Comparison of biological properties of 99m Tc-labeled cyclic RGD Peptide trimer and dimer useful as SPECT radiotracers for tumor imaging

Abstract

Introduction This study sought to evaluate a 99mTc-labeled trimeric cyclic RGD peptide (99mTc-4P-RGD3) as the new radiotracer for tumor imaging. The objective was to compare its biological properties with those of 99mTc-3P-RGD2 in the same animal model. Methods HYNIC-4P-RGD3 was prepared by reacting 4P-RGD3 with excess HYNIC-OSu in the presence of diisopropylethylamine. 99mTc-4P-RGD3 was prepared using a kit formulation, and evaluated for its tumor-targeting capability and biodistribution properties in the BALB/c nude mice with U87MG human glioma xenografts. Planar and SPECT imaging studies were performed in athymic nude mice with U87MG glioma xenografts. For comparison purpose, 99mTc-3P-RGD2 (a αvβ3-targeted radiotracer currently under clinical evaluation for tumor imaging in cancer patients) was also evaluated in the same animal models. Blocking experiments were used to demonstrate the αvβ3 specificity of 99mTc-4P-RGD3. Results 99mTc-4P-RGD3 was prepared with >95% RCP and high specific activity (~200 GBq/µmol). 99mTc-4P-RGD3 and 99mTc-3P-RGD2 shared almost identical tumor uptake and similar biodistribution properties. 99mTc-4P-RGD3 had higher uptake than 99mTc-3P-RGD2 in the intestines and kidneys; but it showed better metabolic stability. The U87MG tumors were clearly visualized by SPECT with excellent contrast with 99mTc-4P-RGD3 and 99mTc-3P-RGD2. Conclusion Increasing peptide multiplicity from 3P-RGD2 to 4P-RGD3 offers no advantages with respect to the tumor-targeting capability. 99mTc-4P-RGD3 is as good a SPECT radiotracer as 99mTc-3P-RGD2 for imaging αvβ3-positive tumors.

Novel Linear Peptides with High Affinity to αvβ3 Integrin for Precise Tumor Identification

“…The αvβ3 integrin is considered to be an established therapeutic target for the treatment of a variety of tumors 32 , 33 , 34 . Cyclic RGD peptide is the well-known ligand to αvβ3 and has been extensively exploited for tumor diagnosis and treatment 35 , 36 , 37 . However, the complexity and high-cost of synthesizing cyclic peptides stipulate the development of alternative ligands for targeting αvβ3 integrin.…”

Fluorescence‐ and multispectral optoacoustic imaging for an optimized detection of deeply located tumors in an orthotopic mouse model of pancreatic carcinoma

“…In addition, the amb3 integrin, which is the major target for cRGD, is connected with angiogenesis, wound healing and cell migration. 45 We thus cannot exclude that some tissue remodeling processes involving integrins still take place at the scar tissue, which could be a source of part of the cRGD-derived signals over the upper abdomen. Taken together, this indicates that the RGD-targeting probe, although sufficient for the perioperative detection of tumor nodules, is not ideal for the improvement of the specificity of therapeutic approaches.…”

“…This is not very surprising, as integrins in general orchestrate cell‐cell and cell‐extracellular matrix adhesive interactions from embryonic development to mature tissue function. In addition, the ανβ3 integrin, which is the major target for cRGD, is connected with angiogenesis, wound healing and cell migration . We thus cannot exclude that some tissue remodeling processes involving integrins still take place at the scar tissue, which could be a source of part of the cRGD‐derived signals over the upper abdomen.…”

Advances in Development of Radiometal Labeled Amino Acid-Based Compounds for Cancer Imaging and Diagnostics

“…The most frequently studied BFCA for Tc-complexes are summarized in Table 2 . In past few years, [ 99m Tc]Tc-HYNIC has been the most commonly used core for the conventional radiolabeling of bioactive peptides for tumor imaging such as RGD peptides [ 38 , 39 ], α-MSH peptide analogues [ 40 , 41 ], bombesin analogues [ 42 , 43 ], substance P analogues [ 44 ], or glucagon-like peptide analogues [ 45 ].…”