Preparation and Biological Evaluation of ⁶⁴Cu Labeled Tyr³-Octreotate Using a Phosphonic Acid-Based Cross-Bridged Macrocyclic Chelator

Abstract

Somatostatin receptors (SSTr) are overexpressed in a wide range of neuroendocrine tumors, making them excellent targets for nuclear imaging and therapy, and radiolabeled somatostatin analogues have been investigated for positron emission tomography imaging and radionuclide therapy of SSTr-positive tumors, especially of the subtype-2 (SSTr2). The aim of this study was to develop a somatostatin analogue, Tyr3-octreotate (Y3-TATE), conjugated to a novel cross-bridged macrocyclic chelator, 11-carboxymethyl-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane-4-methanephosphonic acid (CB-TE1A1P). Unlike traditional cross-bridged macrocycles, such as 4, 11 - bis (carboxymethyl) - 1, 4, 8, 11 -etraazabicyclo[6.6.2]hexadecane (CB-TE2A), CB-TE1A1P-Y3-TATE was radiolabeled with 64Cu in high purity and high specific activity using mild conditions. Saturation binding assays revealed that 64Cu-CB-TE1A1P-Y3-TATE had comparable binding affinity but bound to more binding sites in AR42J rat pancreatic tumor cell membranes than 64Cu-CB-TE2A-Y3-TATE. Both radiopharmaceuticals showed comparable uptake in SSTr2 positive tissues in AR42J tumor-bearing rats. 64Cu-CB-TE1A1PY3- TATE demonstrated improved blood clearance compared to 64Cu-CB-TE2A-Y3-TATE, as the tumor/blood ratios of 64Cu-CB-TE1A1P-Y3-TATE were shown to be significantly higher than those of 64Cu-CB-TE2A-Y3-TATE at 4 and 24 h postinjection. 64Cu-CB-TE1A1P-Y3-TATE, in spite of a relatively high kidney uptake, accumulated less in nontarget organs such as liver, lung, and bone. Small animal PET/CT imaging of 64Cu-CB-TE1A1P-Y3-TATE in AR42J tumor bearing rats validated significant uptake and good contrast in the tumor. This study suggests that CB-TE1A1P is a promising bifunctional chelator for 64Cu-labeled for Y3-TATE, owing to high binding affinity and target tissue uptake, the ability to radiolabel the agent at lower temperatures, and improved tumor/nontarget organ ratios over 64Cu-CB-TE2A-Y3-TATE.

Characterization and Evaluation of 64Cu-Labeled A20FMDV2 Conjugates for Imaging the Integrin αvβ6

“…Here, we described the 64 Cu radiolabeling of the pegylated A20FMDV2 peptide, a peptide shown to target the integrin α v β 6 , via four different chelators. CB-TE1A1P is a cross-bridged cyclam-based macrocycle featuring a phosphonate pendant arm that can readily complex copper(II) under mild conditions at high specific activity [18, 23]. DOTA and NOTA are two commercially available, widely used chelators for a variety of different small molecules [24].…”

“…Similarly, when CB-TE1A1P was tested on the somatostatin agonist Y3-TATE, the kidney uptake level remained consistently low at 5 % ID/g at all time points (up to 24 h p.i.) [23]. These previous instances of low kidney uptake all occur on tracers demonstrating high metabolic stability [29–31].…”

Pycup—A Bifunctional, Cage-like Ligand for 64Cu Radiolabeling

“…64 Cu-complexes have been used for the imaging of a number of protein targeting vectors, such as somatostatin analogs, 29–31 bombesin derivatives, 10, 16, 32 and RGD peptides. 11, 17, 33 We demonstrated that pycup2A could be used as a bifunctional ligand by conjugating it to a known fibrin-targeting peptide.…”

Preclinical Evaluation of a High-Affinity 18F-Trifluoroborate Octreotate Derivative for Somatostatin Receptor Imaging

“…For PET imaging, 68 Ga, 64 Cu, and 18 F along with various radioprosthetics have been conjugated to various octreotide derivatives (11)(12)(13)(14)(15)(16). Of these, certain 68 Ga ligands such as 68 Ga-DOTATOC, 68 Ga-DOTATATE, and 68 Ga-DOTANOC have shown promise for neuroendocrine tumor imaging (17)(18)(19) and are used in clinical trials as well as under the local practice of pharmacy, particularly in Europe.…”