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Preparing a 68Ga-labeled Arginine Glycine Aspartate RGD-peptide for Angiogenesis
Published on: January 7, 2019
Fundamental study of radiogallium-labeled aspartic acid peptides introducing octreotate derivatives
Atsushi Ishizaki1, Kenji Mishiro2, Kazuhiro Shiba3
1Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan.
Objective:
Somatostatin receptors are highly expressed in neuroendocrine tumors, and many radiolabeled somatostatin analogs for diagnosis and treatment have been developed. To simultaneously detect not only primary cancer but also bone metastases, this study aimed to develop a positron emission tomography probe using generator-produced nuclide Gallium-68 (T1/2 = 68 min), in which a carrier for primary cancer, a carrier for bone metastases lesions, and a stable gallium complex are introduced into the one molecule. Based on this strategy, the somatostatin receptor-targeted peptide, [Tyr3]-octreotate (TATE), aspartic acid peptide (Dn) with high binding affinity for hydroxyapatite, and Ga-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) as a stable gallium complex were selected. The novel complexes, Ga-DOTA-Dn-TATE (n = 0, 2, 5, 8, or 11), were designed, synthesized, and evaluated. The radiogallium complexes were prepared using the easy-to-handle radioisotope 67Ga due to relatively long half-life.
Methods:
The radiogallium complex precursor DOTA-Dn-TATE was synthesized by the Fmoc-based solid-phase method and by the air oxidation method to form the disulfide bond. [67Ga]Ga-DOTA-Dn-TATE was synthesized by reacting DOTA-Dn-TATE and 67Ga. Hydroxyapatite binding assays, in vitro cellular uptake experiments in AR42J tumor cells, in biodistribution experiments in AR42J tumor-bearing mice, were performed using [67Ga]Ga-DOTA-Dn-TATE.
Results:
The radiochemical purities of [67Ga]Ga-DOTA-Dn-TATE were > 96.0%. In in vitro and in vivo experiments, [67Ga]Ga-DOTA-D11-TATE had a high affinity for hydroxyapatite and highly accumulated in bone. However, the uptake of [67Ga]Ga-DOTA-D11-TATE into somatostatin receptor-positive AR42J cells was lower than that of [67Ga]Ga-DOTA-TATE, and the accumulation of [67Ga]Ga-DOTA-D11-TATE in tumor was significantly low.
Conclusion:
Ga-DOTA-D11-TATE may not be recognized by somatostatin receptor by the introduction of D11, and the charge adjustment may be important for somatostatin receptor-positive cell uptake.
Insights
Researchers developed a novel Gallium-68 positron emission tomography probe for detecting neuroendocrine tumors and bone metastases. The probe, Ga-DOTA-D11-TATE, showed high bone accumulation but reduced tumor uptake, suggesting charge adjustment is key for receptor targeting.
Area of Science:
- Nuclear Medicine
- Radiochemistry
- Oncology
Background:
- Somatostatin receptors are crucial targets in neuroendocrine tumors.
- Developing dual-targeting probes for primary tumors and bone metastases is a significant challenge.
- Gallium-68 (68Ga) is a promising radionuclide for positron emission tomography (PET) imaging due to its favorable characteristics.
Purpose of the Study:
- To design and synthesize a novel Gallium-68 (68Ga) PET probe capable of simultaneously detecting neuroendocrine tumors and bone metastases.
- To evaluate the efficacy of a bifunctional molecule incorporating a somatostatin analog ([Tyr3]-octreotate, TATE) for tumor targeting and an aspartic acid peptide (Dn) for bone targeting, complexed with 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA).
Main Methods:
- Synthesis of DOTA-Dn-TATE precursors using Fmoc-based solid-phase and air oxidation methods.
- Radiolabeling of the synthesized precursors with Gallium-67 (67Ga) to form [67Ga]Ga-DOTA-Dn-TATE.
- In vitro hydroxyapatite binding assays, cellular uptake studies in AR42J tumor cells, and in vivo biodistribution experiments in AR42J tumor-bearing mice.
Main Results:
- Radiochemical purities of [67Ga]Ga-DOTA-Dn-TATE were consistently above 96.0%.
- [67Ga]Ga-DOTA-D11-TATE demonstrated high affinity for hydroxyapatite and significant accumulation in bone.
- However, [67Ga]Ga-DOTA-D11-TATE exhibited lower uptake in somatostatin receptor-positive AR42J cells and significantly reduced tumor accumulation compared to [67Ga]Ga-DOTA-TATE.
Conclusions:
- The introduction of the D11 peptide may hinder recognition by somatostatin receptors.
- Charge adjustment of the probe molecule is likely a critical factor for effective uptake in somatostatin receptor-positive cells.
- Further optimization is needed to develop a PET probe that effectively targets both primary neuroendocrine tumors and bone metastases.
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