NMR Studies Reveal Structural Differences between the Gallium and Yttrium Complexes of DOTA-<scp>d</scp>-Phe-Tyr<sup>3</sup>-octreotide

Deshmukh, Mandar V.; Voll, Georg; Kühlewein, Angelika; Mäcke, Helmut R.; Schmitt, Jörg; Kessler, Horst; Gemmecker, Gerd

doi:10.1021/jm0496335

Cited by 39 publications

(34 citation statements)

References 38 publications

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“…This keeps the pharmacophoric peptide at a distance from the chelate (21) and may allow higher flexibility of the cyclic peptide and therefore higher receptor binding affinity. Structural differences between Y-DOTATOC and Ga-DOTATOC were also confirmed by 1 H and 13 C NMR studies in solution (23).…”

Section: Discussionmentioning

confidence: 60%

Unexpected Sensitivity of sst₂ Antagonists to N-Terminal Radiometal Modifications

et al. 2012

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Section: Discussionmentioning

confidence: 60%

Unexpected Sensitivity of sst₂ Antagonists to N-Terminal Radiometal Modifications

et al. 2012

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“…Not enough data are available yet to explain these differences. High-resolution nuclear magnetic resonance data and conformational analysis may possibly help to explain the differences (27).…”

Section: Discussionmentioning

confidence: 99%

PET of Somatostatin Receptor–Positive Tumors Using ⁶⁴Cu- and ⁶⁸Ga-Somatostatin Antagonists: The Chelate Makes the Difference

Fani¹,

Pozzo²,

Abiraj³

et al. 2011

J Nucl Med

227

189

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Somatostatin-based radiolabeled peptides have been successfully introduced into the clinic for targeted imaging and radionuclide therapy of somatostatin receptor (sst)-positive tumors, especially of subtype 2 (sst2). The clinically used peptides are exclusively agonists. Recently, we showed that radiolabeled antagonists may be preferable to agonists because they showed better pharmacokinetics, including higher tumor uptake. Factors determining the performance of radioantagonists have only scarcely been studied. Here, we report on the development and evaluation of four 64 Cu or 68 Ga radioantagonists for PET of sst2-positive tumors. Methods: The novel antagonist p-Cl-Phecyclo(D-Cys-Tyr-D-4-amino-Phe(carbamoyl)-Lys-Thr-Cys)D-Tyr-NH 2 (LM3) was coupled to 3 macrocyclic chelators, namely 4,11-bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (CB-TE2A), 1,4,7-triazacyclononane,1-glutaric acid-4,7-acetic acid (NODAGA), and DOTA. 64/nat Cu-and 68/nat Ga-NODAGA-LM3 were prepared at room temperature, and 64/nat Cu-CB-TE2A-LM3 and 68/nat Ga-DOTA-LM3 were prepared at 95°C. Binding affinity and antagonistic properties were determined with receptor autoradiography and immunofluorescence microscopy using human embryonic kidney (HEK)-sst2 cells. In vitro internalization and dissociation was evaluated using the same cell line. Biodistribution and small-animal PET studies were performed with HEK-sst2 xenografts. Results: All metallopeptides demonstrated antagonistic properties. The affinities depend on chelator and radiometal and vary about 10-fold; 68/nat Ga-NODAGA-LM3 has the lowest half maximal inhibitory concentration (1.3 6 0.3 nmol/L). The biodistribution studies show impressive tumor uptake at 1 h after injection, particularly of 64 Cu-and 68 Ga-NODAGA-LM3 (;40 percentage injected dose per gram of tissue [%ID/g]), which were proven to be specific. Background clearance was fast and the tumor washout relatively slow for 64 Cu-NODAGA-LM3 (;15 %ID/g, 24 h after injection) and almost negligible for 64 Cu-CB-TE2A-LM3 (26.9 6 3.3 %ID/g and 21.6 6 2.1 %ID/g, 4 and 24 h after injection, respectively). Tumor-to-normal-tissue ratios were significantly higher for 64 Cu-NODAGA-LM3 than for 64 Cu-CB-TE2A-LM3 (tumor-to-kidney, 12.8 6 3.6 and 1.7 6 0.3, respectively; tumor-to-muscle, 1,342 6 115 and 75.2 6 8.5, respectively, at 24 h, P , 0.001). Small-animal PET shows clear tumor localization and high image contrast, especially for 64 Cu-and 68 Ga-NODAGA-LM3. Conclusion: This article demonstrates the strong dependence of the affinity and pharmacokinetics of the somatostatin-based radioantagonists on the chelator and radiometal. 64 Cu-and 68 Ga-NODAGA-LM3 and 64 Cu-CB-TE2A-LM3 are promising candidates for clinical translation because of their favorable pharmacokinetics and the high image contrast on PET scans.

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“…Also, due to cooperation and networking within the COST action B12 'Radiotracers for in vivo assessment of biological functions' , about [40][41][42][43][44][45][46][47][48][49][50] …”

Section: Discussionmentioning

confidence: 99%

⁶⁸Ga‐PET: a powerful generator‐based alternative to cyclotron‐based PET radiopharmaceuticals

Fani

André

Maecke

2008

Contrast Media & Molecular

303

318

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PET (positron emission tomography) is a powerful diagnostic and imaging technique which requires short-lived positron emitting isotopes. The most commonly used are accelerator-produced (11)C and (18)F. An alternative is the use of metallic positron emitters. Among them (68)Ga deserves special attention because of its availability from long-lived (68)Ge/(68)Ga generator systems which render (68)Ga radiopharmacy independent of an onsite cyclotron. The coordination chemistry of Ga(3+) is dominated by its hard acid character. A variety of mono- and bifunctional chelators have been developed which allow the formation of stable (68)Ga(3+)complexes and convenient coupling to biomolecules. (68)Ga coupling to small biomolecules is potentially an alternative to (18)F- and (11)C-based radiopharmacy. In particular, peptides targeting G-protein coupled receptors overexpressed on human tumour cells have shown preclinically and clinically high and specific tumour uptake. Kit-formulated precursors along with the generator may be provided, similar to the (99)Mo/(99m)Tc-based radiopharmacy, still the mainstay of nuclear medicine.

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NMR Studies Reveal Structural Differences between the Gallium and Yttrium Complexes of DOTA-d-Phe-Tyr³-octreotide

Cited by 39 publications

References 38 publications

Unexpected Sensitivity of sst₂ Antagonists to N-Terminal Radiometal Modifications

Unexpected Sensitivity of sst₂ Antagonists to N-Terminal Radiometal Modifications

PET of Somatostatin Receptor–Positive Tumors Using ⁶⁴Cu- and ⁶⁸Ga-Somatostatin Antagonists: The Chelate Makes the Difference

⁶⁸Ga‐PET: a powerful generator‐based alternative to cyclotron‐based PET radiopharmaceuticals

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NMR Studies Reveal Structural Differences between the Gallium and Yttrium Complexes of DOTA-d-Phe-Tyr3-octreotide

Cited by 39 publications

References 38 publications

Unexpected Sensitivity of sst2 Antagonists to N-Terminal Radiometal Modifications

Unexpected Sensitivity of sst2 Antagonists to N-Terminal Radiometal Modifications

PET of Somatostatin Receptor–Positive Tumors Using 64Cu- and 68Ga-Somatostatin Antagonists: The Chelate Makes the Difference

68Ga‐PET: a powerful generator‐based alternative to cyclotron‐based PET radiopharmaceuticals

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NMR Studies Reveal Structural Differences between the Gallium and Yttrium Complexes of DOTA-d-Phe-Tyr³-octreotide

Unexpected Sensitivity of sst₂ Antagonists to N-Terminal Radiometal Modifications

Unexpected Sensitivity of sst₂ Antagonists to N-Terminal Radiometal Modifications

PET of Somatostatin Receptor–Positive Tumors Using ⁶⁴Cu- and ⁶⁸Ga-Somatostatin Antagonists: The Chelate Makes the Difference

⁶⁸Ga‐PET: a powerful generator‐based alternative to cyclotron‐based PET radiopharmaceuticals