Somatostatin Receptor-Based Molecular Imaging and Therapy for Neuroendocrine Tumors

Tang, Kun; Zhang, Qi; Li, Huanbin; Wen, Zhengwei; Zhang, Hongzheng; Zhang, Hong

doi:10.1155/2013/102819

Cited by 39 publications

(19 citation statements)

References 82 publications

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“…[1][2][3][4] For the specific PET imaging of neuroendocrine tumors (NETs) often overexpressing somatostatin receptors (SSTRs), derivatives of the endogenous peptide somatostatin have a high clinical relevance for PET imaging. For this purpose, mostly such as Tyr 3 -octreotate (TATE) and octreotide analogs, 5,6 have proven to be of high clinical relevance for PET imaging when radiolabeled with positron emitters such as gallium-68 ( 68 Ga) or fluorine-18 ( 18 F). 7,8 have proven to be highly potent PET imaging agents.…”

Section: Introductionmentioning

confidence: 99%

Next Generation of SiFAlin-Based TATE Derivatives for PET Imaging of SSTR-Positive Tumors: Influence of Molecular Design on In Vitro SSTR Binding and In Vivo Pharmacokinetics

Litau¹,

Niedermoser²,

Vogler³

et al. 2015

Bioconjugate Chem.

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The Silicon-Fluoride-Acceptor (SiFA)-(18)F-labeling strategy has been shown before to enable the straightforward and efficient (18)F-labeling of complex biologically active substances such as proteins and peptides. Especially in the case of peptides, the radiolabeling proceeds kit-like in short reaction times and without the need of complex product workup. SiFA-derivatized, (18)F-labeled Tyr(3)-octreotate (TATE) derivatives demonstrated, besides strong somatostatin receptor (SSTR) binding, favorable in vivo pharmacokinetics as well as excellent tumor visualization by PET imaging. In this study, we intended to determine the influence of the underlying molecular design and used molecular scaffolds of SiFAlin-TATE derivatives on SSTR binding as well as on the in vivo pharmacokinetics of the resulting (18)F-labeled peptides. For this purpose, new SiFAlin-(Asp)n-PEG1-TATE analogs (where n = 1-4) were synthesized, efficiently radiolabeled with (18)F in a kit-like manner and obtained in radiochemical yields of 70-80%, radiochemical purities of ≥97%, and nonoptimized specific activities of 20.1-45.2 GBq/μmol within 20-25 min starting from 0.7-1.5 GBq of (18)F. In the following, the radiotracer's lipophilicities and stabilities in human serum were determined. Furthermore, the SSTR-specific binding affinities were evaluated by a competitive displacement assay on SSTR-positive AR42J cells. The obtained in vitro results support the assumption that aspartic acids are able to considerably increase the radiotracer's hydrophilicity and that their number does not affect the SSTR binding potential of the TATE derivatives. The most promising tracer (18)F-SiFAlin-Asp3-PEG1-TATE [(18)F]6 (LogD = -1.23 ± 0.03, IC50 = 20.7 ± 2.5 nM) was further evaluated in vivo in AR42J tumor-bearing nude mice via PET/CT imaging against the clinical gold standard (68)Ga-DOTATATE as well as the previously developed SiFAlin-TATE derivative [(18)F]3. The results of these evaluations showed that [(18)F]6-although showing very similar chemical and in vitro properties to [(18)F]3-exhibits not only a slowed renal clearance compared to [(18)F]3, but also a higher absolute tumor uptake compared to (68)Ga-DOTATATE, and furthermore enables excellent tumor visualization with high image resolution. These results emphasize the importance of systematic study of the influence of molecular design and applied structure elements of peptidic radiotracers, as these may considerably influence in vivo pharmacokinetics while not affecting other parameters such as radiochemistry, lipophilicity, serum stability, or receptor binding potential.

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Section: Introductionmentioning

confidence: 99%

Next Generation of SiFAlin-Based TATE Derivatives for PET Imaging of SSTR-Positive Tumors: Influence of Molecular Design on In Vitro SSTR Binding and In Vivo Pharmacokinetics

Litau¹,

Niedermoser²,

Vogler³

et al. 2015

Bioconjugate Chem.

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“…Multiplexed molecular imaging instead provides a comprehensive, noninvasive view of tumour pathology and anatomy, and enables the rational selection of therapy, as well as insight into the optimal dosage, early-response assessment and subsequent treatment planning 143,208,[218][219][220] . For example, multiplexed PET in the early-response assessment of mice to VEGF 121 /rGel therapy in a breast-cancer model 220 Ga-DOTA-peptide, and the development of cyclotron-generated 18 F-analogues (e.g., FET-AG-TOCA) for wide patient coverage, underscores the potential role of PET in therapy selection and in the evaluation of potential responses to somatostatin-receptortargeted chemotherapies [221][222][223][224][225] (Fig. 3b).…”

Section: Imaging and Chemotherapymentioning

confidence: 99%

Multiplexed imaging for diagnosis and therapy

et al. 2017

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Complex molecular and metabolic phenotypes depict cancers as a constellation of different diseases with common themes. Precision imaging of such phenotypes requires flexible and tuneable modalities capable of identifying phenotypic fingerprints by using a restricted number of parameters whilst ensuring sensitivity to dynamic biological regulation. Common phenotypes can be detected by in vivo imaging technologies, and effectively define the emerging standards for disease classification and patient stratification in radiology. However, for the imaging data to accurately represent a complex fingerprint, the individual imaging parameters need to be measured and analysed in relation to their wider spatial and molecular context. In this respect, targeted palettes of molecular imaging probes facilitate the detection of heterogeneity in oncogene-driven alterations and their response to treatment, and lead to the expansion of rational-design elements for the combination of imaging experiments. In this Review, we evaluate criteria for conducting multiplexed imaging, and discuss its opportunities for improving patient diagnosis and the monitoring of therapy.

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“…[45,46] Somatostatin receptors, especially sstr subtype 2 (sstr 2 ), are overexpressed on a number of human NET include gastrointestinal and pancreatic NET, small-cell lung cancers (SCLC), paragangliomas, pheochromocytomas, medullar thyroid carcinomas (MTCs), and therefore, present a valid target for in vivo tumor imaging and therapy. [43,49] The most sensitive position in somatostatin is peptide bond between trp 8 and lys 9 . To improve its in vivo stability, several sst analogues such as octreotide and lanreotide have been synthesized via molecular modifications ( Figure 3).…”

Section: And Receptormentioning

confidence: 99%

Tumor targeting with ^99mTc radiolabeled peptides: Clinical application and recent development

Rezazadeh

Sadeghzadeh

2018

Chem Biol Drug Des

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Targeting overexpressed receptors on the cancer cells with radiolabeled peptides has become very important in nuclear oncology in the recent years. Peptides are small and have easy preparation and easy radiolabeling protocol with no side-effect and toxicity. These properties made them a valuable tool for tumor targeting. Based on the successful imaging of neuroendocrine tumors with 111 In-octreotide, other receptor-targeting peptides such as bombesin (BBN), cholecystokinin/gastrin analogues, neurotensin analogues, glucagon-like peptide-1, and RGD peptides are currently under development or undergoing clinical trials. The most frequently used radionuclides for tumor imaging are 99m Tc and 111 In for single-photon emission computed tomography and 68 Ga and 18 F for positron emission tomography imaging. This review presents some of the 99m Tc-labeled peptides, with regard to their potential for radionuclide imaging of tumors in clinical and preclinical application. K E Y W O R D S 99m Tc, radiolabeled peptides, SPECT, tumor targeting 206 | REZAZADEH AnD SADEGHZADEH some of them are currently under development or undergoing clinical trials. [13] Some of the most important peptides and their overexpressed receptors on tumors are listed in Table 1. 99m Tc is used for medical imaging in 80% of cases all over the world due to its near ideal nuclear characteristics of 6-hr half-life and γ-ray emission energy of 142 keV. Therefore, 99m Tc-labeled peptides with specific and high receptor affinity are very useful for tumor targeting. [14] The focus of this article remains the main applications of 99m Tc radiolabeled peptides in cancer research and development, which have been used in clinic and most promising candidates for future clinical use.

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Somatostatin Receptor-Based Molecular Imaging and Therapy for Neuroendocrine Tumors

Cited by 39 publications

References 82 publications

Next Generation of SiFAlin-Based TATE Derivatives for PET Imaging of SSTR-Positive Tumors: Influence of Molecular Design on In Vitro SSTR Binding and In Vivo Pharmacokinetics

Next Generation of SiFAlin-Based TATE Derivatives for PET Imaging of SSTR-Positive Tumors: Influence of Molecular Design on In Vitro SSTR Binding and In Vivo Pharmacokinetics

Multiplexed imaging for diagnosis and therapy

Tumor targeting with ^99mTc radiolabeled peptides: Clinical application and recent development

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Somatostatin Receptor-Based Molecular Imaging and Therapy for Neuroendocrine Tumors

Cited by 39 publications

References 82 publications

Next Generation of SiFAlin-Based TATE Derivatives for PET Imaging of SSTR-Positive Tumors: Influence of Molecular Design on In Vitro SSTR Binding and In Vivo Pharmacokinetics

Next Generation of SiFAlin-Based TATE Derivatives for PET Imaging of SSTR-Positive Tumors: Influence of Molecular Design on In Vitro SSTR Binding and In Vivo Pharmacokinetics

Multiplexed imaging for diagnosis and therapy

Tumor targeting with 99mTc radiolabeled peptides: Clinical application and recent development

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Tumor targeting with ^99mTc radiolabeled peptides: Clinical application and recent development