A Cyanine‐Bridged Somatostatin Hybrid Probe for Multimodal SSTR2 Imaging in Vitro and in Vivo: Synthesis and Evaluation

Heing-Becker, Isabelle; Grötzinger, Carsten; Beindorff, Nicola; Prasad, Sonal; Erdmann, Sarah; Exner, Samantha; Haag, Rainer; Licha, Kai

doi:10.1002/cbic.202000791

Cited by 5 publications

(5 citation statements)

References 44 publications

(40 reference statements)

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“…The dual targeting of both integrin αvβ 3 and NRP-1 resulted in a better selectivity and uptake and retention into the tumor. In the last few years, the development of multimodal imaging PET and fluorescence has emerged as a promising tool for the development of new diagnostics and treatment agents [ 39 , 40 , 41 ]. The access of fluorescent tools is very interesting for a better understanding and a better sensibility for in vivo evaluations.…”

Section: Discussionmentioning

confidence: 99%

Preliminary Study of New Gallium-68 Radiolabeled Peptide Targeting NRP-1 to Detect Brain Metastases by Positron Emission Tomography

et al. 2021

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Due to their very poor prognosis and a fatal outcome, secondary brain tumors are one of the biggest challenges in oncology today. From the point of view of the early diagnosis of these brain micro- and macro-tumors, the sensitivity and specificity of the diagnostic tools constitute an obstacle. Molecular imaging, such as Positron Emission Tomography (PET), is a promising technique but remains limited in the search for cerebral localizations, given the commercially available radiotracers. Indeed, the [18F]FDG PET remains constrained by the physiological fixation of the cerebral cortex, which hinders the visualization of cerebral metastases. Tumor angiogenesis is recognized as a crucial phenomenon in the progression of malignant tumors and is correlated with overexpression of the neuropilin-1 (NRP-1) receptor. Here, we describe the synthesis and the photophysical properties of the new gallium-68 radiolabeled peptide to target NRP-1. The KDKPPR peptide was coupled with gallium-68 anchored into a bifunctional NODAGA chelating agent, as well as Cy5 for fluorescence detection. The Cy5 absorbance spectra did not change, whereas the molar extinction coefficient (ε) decreased drastically. An enhancement of the fluorescence quantum yield (φF) could be observed due to the better water solubility of Cy5. [68Ga]Ga-NODAGA-K(Cy5)DKPPR was radiosynthesized efficiently, presented hydrophilic properties (log D = −1.86), and had high in vitro stability (>120 min). The molecular affinity and the cytotoxicity of this new chelated radiotracer were evaluated in vitro on endothelial cells (HUVEC) and MDA-MB-231 cancer cells (hormone-independent and triple-negative line) and in vivo on a brain model of metastasis in a nude rat using the MDA-MB-231 cell line. No in vitro toxicity has been observed. The in vivo preliminary experiments showed promising results, with a high contrast between the healthy brain and metastatic foci for [68Ga]Ga-NODAGA-K(Cy5)DKPPR.

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Section: Discussionmentioning

confidence: 99%

Preliminary Study of New Gallium-68 Radiolabeled Peptide Targeting NRP-1 to Detect Brain Metastases by Positron Emission Tomography

et al. 2021

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“…• a bis-functionalized metal chelator 70,96,98,118,124 • a bis-functionalized fluorophore 68,110,112 • a bifunctional connector like amino acids 64,87 Among the different approaches, this is the most versatile. The fact that the dual imaging dye is conjugated to the vector in a single last step in the construction of the imaging tool allows for the preparation of a wide array of agents by simply changing the vectors, without rebuilding the whole edifice.…”

Section: Dualmentioning

confidence: 99%

“…According to this approach, the synthesis of the dual imaging dye relies on reactions between bifunctional entities that can be a bis-functionalized metal chelator ,,,, a bis-functionalized fluorophore ,, a bifunctional connector like amino acids , …”

Section: Dual Pet/fluorescence Imaging Tools: Variety Of Examplesmentioning

confidence: 99%

PET/Fluorescence Imaging: An Overview of the Chemical Strategies to Build Dual Imaging Tools

et al. 2022

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Molecular imaging is a biomedical research discipline that has quickly emerged to afford the observation, characterization, monitoring, and quantification of biomarkers and biological processes in living organism. It covers a large array of imaging techniques, each of which provides anatomical, functional, or metabolic information. Multimodality, as the combination of two or more of these techniques, has proven to be one of the best options to boost their individual properties, hence offering unprecedented tools for human health. In this review, we will focus on the combination of positron emission tomography and fluorescence imaging from the specific perspective of the chemical synthesis of dual imaging agents. Based on a detailed analysis of the literature, this review aims at giving a comprehensive overview of the chemical strategies implemented to build adequate imaging tools considering radiohalogens and radiometals as positron emitters, fluorescent dyes mostly emitting in the NIR window and all types of targeting vectors.

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“…Ghosh et al (Ghosh et al 2017a , b ). and Licha et al(Heing-Becker et al 2021 ) developed SSTR2-targeted tracers using the chelate or the dye as linkage, respectively. In both approaches, the in vitro and in vivo results were very promising, showing a retention of the pharmacological properties of the parent peptide.…”

Section: Introductionmentioning

confidence: 99%

eTFC-01: a dual-labeled chelate-bridged tracer for SSTR2-positive tumors

Chapeau,

Beekman,

Handula

et al. 2024

EJNMMI radiopharm. chem.

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Background Integrating radioactive and optical imaging techniques can facilitate the prognosis and surgical guidance for cancer patients. Using a single dual-labeled tracer ensures consistency in both imaging modalities. However, developing such molecule is challenging due to the need to preserve the biochemical properties of the tracer while introducing bulky labeling moieties. In our study, we designed a trifunctional chelate that facilitates the coupling of the targeting vector and fluorescent dye at opposite sites to avoid undesired steric hindrance effects. The synthesis of the trifunctional chelate N3-Py-DOTAGA-(tBu)3 (7) involved a five-step synthetic route, followed by conjugation to the linear peptidyl-resin 8 through solid-phase synthesis. After deprotection and cyclization, the near-infrared fluorescent dye sulfo-Cy.5 was introduced using copper free click chemistry, resulting in eTFC-01. Subsequently, eTFC-01 was labeled with [111In]InCl3. In vitro assessments of eTFC-01 binding, uptake, and internalization were conducted in SSTR2-transfected U2OS cells. Ex-vivo biodistribution and fluorescence imaging were performed in H69-tumor bearing mice. Results eTFC-01 demonstrated a two-fold higher IC50 value for SSTR2 compared to the gold standard DOTA-TATE. Labeling of eTFC-01 with [111In]InCl3 gave a high radiochemical yield and purity. The uptake of [111In]In-eTFC-01 in U2OS.SSTR2 cells was two-fold lower than the uptake of [111In]In-DOTA-TATE, consistent with the binding affinity. Tumor uptake in H69-xenografted mice was lower for [111In]In-eTFC-01 at all-time points compared to [111In]In-DOTA-TATE. Prolonged blood circulation led to increased accumulation of [111In]In-eTFC-01 in highly vascularized tissues, such as lungs, skin, and heart. Fluorescence measurements in different organs correlated with the radioactive signal distribution. Conclusion The successful synthesis and coupling of the trifunctional chelate to the peptide and fluorescent dye support the potential of this synthetic approach to generate dual labeled tracers. While promising in vitro, the in vivo results obtained with [111In]In-eTFC-01 suggest the need for adjustments to enhance tracer distribution.

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A Cyanine‐Bridged Somatostatin Hybrid Probe for Multimodal SSTR2 Imaging in Vitro and in Vivo: Synthesis and Evaluation

Cited by 5 publications

References 44 publications

Preliminary Study of New Gallium-68 Radiolabeled Peptide Targeting NRP-1 to Detect Brain Metastases by Positron Emission Tomography

Preliminary Study of New Gallium-68 Radiolabeled Peptide Targeting NRP-1 to Detect Brain Metastases by Positron Emission Tomography

PET/Fluorescence Imaging: An Overview of the Chemical Strategies to Build Dual Imaging Tools

eTFC-01: a dual-labeled chelate-bridged tracer for SSTR2-positive tumors

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