Molecular Imaging of Hydrolytic Enzymes Using PET and SPECT

Rempel, Brian P.; Price, Eric W.; Phenix, Christopher P.

doi:10.1177/1536012117717852

Cited by 24 publications

(15 citation statements)

References 203 publications

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“…Since this enzyme is localized within mitochondria and not typically secreted, it is unlikely to be readily measured in plasma or urine, limiting its potential as a readily accessible biomarker in ALS or other muscle denervating disease. It is possible that a PET or SPECT tracer could be developed to image this enzyme's activity as has been done for other metabolic pathways [40]. Circulating vitamin D has been investigated as a potential biomarker in ALS with mixed results.…”

Section: Discussionmentioning

confidence: 99%

The vitamin D activator CYP27B1 is upregulated in muscle fibers in denervating disease and can track progression in amyotrophic lateral sclerosis

Kazamel

Kwon

et al. 2020

The Journal of Steroid Biochemistry and Molecular Biology

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Extra-renal expression of Cytochrome P450 Family 27 Subfamily B Member 1 (CYP27B1) has been well recognized and reflects the importance of intracrine/paracrine vitamin D signaling in different tissues under physiological and pathological conditions. In a prior RNA sequencing project, we identified CYP27B1 mRNA as upregulated in muscle samples from patients with amyotrophic lateral sclerosis (ALS) compared to normal controls. Our aims here were: (1) to validate this finding in a larger sample set including disease controls, (2) to determine which cell type is expressing CYP27B1 protein in muscle tissue, (3) to correlate CYP27B1 mRNA expression with disease progression in the SOD1 G93A ALS mouse and in ALS patients. We assessed CYP27B1 expression by qPCR, western blot, and immunohistochemistry in a repository of muscle samples from ALS, disease controls (myopathy and non-ALS neuropathic disease), normal subjects, and muscle samples from the SOD1 G93A mouse. Eight ALS patients were studied prospectively over 6-12 months with serial muscle biopsies. We found that CYP27B1 mRNA and protein levels were significantly increased in ALS versus normal and myopathy muscle samples. Neuropathy samples had increased CYP27B1 mRNA and protein expression but at a lower level than the ALS group. Immunohistochemistry showed that CYP27B1 localized to myofibers, especially those with features of denervation. In the SOD1 G93A mouse, CYP27B1 mRNA and protein were detected in skeletal muscle in early pre-symptomatic stages and increased through end-stage. In the human study, increases in CYP27B1 mRNA in muscle biopsies correlated with disease progression rates over the same time period. In summary, we show for the first time that CYP27B1 mRNA and protein expression are elevated in muscle fibers in denervating disease, especially ALS, where mRNA levels can potentially serve as a surrogate marker for tracking

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Section: Discussionmentioning

confidence: 99%

The vitamin D activator CYP27B1 is upregulated in muscle fibers in denervating disease and can track progression in amyotrophic lateral sclerosis

Kazamel

Kwon

et al. 2020

The Journal of Steroid Biochemistry and Molecular Biology

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“…This selective accumulation will amplify the radioactive signal, correlating the uptake with the arginase activity or expression. Meanwhile, the not-metabolized fraction of the radiotracer and the non-targeted metabolites should be cleared and excreted, enhancing the target-to-background ratio in the PET image of arginase [ 241 ].…”

Section: Molecular Imaging Of Arginasementioning

confidence: 99%

Arginase as a Potential Biomarker of Disease Progression: A Molecular Imaging Perspective

Clemente

Waarde

Antunes

et al. 2020

IJMS

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Arginase is a widely known enzyme of the urea cycle that catalyzes the hydrolysis of L-arginine to L-ornithine and urea. The action of arginase goes beyond the boundaries of hepatic ureogenic function, being widespread through most tissues. Two arginase isoforms coexist, the type I (Arg1) predominantly expressed in the liver and the type II (Arg2) expressed throughout extrahepatic tissues. By producing L-ornithine while competing with nitric oxide synthase (NOS) for the same substrate (L-arginine), arginase can influence the endogenous levels of polyamines, proline, and NO•. Several pathophysiological processes may deregulate arginase/NOS balance, disturbing the homeostasis and functionality of the organism. Upregulated arginase expression is associated with several pathological processes that can range from cardiovascular, immune-mediated, and tumorigenic conditions to neurodegenerative disorders. Thus, arginase is a potential biomarker of disease progression and severity and has recently been the subject of research studies regarding the therapeutic efficacy of arginase inhibitors. This review gives a comprehensive overview of the pathophysiological role of arginase and the current state of development of arginase inhibitors, discussing the potential of arginase as a molecular imaging biomarker and stimulating the development of novel specific and high-affinity arginase imaging probes.

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“…PET radiotracers to image enzyme activity can be classified into three groups: substrates, reversible inhibitors and irreversible inhibitors. The design and development of novel PET radiotracers is arduous and shares certain analogies with the drug development process (Figure 2) [14]. Potential radiopharmaceuticals for imaging enzymatic targets should display high affinity and specificity toward the biological target.…”

Section: Caspase-3/7 Pet Imagingmentioning

confidence: 99%

Development of [18F]ICMT-11 for Imaging Caspase-3/7 Activity during Therapy-Induced Apoptosis

Garcia-Arguello

Lopez-Lorenzo

Cornelissen

et al. 2020

Cancers

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Insufficient apoptosis is a recognised hallmark of cancer. A strategy to quantitatively measure apoptosis in vivo would be of immense value in both drug discovery and routine patient management. The first irreversible step in the apoptosis cascade is activation of the “executioner” caspase-3 enzyme to commence cleavage of key structural proteins. One strategy to measure caspase-3 activity is Positron Emission Tomography using isatin-5-sulfonamide radiotracers. One such radiotracer is [18F]ICMT-11, which has progressed to clinical application. This review summarises the design and development process for [18F]ICMT-11, suggesting potential avenues for further innovation.

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Molecular Imaging of Hydrolytic Enzymes Using PET and SPECT

Cited by 24 publications

References 203 publications

The vitamin D activator CYP27B1 is upregulated in muscle fibers in denervating disease and can track progression in amyotrophic lateral sclerosis

The vitamin D activator CYP27B1 is upregulated in muscle fibers in denervating disease and can track progression in amyotrophic lateral sclerosis

Arginase as a Potential Biomarker of Disease Progression: A Molecular Imaging Perspective

Development of [18F]ICMT-11 for Imaging Caspase-3/7 Activity during Therapy-Induced Apoptosis

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