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PSMA-617-linker 2 (free acid from) is a novel peptide linker used for synthesis of PSMA-617 (vipivotide tetraxetan) which is a ligand used to make 177Lu-PSMA-617 [Pluvicto (lutetium (177Lu) vipivotide tetraxetan)], which is a radioactive molecule approved in 2022 to treat cancer.
| Targets |
Prostate-specific membrane antigen (PSMA). [1]
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|---|---|
| ln Vitro |
The uptake and internalization of 177Lu-PSMA-617 were evaluated in PSMA-positive PC-3 PIP cells. After a 4-hour incubation at 37°C, the total cell uptake was 58%, with 12% of the radioligand being internalized. Uptake in PSMA-negative PC-3 flu cells was below 0.5%, indicating PSMA-specific binding. [1]
Plasma protein binding capacity was assessed via an ultrafiltration assay. 177Lu-PSMA-617 showed very low binding to mouse plasma proteins (9.3 ± 1.1%) and some binding to human plasma proteins (57 ± 2.3%). [1] |
| ln Vivo |
Biodistribution studies in PC-3 PIP/flu tumor-bearing mice revealed that 177Lu-PSMA-617 reached a maximum tumor uptake of approximately 56% IA/g at 4 hours post-injection (p.i.), which decreased to about 20% IA/g after 192 hours. It was cleared rapidly from the blood, resulting in <1% IA/g at 1 hour p.i. Renal clearance was also fast, with kidney uptake decreasing from approximately 10% IA/g at 1 hour p.i. to <1% IA/g at 24 hours p.i. Radioactivity levels in all other tissues were below blood levels and decreased continuously over time. [1]
Tumor-to-background ratios were increased for 177Lu-PSMA-617 at all investigated time points compared to the albumin-binding ligands due to its fast renal clearance. [1] |
| Cell Assay |
PSMA-positive PC-3 PIP and PSMA-negative PC-3 flu cells were used. Cells were seeded in 12-well plates. The radioligand solution was diluted in cell culture medium to a final concentration. The experiments were performed in triplicate. Cells were incubated at 37°C for 2 or 4 hours. After incubation, the medium was collected. Cells were washed with PBS. The surface-bound fraction was removed by washing with an acidic buffer (glycine-HCl, pH 2.8). Subsequently, cells were lysed with NaOH to collect the internalized fraction. The radioactivity of the collected fractions (medium, surface-bound, internalized) was measured with a gamma counter. The sum of the surface-bound and internalized fractions was referred to as cell uptake. The internalized fraction was also determined separately. [1]
Plasma protein binding was assessed using an ultrafiltration assay. 177Lu-PSMA-617 was diluted in mouse or human plasma and incubated for 15 minutes at room temperature. An aliquot was loaded onto an ultrafiltration device and centrifuged. The filtered activity was measured to calculate the percentage of plasma protein-bound activity (retained on the filter membrane). Control experiments were performed with PBS (a buffer solution without proteins). [1] |
| Animal Protocol |
In vivo experiments were approved by the local veterinarian department and conducted in accordance with Swiss law. Female, athymic BALB/c nude mice (5-6 weeks old) were subcutaneously inoculated with PC-3 PIP cells (6 × 10^6 cells in 100 μL HBSS) on the right shoulder and with PC-3 flu cells (5 × 10^6 cells in 100 μL HBSS) on the left shoulder, 12-14 days before experiments. For biodistribution studies, mice were injected into a lateral tail vein with 177Lu-PSMA-617 (5 MBq, 1 nmol, 100 μL) diluted in saline containing 0.05% BSA to prevent adsorption. Mice were sacrificed at different time points (1, 4, 24, 48, 96, 192 h post-injection). Selected tissues and organs were collected, weighed, and measured using a gamma counter. Groups of 3-6 mice were used for each time point. [1]
For SPECT/CT imaging studies, mice were injected with 177Lu-PSMA-617 (25 MBq, 1 nmol, 100 μL) diluted in saline containing 0.05% BSA. SPECT/CT scans were performed at 4, 24, and 72 hours after injection. During the scans, mice were anesthetized with a mixture of isoflurane and oxygen. [1] In vivo experiments were approved by the local veterinarian department and conducted in accordance with Swiss law. Female, athymic BALB/c nude mice (5-6 weeks old) were subcutaneously inoculated with PC-3 PIP cells (6 × 10^6 cells in 100 μL HBSS) on the right shoulder and with PC-3 flu cells (5 × 10^6 cells in 100 μL HBSS) on the left shoulder, 12-14 days before experiments. For biodistribution studies, mice were injected into a lateral tail vein with 177Lu-PSMA-617 (5 MBq, 1 nmol, 100 μL) diluted in saline containing 0.05% BSA to prevent adsorption. Mice were sacrificed at different time points (1, 4, 24, 48, 96, 192 h post-injection). Selected tissues and organs were collected, weighed, and measured using a gamma counter. Groups of 3-6 mice were used for each time point. [1] For SPECT/CT imaging studies, mice were injected with 177Lu-PSMA-617 (25 MBq, 1 nmol, 100 μL) diluted in saline containing 0.05% BSA. SPECT/CT scans were performed at 4, 24, and 72 hours after injection. During the scans, mice were anesthetized with a mixture of isoflurane and oxygen. [1] |
| ADME/Pharmacokinetics |
The n-octanol/PBS distribution coefficient (logD) of 177Lu-PSMA-617 was -4.4 ± 0.15, indicating its hydrophilic nature. [1]
Biodistribution studies in mice showed that 177Lu-PSMA-617 was cleared rapidly from the blood, with blood activity levels falling below 1% IA/g at 1 hour post-injection. It was also cleared quickly from the kidneys, with uptake decreasing from ~10% IA/g at 1 hour to <1% IA/g at 24 hours. [1] |
| Toxicity/Toxicokinetics |
Plasma protein binding of 177Lu-PSMA-617 was determined. Binding to mouse plasma proteins was 9.3 ± 1.1%, and binding to human plasma proteins was 57 ± 2.3%. [1]
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| References | |
| Additional Infomation |
177Lu-PSMA-617 is a clinically employed PSMA radioligand used for the treatment of metastatic castration-resistant prostate cancer (mCRPC). In this study, it was used as a benchmark to compare the properties of newly developed albumin-binding PSMA ligands. [1]
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| Molecular Formula |
C33H45N5O9
|
|---|---|
| Molecular Weight |
655.738508939743
|
| Exact Mass |
655.321
|
| CAS # |
1703768-74-4
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| PubChem CID |
138911307
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| Appearance |
White to off-white solid powder
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| LogP |
-0.3
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| Hydrogen Bond Donor Count |
8
|
| Hydrogen Bond Acceptor Count |
10
|
| Rotatable Bond Count |
18
|
| Heavy Atom Count |
47
|
| Complexity |
1080
|
| Defined Atom Stereocenter Count |
3
|
| SMILES |
O=C(C1CCC(CN)CC1)N[C@H](C(NCCCC[C@@H](C(=O)O)NC(N[C@H](C(=O)O)CCC(=O)O)=O)=O)CC1C=CC2C=CC=CC=2C=1
|
| InChi Key |
JHWCOTSIOATVKA-MOTXCXSHSA-N
|
| InChi Code |
InChI=1S/C33H45N5O9/c34-19-20-8-12-23(13-9-20)29(41)36-27(18-21-10-11-22-5-1-2-6-24(22)17-21)30(42)35-16-4-3-7-25(31(43)44)37-33(47)38-26(32(45)46)14-15-28(39)40/h1-2,5-6,10-11,17,20,23,25-27H,3-4,7-9,12-16,18-19,34H2,(H,35,42)(H,36,41)(H,39,40)(H,43,44)(H,45,46)(H2,37,38,47)/t20?,23?,25-,26-,27-/m0/s1
|
| Chemical Name |
(2S)-2-[[(1S)-5-[[(2S)-2-[[4-(aminomethyl)cyclohexanecarbonyl]amino]-3-naphthalen-2-ylpropanoyl]amino]-1-carboxypentyl]carbamoylamino]pentanedioic acid
|
| Synonyms |
PSMA 617-linker PSMA617-linkerPSMA-617-linker
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO : ~125 mg/mL (~190.62 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (3.17 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.08 mg/mL (3.17 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.08 mg/mL (3.17 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.5250 mL | 7.6250 mL | 15.2499 mL | |
| 5 mM | 0.3050 mL | 1.5250 mL | 3.0500 mL | |
| 10 mM | 0.1525 mL | 0.7625 mL | 1.5250 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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