18F-labeled PSMA-targeted PET imaging agents
Inventors
Berkman, Clifford • Stekhova, Svetlana A.
Assignees
Cancer Targeted Technology LLC • Washington State University WSU
Publication Number
US-11554183-B2
Publication Date
2023-01-17
Expiration Date
2034-03-14
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Abstract
Compounds of Marlush formula (I) described in the claims are useful in diagnostic methods for detecting and/or identifying cells presenting PSMA. Disclosed are also methods for preparing the compounds. Representative compounds according to the application are:
Core Innovation
The invention provides small-molecule compounds of formula (I), and their pharmaceutically acceptable salts, which have high affinity and specificity to prostate-specific membrane antigen (PSMA). These compounds are used as diagnostic agents for detecting and/or identifying cells presenting PSMA, such as prostate cancer cells, utilizing the potency and selectivity of small-molecule PSMA inhibitors. The invention also discloses methods for preparing these compounds, particularly focusing on 18F-labeled derivatives suitable for positron emission tomography (PET) imaging.
Conventional approaches, such as antibody-based imaging techniques, encounter problems including detection of dead cells, limited clinical relevance, challenges with immunogenicity, and poor vascular permeability. These limitations reduce the effectiveness of current prostate cancer detection and monitoring methods. Additionally, large antibody molecules can inhibit further binding at neighboring sites, leading to decreased labeling. Despite PSMA's unique enzymatic ability to process small molecules, this property has been underutilized in diagnostic strategies.
By capitalizing on PSMA's capacity to recognize and process small chemical entities, the invention enables the development of diagnostic imaging agents that directly label and visualize PSMA-expressing cells in vivo. The compounds are designed with a radiolabeled pendant group, typically 18F, linked to the parent PSMA inhibitor through specific linkers, allowing for efficient imaging via PET. The invention further details the chemical synthesis routes and protective group strategies employed to optimize labeling and deprotection processes, ensuring high yield and minimal radiolabel loss.
Claims Coverage
The patent contains several independent claims focusing on novel 18F-labeled PSMA-targeting compounds, their salts, compositions, and specific structural features.
Compound of formula (I) with a specific linker and 18F-labeled phenyl or pyridyl group
A compound of the formula: - Where L is a linker comprising either —NH—CH2CH2—(OCH2CH2—)y—C(O)— or a group as defined in the specification. - R1 is an 18F-labeled phenyl or pyridyl group, optionally substituted with halogen, cyano, or nitro. - The compound may be in the form of a pharmaceutically acceptable salt. - All other structural variables and moieties are as explicitly defined in the patent description.
Specific compound structure
A compound having the explicit chemical structure as provided in claim 4 and corresponding figures in the patent, including its defined stereochemistry and substituents.
Salt forms of the defined compounds
- Pharmaceutically acceptable salts of the specifically claimed 18F-labeled PSMA-targeted compounds (as per claims 6 and 7). - The salt forms are explicitly defined by their chemical structure in the claims, such as sodium and potassium salts.
Pharmaceutical compositions comprising the defined compounds or their salts
- A composition comprising any of the claimed compounds (or their salts), together with a pharmaceutically acceptable carrier, excipient, and/or diluent (as in claims 3, 8, 9, 10, 11, 15, 16, 17, and 18). - Specifically includes compositions where the carrier/excipient is sterile saline.
The inventive features are centered on new 18F-labeled PSMA-targeting compounds with specific linkers and substituents, their salt forms, and pharmaceutical compositions thereof.
Stated Advantages
The compounds offer high affinity and specificity for PSMA, allowing detection and identification of PSMA-presenting cells.
The radiolabeled imaging agents enable efficient and specific PET imaging of PSMA-expressing tumors with enhanced tumor-to-blood ratios.
The deprotection and labeling methods minimize radiolabel loss, complete rapidly, and allow high radiochemical yields.
The invention provides improved acid and base stability compared to previous generation agents, resulting in more stable imaging compounds.
The compounds can be formulated as kits or pharmaceutical compositions suitable for clinical and veterinary diagnostic use.
The agents target both tumor cells and neovasculature in solid tumors, expanding the diagnostic range beyond prostate cancer.
Documented Applications
Diagnostic imaging of PSMA-presenting cells, such as prostate cancer cells, using PET or PET/CT.
Imaging of a wide variety of solid tumors expressing PSMA, including lung, renal, glioblastoma, pancreas, bladder, sarcoma, melanoma, breast, colon, germ cell, esophageal, and stomach tumors, as well as certain benign tissues.
Imaging and detection of physiological processes involving PSMA, such as glutamatergic neurotransmission.
Patient stratification for therapeutic interventions based on imaging results.
Use in clinical, veterinary, and research settings, including human, animal, and in vitro applications.
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