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Publication Number
US-11225496-B2
Publication Date
2022-01-18
Expiration Date
Abstract
Provided herein are compounds of Formula (I) or a pharmaceutically acceptable salt thereof. Also provided are compositions including a compound of Formula (I) together with a pharmaceutically acceptable carrier, and methods for imaging prostate cancer cells.
Core Innovation
The invention relates to compounds defined by formula (Ib), or pharmaceutically acceptable salts thereof, wherein L1A is a divalent linking group and R is a chelating agent. The chelating agent optionally chelates a therapeutic radioisotope or a PET-active, SPECT-active, or MRI-active radioisotope, and the compound further specifies that each of R1 and R2 is independently hydrogen, C1-C6 alkyl, or a protecting group, while R3 is hydrogen.
A parameter y takes values 2, 3, 4, 5, or 6, and the disclosure includes related formula embodiments such as Formula (II), Formula (IIa) through Formula (IIg), Formula (If), Formula (Ig), and Formula (Ih). The document further provides multiple specific molecular embodiments and structural variants with divalent linking groups, chelator/radioisotope-conjugate scaffold embodiments, and variable spacer chemistries and lengths.
The disclosure also describes chelator constructs linked with azide- or alkyne-modified PMSA inhibitors, including an alkyne-modified PMSA inhibitor and azide-containing chelator constructs. The chelator classes include DOTA, NOTA, PCTA, DO3A, HBED, NODAG, CB-TE2A, CB-TE1K1P, desferrioxamine, DTPA, and TETA, and the disclosed radioisotopes include 89Zr, 64Cu, 68Ga, 186/188Re, 90Y, 177Lu, 153Sm, 213Bi, 225Ac, and 223Ra.
Claims Coverage
The independent claim covers a compound of formula (Ib) with a divalent linking group L1A and a chelating agent R that can optionally chelate a therapeutic or PET/SPECT/MRI-active radioisotope, with defined substituent constraints on R1, R2, R3, and y. Dependent coverage further narrows the compound by specific chelator moieties, parameter fixation, enumerated radioisotopes, an imaging use, a pharmaceutical composition, and an albumin-binding moiety X.
Compound of formula (Ib) with divalent linking group L1A and chelating agent R
A compound of formula (Ib), or a pharmaceutically acceptable salt thereof, wherein L1A is a divalent linking group and R is a chelating agent optionally chelating a therapeutic radioisotope or a PET-active, SPECT-active, or MRI-active radioisotope.
Substituent and parameter limitations for R1, R2, R3, and y
Each R1 and R2 are independently hydrogen, C1-C6 alkyl or a protecting group, R3 is hydrogen, and y is 2, 3, 4, 5, or 6.
Chelating-agent moiety selection within R
The compound wherein R comprises one or more of DOTA, NOTA, PCTA, DO3A, HBED, NODAG, CB-TE2A, CB-TE1K1P, desferrioxamine, DTPA, or TETA.
Chelating of an enumerated therapeutic or imaging radioisotope
The compound wherein the chelating agent chelates a therapeutic radioisotope or a PET-active, SPECT-active, or MRI-active radioisotope selected from 89Zr, 64Cu, 68Ga, 186/188Re, 90Y, 177Lu, 153Sm, 213Bi, 225Ac, and 223Ra.
Imaging one or more prostate cancer cells in a patient
A method that images one or more prostate cancer cells in a patient by administering the compound and then imaging the patient.
Albumin-binding moiety X
A construct that includes an albumin-binding moiety X.
Overall, the claim coverage centers on formula (Ib) compounds incorporating a divalent linking group and a chelating agent that can optionally bind therapeutic or imaging radioisotopes, with constrained substituent definitions and a defined y range. Dependent coverage narrows to specific chelators, enumerated radioisotopes, imaging use, pharmaceutical composition, and an albumin-binding moiety X.
Stated Advantages
PSMA-specific uptake/internalization in PSMA+ versus PSMA− PC3 models is reported.
Blocked uptake is described using PMPA (2-(phosphonomethyl)pentane-1,5-dioic acid).
Therapeutic outcomes are reported as tumor volume reduction and survival, alongside tumor-to-background metrics and time-dependent tumor uptake.
Improved in vivo properties via inclusion of an albumin-binding moiety X.
Documented Applications
Imaging of prostate cancer cells.
PSMA-targeted radiotherapeutic platform.
In vivo biodistribution and therapy with 177Lu-CTT1403 in NCr nude mice.
Imaging one or more prostate cancer cells in a patient by administering the compound and imaging the patient.
Imaging prostate cancer cells and tumor-associated vasculature.
Pharmaceutical composition comprising the compound and a pharmaceutically acceptable carrier.
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