New Bifunctional Chelator p-SCN-PhPr-NE3TA for Copper-64: Synthesis, Peptidomimetic Conjugation, Radiolabeling, and Evaluation for PET Imaging

Abstract

Bifunctional chelators play an important role in developing metallic radionuclide-based radiopharmaceuticals. In this study, a new bifunctional ligand, p-SCN-PhPr-NE3TA, was synthesized and conjugated to a very late antigen-4 targeting peptidomimetic, LLP2A, for evaluating its application in 64Cu-based positron emission tomography (PET) imaging. The new ligand exhibited strong selective coordination of Cu(II), leading to a robust Cu complex, even in the presence of 10-fold Fe(III). The LLP2A conjugate of p-SCN-PhPr-NE3TA was prepared and successfully labeled with 64Cu under mild conditions. The conjugate 64Cu-NE3TA-PEG4-LLP2A showed significantly higher specific activity, compared with 64Cu-NOTA-PEG4-LLP2A, while maintaining comparable serum stability. Subsequent biodistribution studies and PET imaging in mice bearing B16F10 xenografts confirmed its favorable in vivo performance and high tumor uptake with low background, rendering p-SCN-PhPr-NE3TA a promising bifunctional chelator for 64Cu-based radiopharmaceuticals.

1,4,7‐Triazacyclononane‐Based Bifunctional Picolinate Ligands for Efficient Copper Complexation

“…Among the copper radioisotopes, 64 Cu (β + , t 1/2 = 12.7 h) appears to be a particular good candidate for positron emission tomography (PET) imaging owing to its relatively long decay and the possibility to form an interesting theranostic pair with the β – emitter 67 Cu isotope (β – , t 1/2 = 62 h). Among the numerous compounds used as chelators for 64 Cu labeling, 1,4,7‐triazacyclononane‐1,4,7‐triacetic acid (H 3 nota; Scheme ) has been the subject of intense research efforts, as it forms complexes with in vivo stabilities higher than those of 1,4,7,10‐tetraazacyclododecane‐1,4,7,10‐tetraacetic acid (H 4 dota) and 1,4,8,11‐tetraazacyclotetradecane‐1,4,8,11‐tetraacetic acid (H 4 teta) analogues . Commercially available nota derivatives have been developed owing to the interesting properties of this ligand scaffold for the envisaged applications.…”

Synthesis and Evaluation of New Bifunctional Chelators with Phosphonic Acid Arms for Gallium-68 Based PET Imaging in Melanoma

“…By coupling p -SCN-PhPr-NE2P1A and p -SCN-PhPr-NE2A1P to LLP2A-PEG 4 via a thiourea bond formation, the corresponding products NE2A1P-PEG 4 -LLP2A and NE2P1A-PEG 4 -LLP2A were conveniently obtained in high yields. In addition, NOTA-PEG 4 -LLP2A and NE3TA-PEG 4 -LLP2A were also prepared 22 to compare their in vivo performances.…”

PET and SPECT imaging of melanoma: the state of the art

“…Recently Gai et al designed a new probe 64 Cu-NE3TA-PEG4-LLP2A using the newly discovered chelator p-SCN-PhPr-NE3TA and assessed the diagnostic efficacy of the probe in melanoma xenografts. Small animal PET/CT imaging with 64 Cu-NE3TA-PEG4-LLP2A demonstrated high uptake with a superior tumor-to-muscle ratio at 4 h postinjection [173]. In addition, a study from Beaino et al reported that 177 Lu-DOTA-PEG 4 -LLP2A could accumulate not only in primary melanoma but also in the metastatic lesions in the lung and brain, demonstrating the potential of 177 Lu-DOTA-PEG 4 -LLP2A as an alternative treatment strategy for metastatic VLA-4 expressing melanoma [174].…”