Synthesis and evaluation of Re/99mTc(I) complexes bearing a somatostatin receptor-targeting antagonist and labeled via a novel [N,S,O] clickable bifunctional chelating agent

Radford, Lauren L.; Papagiannopoulou, Dionysia; Gallazzi, Fabio; Berendzen, Ashley; Watkinson, Lisa D.; Carmack, Terry; Lewis, Michael R.; Jurisson, Silvia S.; Hennkens, Heather M.

doi:10.1016/j.bmc.2018.12.028

Cited by 12 publications

(6 citation statements)

References 28 publications

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“…For example, technetium has faster reaction kinetics and a lower reduction potential than rhenium . As a result, differences in their products and stability are sometimes observed. − …”

Section: Resultsmentioning

confidence: 99%

1,4,7-Triazacyclononane-Based Chelators for the Complexation of [¹⁸⁶Re]Re- and [^99mTc]Tc-Tricarbonyl Cores

Hoerres,

Hennkens

2023

Inorg. Chem.

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Metal complexes with the general formula [MI(CO)3(k3-L)]+, where M = Re, 186Re, or 99mTc and L = 1,4,7-triazacyclononane (TACN), NOTA, or NODAGA chelators, have previously been conjugated to peptide-based biological targeting vectors and investigated as potential theranostic radiopharmaceuticals. The promising results demonstrated by these bioconjugate complexes prompted our exploration of other TACN-based chelators for suitability for (radio)labeling with the [M(CO)3]+ core. In this work, we investigated the role of the TACN pendant arms in complexation of the [M(CO)3]+ core through (radio)labeling of TACN chelators bearing acid, ester, mixed acid–ester, or no pendant functional groups. The chelators were synthesized from TACN, characterized, and (radio)labeled with nonradioactive Re-, [186Re]Re-, and [99mTc]Tc-tricarbonyl cores. The nonfunctionalized (3), diacid (4), and monoacid monoester (7 and 8) chelators underwent direct labeling, while the diester (M-5 and M-6) complexes required indirect synthesis from M-4. All six chelators demonstrated stable radiometal coordination. The ester-bearing derivatives, which exhibited more lipophilic character than their acid-bearing counterparts, were prone to ester hydrolysis over time, making them less suitable for radiopharmaceutical development. These studies confirmed that the TACN pendant functional groups were key to efficient labeling with the [M(CO)3]+ core, with ionizable pendant arms favored over nonionizable pendant arms.

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“…For example, technetium has faster reaction kinetics and a lower reduction potential than rhenium . As a result, differences in their products and stability are sometimes observed. − …”

Section: Resultsmentioning

confidence: 99%

1,4,7-Triazacyclononane-Based Chelators for the Complexation of [¹⁸⁶Re]Re- and [^99mTc]Tc-Tricarbonyl Cores

Hoerres,

Hennkens

2023

Inorg. Chem.

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“…For indirect radiolabeling via [ 99m Tc(CO) 3 ] + ( 99m Tc‐tricarbonyl) core, firstly, the precursor fac ‐[ 99m Tc(CO) 3 (H 2 O) 3 ] + was synthesized using in‐house kit prepared with ≥98% radiochemical purity (Figure 1f, left radiochromatogram) as reported in literature. [ 26 ] Later on, the pH of the precursor was adjusted to pH 6 followed by heating with a solution of DTPA‐peptides at 75°C for 30 min. The radiotracer 99m Tc(CO) 3 DTPA‐cPT was synthesized with maximum % RCY of 95.4 ± 1.3% ( n = 3) as estimated by TLS‐SG technique and the radiotracer 99m Tc(CO) 3 DTPA‐ L PT was achieved with % RCY of 90.8 ± 1.4% ( n = 3) as shown in Figure 1e and the scheme of reaction and proposed structures are presented in Scheme 2 according to the literature.…”

Section: Resultsmentioning

confidence: 99%

“…Furthermore, our proposed radiotracer of cyclic peptide is observed to possess $15 folds better EC 50 values other radiotracers such as α-MSH peptide, sst2-ANT peptide, and BBN conjugates as reported in the literature. [26,31,32] 3.9 | AD-induced animal models…”

Section: Internalization Assaymentioning

confidence: 99%

“…The biodistribution outcomes of our proposed cyclic peptide-based radiotracer showed intermittent uptake in liver, while persisted uptake in kidneys and fast clearance up to 3 h indicated renal excretion and it cleared from bladder route that resulted in a prominent decrease in background activity. The fast clearance of the radiotracer is because of the unique advantage of small cyclic peptide probe and excretion is observed to be completed within 24 h. [20,26]…”

Section: Biodistribution Studymentioning

confidence: 99%

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Preclinical assessment of Alzheimer's disease using novel designed ^99mTc‐labeled RGD‐based pro‐apoptotic cyclic peptide as a promising SPECT agent

Rizvi

Ahmad

Munib

et al. 2022

Applied Organom Chemis

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The increased prevalence of neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, and glioma results in increased risks to abolish the healthy life. This is because of inducing alternation causes into the intracellular compartment as well as noncell compartments. Therefore, herein, a simple and facile radiosynthesis strategy was employed for the development of a novel 99mTc (t1/2 = 6 h, Er = 140 keV) labeled diethylenetriamine pentaacetic acid (DTPA) conjugated cyclic heptapeptide (99mTc‐DTPA‐c[RGDKLAK]; cPT). The radiotracer was characterized using various analytical techniques to evaluate the identity, radiolabeling, biocompatibility, in vitro stability, and amenability for preclinical use. The biological specificity and efficacy of the radiolabeled cyclic peptide analog were confirmed by in vivo biodistribution and single‐photon emission computed tomography (SPECT) studies in Alzheimer disease (AD)‐induced animal models. The results demonstrated that 99mTc(CO)3‐DTPA‐cPT showed high radioactivity concentration at the site of αvβ3, α5β1‐integrins expressing brain regions while decreasing radioactivity levels in kidneys and increasing urinary bladder over the period of 3 h suggested the renal clearance route of the radiotracer. The diagnostic outcomes obtained from planar SPECT study are consistent with that of the biodistribution study with a target‐to‐nontarget ratio (T/NT = 28.47 ± 2.53) at 3‐h postinjection. The results are surprisingly supportive to our hypothesis that the small cyclic peptide‐based radiotracer is well‐oriented towards targeted drug delivery and envisaged that our proposed radiotracer 99mTc(CO)3‐DTPA‐cPT has potential diagnostic applications for Alzheimer's disease as a novel SPECT agent.

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“…The combination of its optimal nuclear properties and the diverse coordination chemistry render it highly versatile, able to be incorporated in different chelate systems at different oxidation states, and thus modulating the biological and chemical properties of the radiopharmaceutical. Even though the 99m Tc-based somatostatin agonist hydrazinonicotinamide/ethylenediamine N,N -diacetic acid-Tyr 3octreotide (HYNIC/EDDA-TOC) is used in several European countries ( 99m Tc-Tektrotyd ® ), few preclinical studies have reported the development of somatostatin receptor antagonists radiolabelled with 99m Tc [13][14][15][16].…”

Section: Discussionmentioning

confidence: 99%

Selection of the First 99mTc-Labelled Somatostatin Receptor Subtype 2 Antagonist for Clinical Translation—Preclinical Assessment of Two Optimized Candidates

et al. 2020

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Recently, radiolabelled antagonists targeting somatostatin receptors subtype 2 (SST2) in neuroendocrine neoplasms demonstrated certain superior properties over agonists. Within the ERA-PerMED project “TECANT” two 99mTc-Tetramine (N4)-derivatized SST2 antagonists (TECANT-1 and TECANT-2) were studied for the selection of the best candidate for clinical translation. Receptor-affinity, internalization and dissociation studies were performed in human embryonic kidney-293 (HEK293) cells transfected with the human SST2 (HEK-SST2). Log D, protein binding and stability in human serum were assessed. Biodistribution and SPECT/CT studies were carried out in nude mice bearing HEK-SST2 xenografts, together with dosimetric estimations from mouse-to-man. [99mTc]Tc-TECANT-1 showed higher hydrophilicity and lower protein binding than [99mTc]-TECANT-2, while stability was comparable. Both radiotracers revealed similar binding affinity, while [99mTc]Tc-TECANT-1 had higher cellular uptake (>50%, at 2 h/37 °C) and lower dissociation rate (<30%, at 2 h/37 °C). In vivo, [99mTc]Tc-TECANT-1 showed lower blood values, kidney and muscles uptake, whereas tumour uptake was comparable to [99mTc]Tc-TECANT-2. SPECT/CT imaging confirmed the biodistribution results, providing the best tumour-to-background image contrast for [99mTc]Tc-TECANT-1 at 4 h post-injection (p.i.). The estimated radiation dose amounted to approximately 6 µSv/MBq for both radiotracers. This preclinical study provided the basis of selection of [99mTc]Tc-TECANT-1 for clinical translation of the first 99mTc-based SST2 antagonist.

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Synthesis and evaluation of Re/99mTc(I) complexes bearing a somatostatin receptor-targeting antagonist and labeled via a novel [N,S,O] clickable bifunctional chelating agent

Cited by 12 publications

References 28 publications

1,4,7-Triazacyclononane-Based Chelators for the Complexation of [¹⁸⁶Re]Re- and [^99mTc]Tc-Tricarbonyl Cores

1,4,7-Triazacyclononane-Based Chelators for the Complexation of [¹⁸⁶Re]Re- and [^99mTc]Tc-Tricarbonyl Cores

Preclinical assessment of Alzheimer's disease using novel designed ^99mTc‐labeled RGD‐based pro‐apoptotic cyclic peptide as a promising SPECT agent

Selection of the First 99mTc-Labelled Somatostatin Receptor Subtype 2 Antagonist for Clinical Translation—Preclinical Assessment of Two Optimized Candidates

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Synthesis and evaluation of Re/99mTc(I) complexes bearing a somatostatin receptor-targeting antagonist and labeled via a novel [N,S,O] clickable bifunctional chelating agent

Cited by 12 publications

References 28 publications

1,4,7-Triazacyclononane-Based Chelators for the Complexation of [186Re]Re- and [99mTc]Tc-Tricarbonyl Cores

1,4,7-Triazacyclononane-Based Chelators for the Complexation of [186Re]Re- and [99mTc]Tc-Tricarbonyl Cores

Preclinical assessment of Alzheimer's disease using novel designed 99mTc‐labeled RGD‐based pro‐apoptotic cyclic peptide as a promising SPECT agent

Selection of the First 99mTc-Labelled Somatostatin Receptor Subtype 2 Antagonist for Clinical Translation—Preclinical Assessment of Two Optimized Candidates

Contact Info

Product

Resources

About

1,4,7-Triazacyclononane-Based Chelators for the Complexation of [¹⁸⁶Re]Re- and [^99mTc]Tc-Tricarbonyl Cores

1,4,7-Triazacyclononane-Based Chelators for the Complexation of [¹⁸⁶Re]Re- and [^99mTc]Tc-Tricarbonyl Cores

Preclinical assessment of Alzheimer's disease using novel designed ^99mTc‐labeled RGD‐based pro‐apoptotic cyclic peptide as a promising SPECT agent