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Cysteine cathepsins: their role in tumor progression and recent trends in the development of imaging probes.

Löser R, Pietzsch J - Front Chem (2015)

Bottom Line: The considerable progress in this field over the last two decades has also raised interest in the visualization of these enzymes in their native context, especially with regard to tumor imaging.After a short introduction to structure and general functions of human cysteine cathepsins, we highlight their importance for drug discovery and development and provide a critical update on the current state of knowledge toward their involvement in tumor progression, with a special emphasis on their role in therapy response.In accordance with a radiopharmaceutical point of view, the main focus of this review article will be the discussion of recently developed fluorescence and radiotracer-based imaging agents together with related molecular probes.

View Article: PubMed Central - PubMed

Affiliation: Department of Radiopharmaceutical and Chemical Biology, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf Dresden, Germany ; Department of Chemistry and Food Chemistry, Technische Universität Dresden Dresden, Germany.

ABSTRACT
Papain-like cysteine proteases bear an enormous potential as drug discovery targets for both infectious and systemic human diseases. The considerable progress in this field over the last two decades has also raised interest in the visualization of these enzymes in their native context, especially with regard to tumor imaging. After a short introduction to structure and general functions of human cysteine cathepsins, we highlight their importance for drug discovery and development and provide a critical update on the current state of knowledge toward their involvement in tumor progression, with a special emphasis on their role in therapy response. In accordance with a radiopharmaceutical point of view, the main focus of this review article will be the discussion of recently developed fluorescence and radiotracer-based imaging agents together with related molecular probes.

No MeSH data available.


Related in: MedlinePlus

Cysteine-cathepsin targeting radiotracers labeled with “organic radionuclides.”
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Figure 11: Cysteine-cathepsin targeting radiotracers labeled with “organic radionuclides.”

Mentions: Compound [18F]35 (Figure 11) represents the first 18F-labeled radiotracer targeted against cysteine cathepsins (Löser et al., 2013). This molecular probe is based on an inhibitor of the azadipeptide nitrile chemotype. Azadipeptide nitriles have been characterized as highly potent toward papain-like cysteine proteases and stable against the degradation by other proteases (Löser et al., 2008; Frizler et al., 2011; Yang et al., 2012). To enable the convenient introduction of fluorine-18, the tyrosine residue in P2 position was etherified with a fluoroethyl chain. The non-radioactive reference compound 35 exhibited high binding affinities toward the oncologically relevant cathepsins B, L, S, and K. The Ki-value for cathepsin B was 2.4 nM, whereas those toward cathepsin L, S, and K were in the subnanomolar range. The process of 18F-labeling to obtain the corresponding radiotracer [18F]35 was established as a two-step, one-pot radiosynthesis. In this procedure [18F]fluoride was converted with ethylene glycol-1,2-dinosylate to 2-[18F]fluorethyl nosylate which was reacted without isolation with the corresponding phenolic precursor. This approach resulted in higher radiochemical yields for [18F]35 than the use of 2-[18F]fluoroethyl tosylate, which is the commonly employed agent for 18F-fluoroethylations (Zhang and Suzuki, 2007). The developed procedure was also superior to the direct conversion of corresponding benzenesulfonate precursors with [18F]fluoride. The well-established 18F-labeling process allowed the extensive radiopharmacological characterization of [18F]35 in immunodeficient mice bearing xenografted tumors derived from the human lung carcinoma cell line NCI-H292. Immunohistochemical investigations confirmed the presence of the targeted cathepsins in the neoplastic tissue. Radiotracer [18F]35 was studied for its ex vivo biodistribution and pharmacokinetics and stability in vivo in rats and mice. Slow blood clearance of the 18F-activity results from conjugate formation between [18F]35 and glutathione and retention of the formed metabolite in the erythrocytes, which has been confirmed by in vitro experiments. Despite rapid biotransformation, approximately 35% of the original radiotracer was still detectable in the blood activity fraction at 60 min p.i., which suggests that it should be available to the tumor-associated cysteine cathepsins. Accordingly, the tumor/muscle and tumor/blood ratios in the NCI-H292 carrying mice as determined by dynamic PET imaging were slowly increasing with tumor/muscle ratios reaching values significantly greater than three at 120 min p.i. This can be considered as indicative of a specific tumor accumulation (Löser et al., 2013). Therefore, despite unfavorable pharmacokinetic behavior due to inherent thiol reactivity, azadipeptide nitriles seem to be capable of tumor targeting.


Cysteine cathepsins: their role in tumor progression and recent trends in the development of imaging probes.

Löser R, Pietzsch J - Front Chem (2015)

Cysteine-cathepsin targeting radiotracers labeled with “organic radionuclides.”
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4477214&req=5

Figure 11: Cysteine-cathepsin targeting radiotracers labeled with “organic radionuclides.”
Mentions: Compound [18F]35 (Figure 11) represents the first 18F-labeled radiotracer targeted against cysteine cathepsins (Löser et al., 2013). This molecular probe is based on an inhibitor of the azadipeptide nitrile chemotype. Azadipeptide nitriles have been characterized as highly potent toward papain-like cysteine proteases and stable against the degradation by other proteases (Löser et al., 2008; Frizler et al., 2011; Yang et al., 2012). To enable the convenient introduction of fluorine-18, the tyrosine residue in P2 position was etherified with a fluoroethyl chain. The non-radioactive reference compound 35 exhibited high binding affinities toward the oncologically relevant cathepsins B, L, S, and K. The Ki-value for cathepsin B was 2.4 nM, whereas those toward cathepsin L, S, and K were in the subnanomolar range. The process of 18F-labeling to obtain the corresponding radiotracer [18F]35 was established as a two-step, one-pot radiosynthesis. In this procedure [18F]fluoride was converted with ethylene glycol-1,2-dinosylate to 2-[18F]fluorethyl nosylate which was reacted without isolation with the corresponding phenolic precursor. This approach resulted in higher radiochemical yields for [18F]35 than the use of 2-[18F]fluoroethyl tosylate, which is the commonly employed agent for 18F-fluoroethylations (Zhang and Suzuki, 2007). The developed procedure was also superior to the direct conversion of corresponding benzenesulfonate precursors with [18F]fluoride. The well-established 18F-labeling process allowed the extensive radiopharmacological characterization of [18F]35 in immunodeficient mice bearing xenografted tumors derived from the human lung carcinoma cell line NCI-H292. Immunohistochemical investigations confirmed the presence of the targeted cathepsins in the neoplastic tissue. Radiotracer [18F]35 was studied for its ex vivo biodistribution and pharmacokinetics and stability in vivo in rats and mice. Slow blood clearance of the 18F-activity results from conjugate formation between [18F]35 and glutathione and retention of the formed metabolite in the erythrocytes, which has been confirmed by in vitro experiments. Despite rapid biotransformation, approximately 35% of the original radiotracer was still detectable in the blood activity fraction at 60 min p.i., which suggests that it should be available to the tumor-associated cysteine cathepsins. Accordingly, the tumor/muscle and tumor/blood ratios in the NCI-H292 carrying mice as determined by dynamic PET imaging were slowly increasing with tumor/muscle ratios reaching values significantly greater than three at 120 min p.i. This can be considered as indicative of a specific tumor accumulation (Löser et al., 2013). Therefore, despite unfavorable pharmacokinetic behavior due to inherent thiol reactivity, azadipeptide nitriles seem to be capable of tumor targeting.

Bottom Line: The considerable progress in this field over the last two decades has also raised interest in the visualization of these enzymes in their native context, especially with regard to tumor imaging.After a short introduction to structure and general functions of human cysteine cathepsins, we highlight their importance for drug discovery and development and provide a critical update on the current state of knowledge toward their involvement in tumor progression, with a special emphasis on their role in therapy response.In accordance with a radiopharmaceutical point of view, the main focus of this review article will be the discussion of recently developed fluorescence and radiotracer-based imaging agents together with related molecular probes.

View Article: PubMed Central - PubMed

Affiliation: Department of Radiopharmaceutical and Chemical Biology, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf Dresden, Germany ; Department of Chemistry and Food Chemistry, Technische Universität Dresden Dresden, Germany.

ABSTRACT
Papain-like cysteine proteases bear an enormous potential as drug discovery targets for both infectious and systemic human diseases. The considerable progress in this field over the last two decades has also raised interest in the visualization of these enzymes in their native context, especially with regard to tumor imaging. After a short introduction to structure and general functions of human cysteine cathepsins, we highlight their importance for drug discovery and development and provide a critical update on the current state of knowledge toward their involvement in tumor progression, with a special emphasis on their role in therapy response. In accordance with a radiopharmaceutical point of view, the main focus of this review article will be the discussion of recently developed fluorescence and radiotracer-based imaging agents together with related molecular probes.

No MeSH data available.


Related in: MedlinePlus