Delving into the Latest Updates on PSMA inhibitors(Alpha-9 Theranostics) with Synapse

Overview

Basic Info

Drug Type

Peptide Conjugate Radionuclide, Therapeutic radiopharmaceuticals

Synonyms-

Target

PSMA

Action

inhibitors

Mechanism

PSMA inhibitors(Prostate-specific membrane antigen inhibitors)

Therapeutic Areas

NeoplasmsUrogenital Diseases

Active Indication

Prostatic Cancer

Inactive Indication-

Originator Organization

Alpha-9 Oncology, Inc.

Active Organization

Alpha-9 Oncology, Inc.

Inactive Organization-

License Organization-

Drug Highest PhasePreclinical

First Approval Date-

Regulation-

Structure/Sequence

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CTT1403 (¹⁷⁷Lu-CTT2001), an irreversible phosphoramidate PSMA inhibitor developed by Cancer Targeted Technology, was initially synthesized using a two-step radiolabeling method and has previously been evaluated in first-in-human studies. This two-step approach protected the phosphoramidate pharmacophore-containing a temperature- and pH-labile PN bond-from the harsh conditions required for lutetium-177 (¹⁷⁷Lu) chelation. Although the final chemical structure of CTT1403 is identical regardless of the radiolabeling route, it was not clear that CTT2001 could tolerate one-step labeling conditions while preserving PSMA-binding integrity. Therefore, the aim of the study was to develop, optimize, and automate a one-step radiolabeling method for CTT1403 and to confirm that the resulting product is biologically equivalent and exhibits comparable in vitro and in vivo behavior to CTT1403 produced by the original two-step process.

METHODS:

CTT2001 was synthesized and radiolabeled with ¹⁷⁷Lu using an optimized one-step procedure that was subsequently automated on a Trasis AllinOne synthesizer. Radiochemical purity, stability, cellular uptake/internalization, and biodistribution in PC3-PIP tumor-bearing mice were evaluated.

RESULTS:

CTT1403 synthesized via the one-step method demonstrated cellular uptake and internalization in PC3-PIP cells, as well as in vivo biodistribution in PC3-PIP tumor-bearing mice, that were comparable to those of the two-step-labeled product. The one-step procedure was successfully automated on the Trasis All-in-One synthesizer, producing CTT1403 with a radiochemical yield of 86.5 ± 4.27% (n = 3), a molar activity of 30.3 ± 1.11 MBq/nmol, and a radiochemical purity of 97.6 ± 0.80% (n = 3) in a total synthesis time of 38 min. The final product remained stable for at least 24 h at -4 °C and -20 °C.

CONCLUSIONS:

The one-step radiolabeling method yields CTT1403 that is biologically equivalent to the two-step product and can be reliably produced using fully automated synthesis. This streamlined, efficient, and reproducible approach supports routine clinical manufacturing of CTT1403.

01 Mar 2026·NUCLEAR MEDICINE AND BIOLOGY

H3RESCA chelator-enabled [18F]AlF labeling: An optimized temperature-resilient platform for PSMA-targeted PET tracers in prostate cancer

Article

Author: Wang, Cheng ; Li, Jingye ; Hu, Zhoumi ; Zhang, Qingyu ; Liu, Jianjun ; Zhang, Yukai ; Zhang, Bowu

OBJECTIVE:

Prostate-specific membrane antigen (PSMA) has emerged as a pivotal biomarker for the molecular imaging and targeted therapy of prostate cancer. To address the ongoing need for PSMA-targeting radiotracers with improved mild-labeling capability and reduced non-target organ exposure, beyond currently approved agents (e.g., [⁶⁸Ga]Ga-PSMA-11) that require higher temperatures or show hepatobiliary clearance, a novel ¹⁸F-labeled PSMA inhibitor, [¹⁸F]AlF-H₃RESCA-PSMA, was developed for PET imaging of prostate cancer.

METHODS:

H₃RESCA-PSMA was synthesized with an acyclic pentadentate chelator and radiolabeled with [¹⁸F]AlF at room temperature. Biodistribution and PET/CT studies were performed in PSMA-positive tumor xenografts, with [¹⁸F]AlF-PSMA-RESCA1 as comparator.

RESULTS:

Radiochemical yield was 75.5 ± 5.0%. [¹⁸F]AlF-H₃RESCA-PSMA showed 2-fold higher tumor uptake and slower wash-out versus PSMA-RESCA1, while exhibiting markedly reduced liver and kidney retention. PET images revealed superior tumor contrast and faster background clearance.

CONCLUSIONS:

[¹⁸F]AlF-H₃RESCA-PSMA offers enhanced PSMA-targeting specificity and imaging contrast, supporting its clinical translation for prostate cancer PET.

12 Feb 2026·JOURNAL OF MEDICINAL CHEMISTRY

Quinoline/Naphthalene-Embedded PSMA Probes for Precise PET Imaging with Minimized Undesired Retention

Article

Author: Guo, Zhide ; Li, Ben ; Zhuang, Rongqiang ; Liu, Hongwu ; Zhang, Xianzhong ; Li, Yesen ; Sun, Jiahui ; Chen, Shihan ; Chi, Yiqing ; Huang, Jieying ; Yu, Qian ; Yang, Guangjie ; Zhang, Mingxin ; He, Zhexin

Accumulation in nontarget tissues, particularly the salivary glands, remains a major challenge for prostate-specific membrane antigen (PSMA)-targeted radiotherapeutics, narrowing the theranostic window. In this work, we developed quinoline/naphthalene-derived PSMA radiotracers ([¹⁸F]AlF-NNA₈P₁, [¹⁸F]AlF-NNB₈P₁, and [¹⁸F]AlF-NCB₈P₁) to minimize nontarget accumulation through systematic molecular optimization. All probes exhibited excellent stability in vitro and in vivo. In PSMA-positive PC3-PIP cells, a significant uptake was observed with nanomolar binding affinities. Visual drug screening and first-in-human studies were conducted. In PSMA-positive tumor models, micro-positron emission tomography (PET) imaging and biodistribution demonstrated high tumor uptake, significantly blocked by coinjection with PSMA inhibitors. The probes showed blood clearance primarily and a low background retention. In initial clinical evaluations, [¹⁸F]AlF-NCB₈P₁ outperformed the widely used [¹⁸F]PSMA-1007, enabling clear visualization of metastatic lesions. The preclinical and clinical results validate that these quinoline/naphthalene-based radiotracers hold promise for enriching the prostate cancer (PCa) precision oncology toolkit, paving the way for next-generation theranostic agents with improved precision and safety.

100 Deals associated with PSMA inhibitors(Alpha-9 Theranostics)

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