Copper-64 Labeled Macrobicyclic Sarcophagine Coupled to a GRP Receptor Antagonist Shows Great Promise for PET Imaging of Prostate Cancer

Abstract

The gastrin-releasing peptide receptor (GRPr) is an important molecular target for the visualization and therapy of tumors and can be targeted with radiolabeled bombesin derivatives. The present study aims to develop statine-based bombesin receptor antagonists suitable for labeling with 64Cu for imaging by positron emission tomography (PET). The potent GRPr antagonist D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2 was conjugated to the sarcophagine (3,6,10,13,16,19-hexaazabicyclo[6.6.6] icosane=Sar) derivative 5-(8-methyl-3,6,10,13,16,19-hexaaza-bicyclo[6.6.6]icosan-1-ylamino)-5-oxopentanoic acid (MeCOSar) via PEG4 (LE1) and PEG2 (LE2) spacers and radiolabeled with 64Cu2+ with >95% yield and specific activities of about 100 MBq/nmol. Both Cu(II) conjugates have high affinity for GRPr (IC50: natCu-LE1, 1.4±0.1 nM; natCu-LE2, 3.8±0.6 nM). The antagonistic properties of both conjugates were confirmed by Ca2+-flux measurements. Biodistribution studies of Cu-64-LE1 exhibited specific targeting of the tumor (19.6±4.7% IA/g at 1 h p.i.) and GRPr-positive organs. Biodistribution and PET images at 4 and 24 h postinjection showed increasing tumor-to-background ratios with time. This was illustrated by the acquisition of PET images showing high tumor-to-normal tissue contrast. This study demonstrates the high affinity of the MeCOSar-PEGx-bombesin conjugates to GRPr. The stability of 64Cu complexes of MeCOSar, the long half-life of 64Cu, and the suitable biodistribution profile of the 64Cu-labeled peptides lead to PET images of high contrast suitable for potential translation into the clinic.

Bombesin-Targeted PET of Prostate Cancer

“…Recently, Gourni et al (22) chose to couple the Sar chelator-MeCoSar, already used along with somatostatin analogs-to PEG4-JMV594 for Cu(II) complex formation. The chelate had a 21 charge and was highly stable.…”

Synthesis, radiolabeling, and evaluation of gastrin releasing peptide receptor antagonist 68Ga‐HBED‐CC‐RM26

“…The peptide sequence D‐Phe‐Gln‐Trp‐Ala‐Val‐Gly‐His‐Sta‐Leu‐NH 2 named as JMV594 has emerged as the most promising GRPr‐specific antagonist peptide . Different spacers and chelators have been introduced a N‐terminal of the peptide sequence and radiolabeled with 68 Ga/ 64 Cu for imaging purposes . Some of the antagonist peptide tracers including 68 Ga‐RM2 [DOTA‐4‐amino‐(1‐carboxymethyl) piperidine‐D‐Phe‐Gln‐Trp‐Ala‐Val‐Gly‐His‐Sta‐Leu‐NH 2 ], 68 Ga‐SB3 [DOTA‐p‐aminomethylaniline‐diglycolic acid‐DPhe‐Gln‐Trp‐Ala‐Val‐Gly‐His‐Leu‐NHEt] and 68 Ga‐RM26 [NOTA‐D‐Phe‐Gln‐Trp‐Ala‐Val‐Gly‐His‐Sta‐Leu‐NH 2 ] have successfully translated from pre‐clinical to clinical studies .…”

Optimization of Hexadentate Bispidine Ligands as Chelators for 64CuII PET Imaging

“…As well as undergoing reasonably fast complexation and facile functionalization with biological vectors, ligands of 64 Cu for positron emission tomography (PET) need to yield stable and inert Cu II complexes at nanomolar concentrations under physiological conditions . Among the range of well‐established ligands used in this field, due to the facile synthesis, the large synthetic variability, the ease of derivatization with biological vectors and the relatively high complex stability and inertness, bispidines (3,7‐diazabicyclo[3.3.1]nonanes; see Figure for the bispidine ligands discussed in this manuscript) have been shown to have significant advantages for 64 Cu‐based PET imaging . Among other reasons, these arise from the rigid adamantane‐derived backbone—preorganized and complementary for tetragonally distorted octahedral geometries—that is well suited and selective for binding Cu II ; it is also for this reason that bispidines have been described as a favorable ligand platform for medicinal applications .…”