Metal/radiometal-labeled PSMA inhibitors for PSMA-targeted imaging and radiotherapy

Abstract

The present application relates to metal / radioactive metal labeled PSMA inhibitors for PSMA targeted imaging and radiotherapy. The invention relates to low-molecular weight gadolinium (Gd)-based MR contrast agents for PSMA- specific Ti-weighted MR imaging are disclosed. The (Gd)-based MR contrast agents exhibit high binding affinity for PSMA and exhibit specific Ti contrast enhancement at PSMA+ cells. The PSMA-targeted Gd-based MR contrast agents can be used for PSMA- targeted imaging in vivo. 86Y-labeled PSMA-binding ureas also are provided, wherein the PSMA-binding ureas also are suitable for use with other radiotherapeutics.

Description

[0001] This application is a divisional application of the application dated May 6, 2015, the application number is 201580036857.1, and the title of the invention is "Metal / radiometal-labeled PSMA inhibitor for PSMA-targeted imaging and radiotherapy".

[0002] Cross References to Related Applications

[0003] This application claims the benefit of U.S. Provisional Application No. 61 / 989,428, filed May 6, 2014, and U.S. Provisional Application No. 62 / 117,603, filed February 18, 2015, each of which is incorporated by reference in its entirety into this article. technical field

[0004] This application relates to, but is not limited to, metal / radiometal-labeled PSMA inhibitors for PSMA-targeted imaging and radiation therapy. Background technique

[0005] Prostate-specific membrane antigen (PSMA) is increasingly recognized as a viable target for other forms of imaging and therapy of prostate and cancer (Ghosh and Heston, 2004; Milowsky et al., 2007; Olson et al., 2007). PSMA ...

Examples

Embodiment 1

[0312] Synthesis and Evaluation of Gadolinium (Gd)-Based Contrast Agents

[0313] overview

[0314] Magnetic resonance (MR) imaging is advantageous as it can simultaneously provide anatomical, functional and molecular information. MR molecular imaging can combine the ubiquity of this established clinical pattern and its high spatial resolution with in vivo molecular lineage profiling. However, due to the inherently low sensitivity of MR, high local concentrations of biological targets are required to generate discernible MR contrast. Due to the high concentration of prostate-specific membrane antigen (PSMA) in target cells, limited expression in non-target tissues, and accessibility on the cell surface, we hypothesized that prostate-specific membrane antigen (PSMA), for prostate cancer Attractive target for imaging and therapy, may serve as a suitable biomarker for MR-based molecular imaging. For this purpose, three high-affinity, low molecular weight gadolinium(Gd)(III...

Embodiment 2

[0347] Receptor concentration of PSMA

[0348] Number of receptors per cell (N.R.C.) = 4.9 x 10 6 one, r 细胞 =8.75μm

[0349]

[0350]

[0351] Therefore, in order to observe 0.05 seconds -1 change (approximately 10% enhancement, taking into account tissue T 0 1 = 2 seconds), requires relaxivity (if acceptor:contrast 1:1)

[0352]

Embodiment 3

[0354] 86 Preclinical Evaluation of a Y-Labeled Prostate-Specific Membrane Antigen Inhibitor for Dosimetry Estimation

[0355] overview

[0356] 86 Y (half-life=14.74h, 33%β + ) within an emerging class of positron-emitting isotopes with relatively long physical half-lives, enabling extended imaging of biological processes. Three low-molecular-weight 86 Preparation and biodistribution of Y-labeled PSMA-conjugated urea ( Figure 14 ), and the most pharmacokinetically favorable agent in non-human primates was used in the preparation of the corresponding 90 Y-and 177 Dosimetric Imaging of Lu-Labeled Reagents in Clinical Trials.

[0357] in preparation[ 86 Y]-4-6 used a multi-step synthesis. PSMA inhibition constants were assessed by competitive binding assays. In vivo characterization using tumor-bearing male mice up to 24h after injection by [ 86 Y]-4-6 PET / CT and passed [ 86 Y]-4 and [ 86Y]-6 biodistribution studies were performed. Record quantitative whole-bo...

[0001] This application is a divisional application of the application dated May 6, 2015, the application number is 201580036857.1, and the title of the invention is "Metal / radiometal-labeled PSMA inhibitor for PSMA-targeted imaging and radiotherapy".

[0002] Cross References to Related Applications

[0003] This application claims the benefit of U.S. Provisional Application No. 61 / 989,428, filed May 6, 2014, and U.S. Provisional Application No. 62 / 117,603, filed February 18, 2015, each of which is incorporated by reference in its entirety into this article. technical field

[0004] This application relates to, but is not limited to, metal / radiometal-labeled PSMA inhibitors for PSMA-targeted imaging and radiation therapy. Background technique

[0005] Prostate-specific membrane antigen (PSMA) is increasingly recognized as a viable target for other forms of imaging and therapy of prostate and cancer (Ghosh and Heston, 2004; Milowsky et al., 2007; Olson et al., 2007). PSMA ...

Examples

Embodiment 1

[0312] Synthesis and Evaluation of Gadolinium (Gd)-Based Contrast Agents

[0313] overview

[0314] Magnetic resonance (MR) imaging is advantageous as it can simultaneously provide anatomical, functional and molecular information. MR molecular imaging can combine the ubiquity of this established clinical pattern and its high spatial resolution with in vivo molecular lineage profiling. However, due to the inherently low sensitivity of MR, high local concentrations of biological targets are required to generate discernible MR contrast. Due to the high concentration of prostate-specific membrane antigen (PSMA) in target cells, limited expression in non-target tissues, and accessibility on the cell surface, we hypothesized that prostate-specific membrane antigen (PSMA), for prostate cancer Attractive target for imaging and therapy, may serve as a suitable biomarker for MR-based molecular imaging. For this purpose, three high-affinity, low molecular weight gadolinium(Gd)(III...

Embodiment 2

[0347] Receptor concentration of PSMA

[0348] Number of receptors per cell (N.R.C.) = 4.9 x 10 6 one, r 细胞 =8.75μm

[0349]

[0350]

[0351] Therefore, in order to observe 0.05 seconds -1 change (approximately 10% enhancement, taking into account tissue T 0 1 = 2 seconds), requires relaxivity (if acceptor:contrast 1:1)

[0352]

Embodiment 3

[0354] 86 Preclinical Evaluation of a Y-Labeled Prostate-Specific Membrane Antigen Inhibitor for Dosimetry Estimation

[0355] overview

[0356] 86 Y (half-life=14.74h, 33%β + ) within an emerging class of positron-emitting isotopes with relatively long physical half-lives, enabling extended imaging of biological processes. Three low-molecular-weight 86 Preparation and biodistribution of Y-labeled PSMA-conjugated urea ( Figure 14 ), and the most pharmacokinetically favorable agent in non-human primates was used in the preparation of the corresponding 90 Y-and 177 Dosimetric Imaging of Lu-Labeled Reagents in Clinical Trials.

[0357] in preparation[ 86 Y]-4-6 used a multi-step synthesis. PSMA inhibition constants were assessed by competitive binding assays. In vivo characterization using tumor-bearing male mice up to 24h after injection by [ 86 Y]-4-6 PET / CT and passed [ 86 Y]-4 and [ 86Y]-6 biodistribution studies were performed. Record quantitative whole-bo...

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