Radioligands for pretargeted pet imaging and methods of their therapeutic use

Abstract

Described herein are Tz / TCO-based pretargeting strategies using an Al[18F]-NOTA-labeled tetrazine radioligand. This imaging strategy enables delineation of cancer at earlier time points compared to other imaging strategies and further decreases the radiation dose to healthy tissues compared to directly labeled antibodies. Al-based 18F imaging of small molecules, such as tetrazine, has not been previously achieved due to the decomposition of tetrazine during radiofluorination. Radiofluorination is advantageous over other radiolabeling methods because, in addition to having a shorter half-life, 18F is more readily available to produce and therefore integrated into hospital workflows.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application claims priority to and the benefit of, and incorporates herein by reference in its entirety, U.S. Provisional Patent Application No. 62 / 159,763, filed May 11, 2015.GOVERNMENT SUPPORT[0002]This invention was made with government support under grant 1K99 CA178205-01 awarded by the National Institutes of Health (NIH) / National Cancer Institute (NCI) and grants P30 CA08748, K25 EB016673, TR; R00 CA1440138, BMZ; 2R42CA128362, awarded by the National Institutes of Health (NIH). The government has certain rights in the invention.FIELD OF THE INVENTION[0003]This invention relates generally to pretargeted positron emission tomography (PET) imaging of cancer. In particular embodiments, the invention relates to radioligands for pretargeted PET imaging of cancer (e.g., colorectal, pancreatic, etc.).BACKGROUND[0004]Over the past 25 years, antibodies have emerged as effective vectors for the sensitive and specific delivery of radioisoto...

AI Technical Summary

Benefits of technology

[0015]Described herein are Tz / TCO-based pretargeting strategies using (1) a 64Cu-sarcophagine-based tetrazine radioligand for pretargeted PET imaging with more rapid excretion of the excess radioligand through the bladder and kidneys and (2) an Al[18F]-NOTA-labeled tetrazine radioligand. These imaging strategies enable delineation of cancer at earlier time points compared to other imaging strategies and further decrease the radiation dose to healthy tissues compared to directly labeled antibodies.

[0017]In certain embodiments, the present disclosure describes the synthesis and characterization of in vivo behavior of two 64Cu-labeled tetrazine radioligands: 64Cu-Tz-PEG7-NOTA and 64Cu-Tz-SarAr. These two radioligands possess structural alterations that modulate their pharmacokinetic profile compared to prior imaging systems. In some example embodiments, the system described herein produces higher activity concentrations in the tumor and, due to the renal excretion of the unbound radioligand disclosed herein, provides improved tumor-to-background activity concentration ratios at early time points. Furthermore, the presently disclosed methodologies function at significantly lower dose rates required by directly labeled radioimmunoconjugates. In some certain embodiments, the present imaging strategies can be effective for any cancer (e.g., colorectal, pancreatic) for which a non-internalizing, biomarker-targeted antibody exists.

[0018]In certain embodiments, a TCO-bearing immuno-conjugate of the anti-CA19.9 antibody 5B1 and an Al[18F]-NOTA-labeled tetrazine radioligand were harnessed for the visualization of CA19.9-expressing BxPC3 pancreatic cancer xenografts. Al-based 18F imaging of small molecules, such as tetrazine, has not been previously achieved due to the decomposition of tetrazine during radiofluorination. Radiofluorination is advantageous over other radiolabeling methods because, in addition to having a shorter half-life, 18F is more readily available to produce, and therefore, more suited to be integrated into hospital workflows. Biodistribution and 18F-PET imaging data clearly demonstrate that this methodology effectively delineates tumor mass with activity concentrations up to 6.4% ID / g at 4 h after injection of the radioligand.

Problems solved by technology

Al-based 18F imaging of small molecules, such as tetrazine, has not been previously achieved due to the decomposition of tetrazine during radiofluorination.

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