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Preparation and biological evaluation of (64)Cu labeled Tyr(3)-octreotate using a phosphonic acid-based cross-bridged
Yunjun Guo1, Riccardo Ferdani, Carolyn J Anderson
1Mallinckrodt Institute of Radiology, Washington University, St. Louis, MO, USA.
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, Tyr(3)-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-tetraazabicyclo[6.6.2]hexadecane (CB-TE2A), CB-TE1A1P-Y3-TATE was radiolabeled with (64)Cu in high purity and high specific activity using mild conditions. Saturation binding assays revealed that (64)Cu-CB-TE1A1P-Y3-TATE had comparable binding affinity but bound to more binding sites in AR42J rat pancreatic tumor cell membranes than (64)Cu-CB-TE2A-Y3-TATE. Both radiopharmaceuticals showed comparable uptake in SSTr2 positive tissues in AR42J tumor-bearing rats. (64)Cu-CB-TE1A1P-Y3-TATE demonstrated improved blood clearance compared to (64)Cu-CB-TE2A-Y3-TATE, as the tumor/blood ratios of (64)Cu-CB-TE1A1P-Y3-TATE were shown to be significantly higher than those of (64)Cu-CB-TE2A-Y3-TATE at 4 and 24 h postinjection. (64)Cu-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 (64)Cu-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 (64)Cu-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 (64)Cu-CB-TE2A-Y3-TATE.
Insights
A novel chelator, CB-TE1A1P, was developed for radiolabeling somatostatin analogues like Y3-TATE with copper-64. This new agent shows improved tumor targeting and reduced off-target accumulation for neuroendocrine tumor imaging and therapy.
Area of Science:
- Nuclear Medicine
- Radiopharmaceutical Chemistry
- Oncology
Background:
- Somatostatin receptors (SSTr) are overexpressed in neuroendocrine tumors, making them targets for imaging and therapy.
- Radiolabeled somatostatin analogues are used for positron emission tomography (PET) imaging and radionuclide therapy of SSTr-positive tumors, particularly subtype-2 (SSTr2).
Purpose of the Study:
- To develop a novel somatostatin analogue, Tyr(3)-octreotate (Y3-TATE), conjugated to a new cross-bridged macrocyclic chelator, 11-carboxymethyl-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane-4-methanephosphonic acid (CB-TE1A1P).
- To evaluate the radiolabeling efficiency, binding characteristics, and in vivo performance of the (64)Cu-labeled CB-TE1A1P-Y3-TATE conjugate for PET imaging.
Main Methods:
- Radiolabeling of CB-TE1A1P-Y3-TATE and CB-TE2A-Y3-TATE with copper-64 ((64)Cu) under mild conditions.
- Saturation binding assays using AR42J rat pancreatic tumor cell membranes.
- In vivo studies in AR42J tumor-bearing rats to assess biodistribution, blood clearance, and tumor uptake.
- Small animal PET/CT imaging.
Main Results:
- (64)Cu-CB-TE1A1P-Y3-TATE was successfully radiolabeled with high purity and specific activity under mild conditions.
- The new conjugate exhibited comparable binding affinity but increased binding site availability compared to (64)Cu-CB-TE2A-Y3-TATE.
- (64)Cu-CB-TE1A1P-Y3-TATE showed improved blood clearance and higher tumor/blood ratios, with reduced accumulation in nontarget organs (liver, lung, bone) compared to the control.
- PET/CT imaging confirmed significant tumor uptake and good contrast.
Conclusions:
- CB-TE1A1P is a promising bifunctional chelator for developing (64)Cu-labeled Y3-TATE for neuroendocrine tumor imaging and therapy.
- The novel conjugate offers high binding affinity, target tissue uptake, efficient radiolabeling, and improved tumor-to-nontarget ratios.
- This agent holds potential for enhanced diagnostic and therapeutic applications in SSTr-positive cancers.
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