Novel 99mTc ‘4 + 1’ peptide conjugates: Tuning the biodistribution by variation of coligands

Kunstler, Jens-Uwe; Seidel, Gesine; Bergmann, Ralf; Gniazdowska, Ewa; Walther, M.; Schiller, Eik; Decristoforo, Clemens; Stephan, Holger; Haubner, Roland; Steinbach, Jörg

doi:10.1016/j.ejmech.2010.05.010

Cited by 16 publications

(16 citation statements)

References 27 publications

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“…Furthermore, the in vivo studies showed that in spite of the good physicochemical properties the activity in liver and gastrointestinal tract is high, which is suboptimal for diagnosis or therapy. The considerable influence that the chelating system of the technetium‐labelled small biomolecules has not only in the pharmacokinetic properties but also in the interaction with the biological systems is well documented in the literature. Consequently, other molecules bearing the same pharmacophore but different coordination modality will be studied to optimize the in vitro and in vivo properties of potential radiopharmaceuticals directed towards the estrogen receptors.…”

Section: Discussionmentioning

confidence: 99%

Development and characterization of a ^99mTc‐tricarbonyl–labelled estradiol derivative obtained by “Click Chemistry” with potential application in estrogen receptors imaging

Tejería

Giglio

Dematteis

et al. 2017

Labelled Comp Radiopharmac

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Assessment of the presence of estrogen receptors in breast cancer is crucial for treatment planning. With the objective to develop a potential agent for estrogen receptors imaging, we present the development and characterization of a Tc-tricarbonyl-labelled estradiol derivative. Using ethinylestradiol as starting material, an estradiol derivative bearing a 1,4-disubstituted 1,2,3-triazole-containing tridentate ligand system was synthesized by "Click Chemistry" and fully characterized. Labelling with high yield and radiochemical purity was achieved through the formation of a Tc-tricarbonyl complex. The radiolabelled compound was stable, exhibited moderate binding to plasma protein (approximately 33%) and lipophilicity in the adequate range (logP 1.3 ± 0.1 at pH 7.4). Studies in MCF7 showed promising uptake values (approximately 2%). However, more than 50% of the activity is quickly released from the cell. Biodistribution experiments in normal rats confirmed the expected "in vivo" stability of the radiotracer but showed very high gastrointestinal and liver activity, which is inconvenient for in vivo applications. Taking into consideration the well-documented influence of the chelating system in the physicochemical and biological behaviour of technetium-labelled small biomolecules, research will be continued using the same pharmacophore but different complexation modalities of technetium.

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Section: Discussionmentioning

confidence: 99%

Development and characterization of a ^99mTc‐tricarbonyl–labelled estradiol derivative obtained by “Click Chemistry” with potential application in estrogen receptors imaging

Tejería

Giglio

Dematteis

et al. 2017

Labelled Comp Radiopharmac

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“…These compounds vary in their choice of chelator, the linker between the chelator and the peptide, and the peptide itself. For example, Kunstler et al [19] reported that, in a series of three 99m Tc “4 + 1” mixed-ligand RGD derivatives, decreased chelator lipophilicity was associated with decreased hepatobiliary excretion and increased urinary excretion. Decristoforo et al [20] made a similar observation when they compared four different Tc-cores, including 99m Tc-EDDA/HYNIC-peptide (where EDDA is ethylenediamine N,N ′-diacetic acid, and HYNIC is hydrazinonicotinamide) which had the most favorable pharmacokinetics, including low intestinal excretion and rapid renal clearance.…”

Section: Discussionmentioning

confidence: 99%

Specific uptake of 99mTc-NC100692, an αvβ3-targeted imaging probe, in subcutaneous and orthotopic tumors

Dearling

Barnes

Panigrahy

et al. 2013

Nuclear Medicine and Biology

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Introduction The αvβ3 integrin, which is expressed by angiogenic epithelium and some tumor cells, is an attractive target for the development of both imaging agents and therapeutics. While optimal implementation of αvβ3-targeted therapeutics will require a priori identification of the presence of the target, the clinical evaluation of these compounds has typically not included parallel studies with αvβ3-targeted diagnostics. This is at least partly due to the relatively limited availability of PET radiopharmaceuticals in comparison to those labeled with 99mTc. In an effort to begin to address this limitation, we evaluated the tumor uptake of 99mTc-NC100692, a cyclic RGD peptide that binds to αvβ3 with ~1-nM affinity in an αvβ3-positive tumor model as well as its in vivo specificity. Methods MicroSPECT imaging was used to assess the ability of cilengitide, a therapeutic with high affinity for αvβ3, to block and displace 99mTc-NC100692 in an orthotopic U87 glioma tumor. The specificity of 99mTc-NC100692 was quantitatively evaluated in mice bearing subcutaneous U87MG tumors, by comparison of the biodistribution of 99mTc-NC100692 with that of the non-specific structural analogue 99mTc-AH-111744 and by blocking uptake of 99mTc-NC100692 with excess unlabeled NC100692. Results MicroSPECT imaging studies demonstrated that uptake of 99mTc-NC100692 in the intracranial tumor model was both blocked and displaced by the αvβ3-targeted therapeutic cilengitide. Biodistribution studies provided quantitative confirmation of these imaging results. Tumor uptake of 99mTc-NC100692 at 1 h post-injection was 2.8 ± 0.7% ID/g compared to 0.38 ± 0.1% ID/g for 99mTc-AH-111744 (p < 0.001). Blocking 99mTc-NC100692 uptake by pre-injecting the mice with excess unlabeled NC100692 reduced tumor uptake by approximately fivefold, to 0.68 ± 0.3% ID/g (p = 0.01). Conclusion These results confirm that 99mTc-NC100692 does, in fact, target the αvβ3 and may, therefore, be useful in identifying patients prior to anti-αvβ3 therapy as well as monitoring the response of these patients to therapy.

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“…Since the lipophilicity of radiometal chelates and whole probe molecules affects the excretion pathway of radiolabeled probes, − our efforts were focused on increasing the hydrophilicity of whole 99m Tc-labeled probes. To reduce the bile-excretory characteristics of the lipophilic 99m Tc-Pen chelate, we removed the two methyl groups in Pen.…”

Section: Introductionmentioning

confidence: 99%

Manipulating Pharmacokinetics of Purification-Free ^99mTc-Labeled Bivalent Probes for In Vivo Imaging of Saturable Targets

et al. 2020

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The accumulation of 99m Tc-labeled probes targeting saturable systems of the body is hindered by the presence of a large excess of unlabeled ligands needed to ensure high radiochemical yields in a short reaction time. To address the issue, we recently reported a novel concept of a metal-coordinationmediated synthesis of a bivalent 99m Tc-labeled probe from a monovalent ligand using D-penicillamine (Pen) as a chelating molecule and c(RGDfK) as a model targeting device. The Pen-conjugated c(RGDfK) via a hexanoate linkage (Pen-Hx-c(RGDfK)) provided a bivalent [ 99m Tc]Tc-[(Pen-Hx-c(RGDfK)) 2 that possessed much higher integrin α v β 3 binding affinity than Pen-Hx-c(RGDfK) and visualized a murine tumor without purification. However, high radioactivity levels were observed in the abdominal regions, which necessitated improved pharmacokinetics of the probes for practical applications. In this study, a pharmacokinetic (PK) modifier was introduced to manipulate the pharmacokinetics of the 99m Tc-Pen 2 -based bivalent probe. The Hx linkage in Pen-Hx-c(RGDfK) was replaced with acetyl-D-serine-D-serineglycine (Ac-ssG) or hexanoyl-D-serine-D-serine-D-serine (Hx-sss) to prepare Pen-Ac-ssG-c(RGDfK) or Pen-Hx-sss-c(RGDfK). Pen-Ac-ssG-c(RGDfK) impaired the complexation ability of Pen-Hx-c(RGDfK), and a monovalent 99m Tc-labeled compound was generated at low ligand concentration. However, Pen-Hx-sss-c(RGDfK) provided the objective bivalent 99m Tc-labeled probe in high radiochemical yields at a concentration similar to that of Pen-Hx-c(RGDfK). [ 99m Tc]Tc-[Pen-Hx-sss-c(RGDfK)] 2 also possessed stability and integrin α v β 3 binding affinity similar to those of [ 99m Tc]Tc-[Pen-Hx-c(RGDfK)] 2 . As a result, [ 99m Tc]Tc-[Pen-Hx-sssc(RGDfK)] 2 exhibited tumor and abdominal radioactivity levels similar to and significantly lower than those of [ 99m Tc]Tc-[Pen-Hxc(RGDfK)] 2 . These findings indicate the incorporation of a tripeptide PK modifier to Pen-Hx-c(RGDfK) preserved the complexation ability and improved the pharmacokinetics of the resulting 99m Tc-labeled bivalent probe without impairing the targeting ability. Thus, the [Pen-Hx-(PK modifier)-(targeting device)] would constitute a basic formulation for preparing the 99m Tc-Pen 2 -based bivalent probes for imaging saturable targets of the body.

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Novel 99mTc ‘4 + 1’ peptide conjugates: Tuning the biodistribution by variation of coligands

Cited by 16 publications

References 27 publications

Development and characterization of a ^99mTc‐tricarbonyl–labelled estradiol derivative obtained by “Click Chemistry” with potential application in estrogen receptors imaging

Development and characterization of a ^99mTc‐tricarbonyl–labelled estradiol derivative obtained by “Click Chemistry” with potential application in estrogen receptors imaging

Specific uptake of 99mTc-NC100692, an αvβ3-targeted imaging probe, in subcutaneous and orthotopic tumors

Manipulating Pharmacokinetics of Purification-Free ^99mTc-Labeled Bivalent Probes for In Vivo Imaging of Saturable Targets

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Novel 99mTc ‘4 + 1’ peptide conjugates: Tuning the biodistribution by variation of coligands

Cited by 16 publications

References 27 publications

Development and characterization of a 99mTc‐tricarbonyl–labelled estradiol derivative obtained by “Click Chemistry” with potential application in estrogen receptors imaging

Development and characterization of a 99mTc‐tricarbonyl–labelled estradiol derivative obtained by “Click Chemistry” with potential application in estrogen receptors imaging

Specific uptake of 99mTc-NC100692, an αvβ3-targeted imaging probe, in subcutaneous and orthotopic tumors

Manipulating Pharmacokinetics of Purification-Free 99mTc-Labeled Bivalent Probes for In Vivo Imaging of Saturable Targets

Contact Info

Product

Resources

About

Development and characterization of a ^99mTc‐tricarbonyl–labelled estradiol derivative obtained by “Click Chemistry” with potential application in estrogen receptors imaging

Development and characterization of a ^99mTc‐tricarbonyl–labelled estradiol derivative obtained by “Click Chemistry” with potential application in estrogen receptors imaging

Manipulating Pharmacokinetics of Purification-Free ^99mTc-Labeled Bivalent Probes for In Vivo Imaging of Saturable Targets