The role of coordination chemistry in the development of target-specific radiopharmaceuticals

Liu, Shuang

doi:10.1039/b309961j

Cited by 335 publications

(271 citation statements)

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“…Such a strategy is commonly reported as bifunctional chelate (BFC) approach. 20 Hence, starting from the already known potent and selective TSPO ligand CB86 (Chart 1), 15 we designed a new namely,[2][3][4][5][6][7][8] 1), where, the di(2-picolyl)amine moiety could be used for the synthesis of coordination complexes containing a metallo drug to be used in diagnosis and therapy.Preliminarily, we performed in vitro studies on the newly synthesized TSPO-selective BFC ligand CB256 in order to assess its affinity toward TSPO. In addition, since it is wellknown that TSPO ligands are able to induce apoptosis, we also investigated the cytotoxic activity and the ability to cause morphological changes of the mitochondrion and of the nucleus, the collapse of the mitochondrial membrane potential (ΔΨ m ), and alterations of the cell cycle progression in C6…”

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Synthesis, Characterization, and in Vitro Evaluation of a New TSPO-Selective Bifunctional Chelate Ligand

Denora

Margiotta

Laquintana

et al. 2014

ACS Med. Chem. Lett.

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The 18-kDa translocator protein (TSPO) is overexpressed in many types of cancers and is also abundant in activated microglial cells occurring in inflammatory neurodegenerative diseases. Thus, TSPO has become an extremely attractive subcellular target not only for imaging disease states overexpressing this protein, but also for a selective mitochondrial drug delivery. In this work we report the synthesis, the characterization, and the in vitro evaluation of a new TSPO-, which fulfils the requirements for a bifunctional chelate approach. The goal was to provide a new TSPO ligand that could be used further to prepare coordination complexes of a metallo drug to be used in diagnosis and therapy. However, the ligand itself proved to be a potent tumor cell growth inhibitor and DNA double-strand breaker. KEYWORDS: TSPO, PBR, bifunctional chelate approach, apoptosis, DNA cleavage T he 18-kDa mitochondrial translocator protein (TSPO), 1 also known as peripheral-type benzodiazepine receptor or PBR, has become an attractive target for therapeutic and imaging purposes. 2−5 TSPO is poorly expressed in healthy human brain and liver, while it is much more abundant in steroid-synthesizing and rapidly proliferating tissues. In contrast, aberrant TSPO expression has been observed in multiple diseases, including brain, breast, colon, prostate, and ovarian cancers, as well as astrocytomas and hepatocellular and endometrial carcinomas. 6,7 Moreover, TSPO expression is also increased in activated microglial cells occurring in inflammatory neurodegenerative diseases such as Alzheimer, Parkinson, Huntington, and multiple sclerosis. 8 Thus, TSPO has become an extremely attractive subcellular target not only for an early detection of disease states overexpressing this protein, but also for a selective mitochondrial drug delivery. 9−14 Although a wide number of TSPO ligands have been synthesized, only few of them have the ability to deliver metal-based drugs. 15 In particular, very recently were reported potent and selective imidazopyridine-based TSPO ligands, which could carry both a cytostatic platinum species and a rhenium complex as a model of 99m Tc imaging agent. 13,16−19 In the compounds so far investigated, atoms already present in the TSPO ligand were used as donors for anchoring the metal core. A further development could be represented by the use of conjugates in which the TSPO-targeting moiety is covalently linked with an appropriate chelating system, such as di(2-picolyl)amine, forming a strong coordination compound with metal ions in the pertinent oxidation state. The use of an appropriate linker could rule out possible interactions between the metal-core and the targeting moiety so to leave unaltered the pharmacokinetic profile of the tracer. Such a strategy is commonly reported as bifunctional chelate (BFC) approach. 20 Hence, starting from the already known potent and selective TSPO ligand CB86 (Chart 1), 15 we designed a new namely,[2][3][4][5][6][7][8] 1), where, the di(2-picolyl)amine moiety could be used f...

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confidence: 99%

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confidence: 99%

Synthesis, Characterization, and in Vitro Evaluation of a New TSPO-Selective Bifunctional Chelate Ligand

Denora

Margiotta

Laquintana

et al. 2014

ACS Med. Chem. Lett.

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“…It was reported that introduction of the polyethylene glycol (PEG) linker can improve not only tumor uptake but also excretion kinetics of 125 I-and 18 F-labeled c(RGDyK) and 64 Cu-labeled E[c(RGDyK)] 2 (25)(26)(27)(28). PKM linkers and their applications to improve the excretion kinetics of radiolabeled small biomolecules have been reviewed recently (13,24,(29)(30)(31).…”

Section: Introductionmentioning

confidence: 99%

“…The RGD peptide serves as "vehicles" to carry radionuclide ( 99m Tc, 18 F and 64 Cu) to the integrin α v β 3 overexpressed on tumor cells and activated endothelial cells of the tumor neovasculature. 99m Tc is the choice of radionuclide for single photon computed tomography (SPECT) and planar imaging due to its optimal nuclear properties (half-life, abundance and energy of gamma photons) and easy availability at low cost (12)(13)(14). For the 99m Tc-labeling, 6-hydrazinonicotinic acid (HYNIC) has been used as a bifunctional coupling agent while tricine and a water-soluble phosphine or pyridine analog are used as coligands to prepare ternary ligand 99m Tc complexes [ 99m Tc(HYNIC-SU016)(tricine) (L)] (L = ISONIC (isonicotinic acid), TPPTS (trisodium triphenylphosphine-3,3′,3″-trisulfonate, and PDA (2,5-pyridinedicarboxylic acid)) (1-3).…”

Section: Introductionmentioning

confidence: 99%

Impact of PKM Linkers on Biodistribution Characteristics of the ^99mTc-Labeled Cyclic RGDfK Dimer

Liu

Hsieh

et al. 2006

Bioconjugate Chem.

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This report describes synthesis of three new cyclic RGDfK peptide conjugates, HYNIC-PKM-SU016 (PKM = E, K and PEG4), and in vivo evaluation of the impact of PKM linkers on biodistribution characteristics of their ternary ligand complexes [ 99m Tc(HYNIC-PKM-SU016)(tricine)(TPPTS)] in athymic nude mice bearing the MDA-MB-435 human breast cancer xenografts. Results from biodistribution studies show that PKM linkers have minimal impact on the integrin α v β 3 binding capability of radiotracers. Even though they have different charges under physiological conditions, all three linkers (E, K and PEG4) are able to reduce the uptake of 99m Tc-labeled E[c(RGDfK)] 2 in blood, kidneys, liver and lungs, and increase target-to-background (T/B) ratios at >30 min postinjection. E and K may have advantages over PEG4 due to a combination of relatively low liver uptake, high tumor/liver and tumor/lung ratios of ternary ligand complexes [ 99m Tc(HYNIC-PKM-SU016)(tricine)(TPPTS)] (PKM = E and K).

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“…A number of biomolecules, such as monoclonal antibodies and peptides, have been exploited as carriers for radionuclides; some have been granted approval by the Food and Drug Administration. [45] Of all the vitamins investigated as carriers for target delivery, vitamin B 12 is probably the least studied. Earlier works with 57 Co-labeled cobalamins aimed to elucidate the accumulation of vitamin B 12 in transplanted tumors.…”

Section: Diagnostic Vitamin B 12 -Metal Conjugatesmentioning

confidence: 99%

Vitamin B₁₂–Metal Conjugates for Targeted Chemotherapy and Diagnosis: Current Status and Future Prospects

2017

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Vitamin B 12 (cyanocobalamin) is a vital nutrient characterized by very low bioavailability. Owing to their extremely high proliferation rates, tumor cells show increased demand for nutrients in comparison with healthy ones, including the greater uptake of vitamin B 12 . This avidity for cyanocobalamin can thus be exploited for the site-specific delivery of drugs directly into tumor cells by conjugation of vitamin B 12 (carrier)

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The role of coordination chemistry in the development of target-specific radiopharmaceuticals

Cited by 335 publications

References 133 publications

Synthesis, Characterization, and in Vitro Evaluation of a New TSPO-Selective Bifunctional Chelate Ligand

Synthesis, Characterization, and in Vitro Evaluation of a New TSPO-Selective Bifunctional Chelate Ligand

Impact of PKM Linkers on Biodistribution Characteristics of the ^99mTc-Labeled Cyclic RGDfK Dimer

Vitamin B₁₂–Metal Conjugates for Targeted Chemotherapy and Diagnosis: Current Status and Future Prospects

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The role of coordination chemistry in the development of target-specific radiopharmaceuticals

Cited by 335 publications

References 133 publications

Synthesis, Characterization, and in Vitro Evaluation of a New TSPO-Selective Bifunctional Chelate Ligand

Synthesis, Characterization, and in Vitro Evaluation of a New TSPO-Selective Bifunctional Chelate Ligand

Impact of PKM Linkers on Biodistribution Characteristics of the 99mTc-Labeled Cyclic RGDfK Dimer

Vitamin B12–Metal Conjugates for Targeted Chemotherapy and Diagnosis: Current Status and Future Prospects

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Product

Resources

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Impact of PKM Linkers on Biodistribution Characteristics of the ^99mTc-Labeled Cyclic RGDfK Dimer

Vitamin B₁₂–Metal Conjugates for Targeted Chemotherapy and Diagnosis: Current Status and Future Prospects