Linker Information

General Information of This Linker
Linker ID
LIN00071
Linker Name
Phosphonic Acid Linker
Structure
Formula
C25H33N5O13P2
#Ro5 Violations (Lipinski): 4 Molecular Weight (mw) 673.509
Lipid-water partition coefficient (xlogp) -2.2651
Hydrogen Bond Donor Count (hbonddonor) 10
Hydrogen Bond Acceptor Count (hbondacc) 9
Rotatable Bond Count (rotbonds) 17
Canonical smiles
NCC(=O)NC(Cc1ccc(OCC(=O)NC(Cc2ccccc2)C(=O)O)cc1)C(=O)NCC(=O)NC(P(=O)(O)O)P(=O)(O)O
InChI
InChI=1S/C25H33N5O13P2/c26-12-20(31)28-18(23(34)27-13-21(32)30-25(44(37,38)39)45(40,41)42)10-16-6-8-17(9-7-16)43-14-22(33)29-19(24(35)36)11-15-4-2-1-3-5-15/h1-9,18-19,25H,10-14,26H2,(H,27,34)(H,28,31)(H,29,33)(H,30,32)(H,35,36)(H2,37,38,39)(H2,40,41,42)/t18-,19-/m0/s1
InChIKey
JTOYLKNPJGEPFO-OALUTQOASA-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-P17-079 [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 [1]
Indication Metastatic castration-resistant prostate cancer
Efficacy Data Cell uptake rate
4.50%
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.

   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 2 Reporting the Activity Data of This PDC [1]
Indication Metastatic castration-resistant prostate cancer
Efficacy Data Cell uptake rate
8%
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.

   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 3 Reporting the Activity Data of This PDC [1]
Indication Metastatic castration-resistant prostate cancer
Efficacy Data Cell uptake rate
14%
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.

   Click to Show/Hide
In Vitro Model Prostate carcinoma PC3-PIP PSMA-positive cell CVCL_0035
Experiment 4 Reporting the Activity Data of This PDC [1]
Indication Metastatic castration-resistant prostate cancer
Efficacy Data Cell uptake rate
17%
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 [1]
Indication Metastatic castration-resistant prostate cancer
Efficacy Data Cell uptake rate
20%
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.

   Click to Show/Hide
In Vitro Model Prostate carcinoma PC3-PIP PSMA-positive cell CVCL_0035
References
Ref 1 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.