Somatostatin analogues labeled with copper radioisotopes: current status

Marciniak, Aleksandra; Brasuń, Justyna

doi:10.1007/s10967-017-5323-x

Cited by 17 publications

(11 citation statements)

References 57 publications

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“…In addition, the preclinical studies have recently been extended to antagonistic peptides labeled with 64 Cu [ 9 ]. In recent years, Copper-64 has gained popularity in nuclear medicine primarily because of its longer half-life (t 1/2 = 12.7 hours), which enables PET imaging at later time points with higher tumor-to-normal organ contrasts [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

“…Since efficient labeling—including fast formation kinetics (high labeling yields at low concentrations) and high kinetic and thermodynamic stability—is of paramount importance for a clinical PET tracer, efforts were made to develop suitable bifunctional chelators and conjugation methods for biomolecules [ 12 – 16 ]. The literature on radiocopper-based radiopharmaceuticals in general was summarized by Hao et al [ 17 ] and Shokeen et al [ 10 , 18 ], while the literature on radiocopper-labeled somatostatin analogues was recently summarized by Brasun et al [ 9 ].…”

Section: Introductionmentioning

confidence: 99%

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The somatostatin receptor 2 antagonist 64Cu-NODAGA-JR11 outperforms 64Cu-DOTA-TATE in a mouse xenograft model

et al. 2018

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Copper-64 is an attractive radionuclide for PET imaging and is frequently used in clinical applications. The aim of this study was to perform a side-by-side comparison of the in vitro and in vivo performance of 64Cu-NODAGA-JR11 (NODAGA = 1,4,7-triazacyclononane,1-glutaric acid,4,7-acetic acid, JR11 = p-Cl-Phe-cyclo(D-Cys-Aph(Hor)-D-Aph(cbm)-Lys-Thr-Cys)D-Tyr-NH2), a somatostatin receptor 2 antagonist, with the clinically used sst2 agonist 64Cu-DOTA-TATE ((TATE = D-Phe-cyclo(Cys-Tyr-D-Trp-Lys-Thr-Cys)Thr). In vitro studies demonstrated Kd values of 5.7±0.95 nM (Bmax = 4.1±0.18 nM) for the antagonist 64/natCu-NODAGA-JR11 and 20.1±4.4. nM (Bmax = 0.48±0.18 nM) for the agonist 64/natCu-DOTA-TATE. Cell uptake studies showed the expected differences between agonists and antagonists. Whereas 64Cu-DOTA-TATE (the agonist) showed very effective internalization in the cell culture assay (with 50% internalized at 4 hours post-peptide addition under the given experimental conditions), 64Cu-NODAGA-JR11 (the antagonist) showed little internalization but strong receptor-mediated uptake at the cell membrane. Biodistribution studies of 64Cu-NODAGA-JR11 showed rapid blood clearance and tumor uptake with increasing tumor-to-relevant organ ratios within the first 4 hours and in some cases, 24 hours, respectively. The tumor washout was slow or non-existent in the first 4 hours, whereas the kidney washout was very efficient, leading to high and increasing tumor-to-kidney ratios over time. Specificity of tumor uptake was proven by co-injection of high excess of non-radiolabeled peptide, which led to >80% tumor blocking. 64Cu-DOTA-TATE showed less favorable pharmacokinetics, with the exception of lower kidney uptake. Blood clearance was distinctly slower and persistent higher blood values were found at 24 hours. Uptake in the liver and lung was relatively high and also persistent. The tumor uptake was specific and similar to that of 64Cu-NODAGA-JR11 at 1 h, but release from the tumor was very fast, particularly between 4 and 24 hours. Tumor-to-normal organ ratios were distinctly lower after 1 hour. This is indicative of insufficient in vivo stability. PET studies of 64Cu-NODAGA-JR11 reflected the biodistribution data with nicely delineated tumor and low background. 64Cu-NODAGA-JR11 shows promising pharmacokinetic properties for further translation into the clinic.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The somatostatin receptor 2 antagonist 64Cu-NODAGA-JR11 outperforms 64Cu-DOTA-TATE in a mouse xenograft model

et al. 2018

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“…Many systems already presented before, such as DOTATOC/TATE or NODAGATOC/TATE, or others more copper-specific BFCAs, such as TETA (1,4,8,11-tetraazacyclotetradecane- N , N ′, N ″, N ‴-tetraacetic acid) [ 114 ], and its more stable derivatives such as cross-bridge CB-TE2A (4,11-bis(carboxymethyl)-1,4,8,11-tetraazabicyclo [6.6.2]hexadecane) [ 115 ], and CPTA (4-[(1,4,8,11-tetraazacyclotetradec-1-yl)methyl]benzoic acid]) [ 116 ] or sarcophagine derivatives [ 117 ] have been studied. A review on the development of copper radiolabeled somatostatin analogs was recently published by Marciniak et al [ 118 ].…”

Section: Targeting Of Somatostatin Receptors With Radiopharmaceutimentioning

confidence: 99%

Overview of Radiolabeled Somatostatin Analogs for Cancer Imaging and Therapy

et al. 2020

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Identified in 1973, somatostatin (SST) is a cyclic hormone peptide with a short biological half-life. Somatostatin receptors (SSTRs) are widely expressed in the whole body, with five subtypes described. The interaction between SST and its receptors leads to the internalization of the ligand–receptor complex and triggers different cellular signaling pathways. Interestingly, the expression of SSTRs is significantly enhanced in many solid tumors, especially gastro-entero-pancreatic neuroendocrine tumors (GEP-NET). Thus, somatostatin analogs (SSAs) have been developed to improve the stability of the endogenous ligand and so extend its half-life. Radiolabeled analogs have been developed with several radioelements such as indium-111, technetium-99 m, and recently gallium-68, fluorine-18, and copper-64, to visualize the distribution of receptor overexpression in tumors. Internal metabolic radiotherapy is also used as a therapeutic strategy (e.g., using yttrium-90, lutetium-177, and actinium-225). With some radiopharmaceuticals now used in clinical practice, somatostatin analogs developed for imaging and therapy are an example of the concept of personalized medicine with a theranostic approach. Here, we review the development of these analogs, from the well-established and authorized ones to the most recently developed radiotracers, which have better pharmacokinetic properties and demonstrate increased efficacy and safety, as well as the search for new clinical indications.

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“…Among the technical advantages of PET/CT over SPECT are the higher spatial resolution and image quantification capabilities. This and the proven usefulness of 68 Ga-labeled SSAs in NET-theranostics 12 has triggered research aiming at the development of probes labeled with other β + -emitters such as 64 Cu 13, 44 Sc 14 and 18 F. The focus of this review will lie on the latter since 18 F is the most widely available PET-nuclide and its half-life (110 min), as well as low positron energy (maximum β + energy = 635 keV), make it a close-to-ideal choice. More than 150 operating cyclotrons in the US ensure the availability of [ 18 F]fluoride as well as 18 F-labeled probes in a large area 6.…”

Section: Introduction To 18f-labeled Ssasmentioning

confidence: 99%

The Search for an Alternative to [⁶⁸Ga]Ga-DOTA-TATE in Neuroendocrine Tumor Theranostics: Current State of ¹⁸F-labeled Somatostatin Analog Development

Waldmann¹,

Stuparu²,

Dam³

et al. 2019

Theranostics

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The trend to inform personalized molecular radiotherapy with molecular imaging diagnostics, a concept referred to as theranostics, has transformed the field of nuclear medicine in recent years. The development of theranostic pairs comprising somatostatin receptor (SSTR)-targeting nuclear imaging probes and therapeutic agents for the treatment of patients with neuroendocrine tumors (NETs) has been a driving force behind this development. With the Neuroendocrine Tumor Therapy (NETTER-1) phase 3 trial reporting encouraging results in the treatment of well-differentiated, metastatic midgut NETs, peptide radioligand therapy (RLT) with the 177 Lu-labeled somatostatin analog (SSA) [ 177 Lu]Lu-DOTA-TATE is now anticipated to become the standard of care. On the diagnostics side, the field is currently dominated by 68 Ga-labeled SSAs for the molecular imaging of NETs with positron emission tomography-computed tomography (PET/CT). PET/CT imaging with SSAs such as [ 68 Ga]Ga-DOTA-TATE, [ 68 Ga]Ga-DOTA-TOC, and [ 68 Ga]Ga-DOTA-NOC allows for NET staging with high accuracy and is used to qualify patients for RLT. Driven by the demand for PET/CT imaging of NETs, a commercial kit for the production of [ 68 Ga]Ga-DOTA-TATE (NETSPOT) was approved by the U.S. Food and Drug Administration (FDA). The synthesis of 68 Ga-labeled SSAs from a 68 Ge/ 68 Ga-generator is straightforward and allows for a decentralized production, but there are economic and logistic difficulties associated with these approaches that warrant the search for a viable, generator-independent alternative. The clinical introduction of an 18 F-labeled SSTR-imaging probe can help mitigate the shortcomings of the generator-based synthesis approach, but despite extensive research efforts, none of the proposed 18 F-labeled SSAs has been translated past prospective first-in-humans studies so far. Here, we review the current state of probe-development from a translational viewpoint and make a case for a clinically viable, 18 F-labeled alternative to the current standard [ 68 Ga]Ga-DOTA-TATE.

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Somatostatin analogues labeled with copper radioisotopes: current status

Cited by 17 publications

References 57 publications

The somatostatin receptor 2 antagonist 64Cu-NODAGA-JR11 outperforms 64Cu-DOTA-TATE in a mouse xenograft model

The somatostatin receptor 2 antagonist 64Cu-NODAGA-JR11 outperforms 64Cu-DOTA-TATE in a mouse xenograft model

Overview of Radiolabeled Somatostatin Analogs for Cancer Imaging and Therapy

The Search for an Alternative to [⁶⁸Ga]Ga-DOTA-TATE in Neuroendocrine Tumor Theranostics: Current State of ¹⁸F-labeled Somatostatin Analog Development

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Somatostatin analogues labeled with copper radioisotopes: current status

Cited by 17 publications

References 57 publications

The somatostatin receptor 2 antagonist 64Cu-NODAGA-JR11 outperforms 64Cu-DOTA-TATE in a mouse xenograft model

The somatostatin receptor 2 antagonist 64Cu-NODAGA-JR11 outperforms 64Cu-DOTA-TATE in a mouse xenograft model

Overview of Radiolabeled Somatostatin Analogs for Cancer Imaging and Therapy

The Search for an Alternative to [68Ga]Ga-DOTA-TATE in Neuroendocrine Tumor Theranostics: Current State of 18F-labeled Somatostatin Analog Development

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The Search for an Alternative to [⁶⁸Ga]Ga-DOTA-TATE in Neuroendocrine Tumor Theranostics: Current State of ¹⁸F-labeled Somatostatin Analog Development