]Lu-PSMA-617 also showed excellent cell uptake under a similar condition. It is noted that [177Lu]Lu-2 showed a very similar uptake kinetics as that of [177Lu]Lu-PSMA-617, while [177Lu]Lu-1 displayed a significantly higher and faster uptake. Apparently, a small change in the chemical structure of the location of the bisphosphonate group between [177Lu]Lu-1 and [177Lu]Lu-2 may have contributed to this observation. No obvious reason could be contributed to the superior cell uptake of [177Lu]Lu-1. This distinctive difference in in vitro cell uptake may also be responsible for variations of PSMA-positive tumor uptakes in vivo.

   Click to Show/Hide
In Vitro Model Prostate carcinoma PC3-PIP PSMA-positive cell CVCL_0035
Experiment 5 Reporting the Activity Data of This PDC [2]
Indication Metastatic castration-resistant prostate cancer
Efficacy Data Cell uptake rate
10%
Administration Time 120 min
Administration Dosage 37 kBq
Evaluation Method Gamma counter assay
MOA of PDC
Prostate-specific membrane antigen (PSMA) is an excellent target for imaging and radionuclide therapy of prostate cancer. Recently, [177Lu]Lu-PSMA-617 (Pluvicto) was approved by the FDA for radionuclide therapy. To develop hetero-bivalent agents targeting both PSMA and bone metastasis, [177Lu]Lu-P17-079 ([177Lu]Lu-1) and [177Lu]Lu-P17-081 ([177Lu]Lu-2) were prepared. In vivo biodistribution studies of [177Lu]Lu-PSMA-617, [177Lu]Lu-1, and [177Lu]Lu-2 in mice bearing PC3-PIP (PSMA positive) tumor showed high uptake in PSMA-positive tumor (14.5, 14.7, and 11.3% ID/g at 1 h, respectively) and distinctively different bone uptakes (0.52, 6.52, and 5.82% ID/g at 1 h, respectively). PET imaging using [68Ga]Ga-P17-079 ([68Ga]Ga-1) in the same mouse model displayed excellent images confirming the expected dual-targeting to PSMA-positive tumor and bone. Results suggest that [177Lu]Lu-P17-079 ([177Lu]Lu-1) is a promising candidate for further development as a hetero-bivalent radionuclide therapy agent targeting both PSMA expression and bone metastases for the treatment of prostate cancer.

   Click to Show/Hide
Description
As expected, the PSMA-targeting hetero-bivalent agents, [177Lu]Lu-1 and [177Lu]Lu-2, displayed excellent cell uptake in PC3-PIP PSMA-positive cells. Furthermore, [177Lu]Lu-1 displayed a higher uptake (about 2 times higher, p < 0.05) as that of [177Lu]Lu-2. The higher uptake in PSMA-positive cells suggested that [177Lu]Lu-1 may more readily penetrate the cell membrane and may be more localized in the PSMA-positive tumor cells. The uptake was specifically inhibited by blocking study (in the presence of 1 uM cold PSMA-617). Both agents did not show any significant cell uptakes in PSMA-negative cells (PC3 cells). Cell uptake kinetics of [177Lu]Lu-1 and [177Lu]Lu-2 showed very rapid uptakes in PC3-PIP PSMA-positive cells (5, 15, 30, 60, and 120 min, respectively). As a positive control, [177Lu]Lu-PSMA-617 also showed excellent cell uptake under a similar condition. It is noted that [177Lu]Lu-2 showed a very similar uptake kinetics as that of [177Lu]Lu-PSMA-617, while [177Lu]Lu-1 displayed a significantly higher and faster uptake. Apparently, a small change in the chemical structure of the location of the bisphosphonate group between [177Lu]Lu-1 and [177Lu]Lu-2 may have contributed to this observation. No obvious reason could be contributed to the superior cell uptake of [177Lu]Lu-1. This distinctive difference in in vitro cell uptake may also be responsible for variations of PSMA-positive tumor uptakes in vivo.

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In Vitro Model Prostate carcinoma PC3-PIP PSMA-positive cell CVCL_0035
References
Ref 1 New PSMA-Targeting Ligands: Transformation from Diagnosis (Ga-68) to Radionuclide Therapy (Lu-177). J Med Chem. 2022 Oct 13;65(19):13001-13012. doi: 10.1021/acs.jmedchem.2c00852. Epub 2022 Sep 14.
Ref 2 Lu-177-Labeled Hetero-Bivalent Agents Targeting PSMA and Bone Metastases for Radionuclide Therapy. J Med Chem. 2023 Sep 14;66(17):12602-12613. doi: 10.1021/acs.jmedchem.3c01294. Epub 2023 Sep 5.