Novel molecular imaging of cell death in experimental cerebral stroke

Reshef, Ayelet; Shirvan, Anat; Grimberg, Hagit; Levin, Galit; Cohen, Avi; Mayk, Adi; Kidron, Debora; Djaldetti, Ruth; Melamed, Eldad; Ziv, Ilan

doi:10.1016/j.brainres.2007.01.095

Cited by 36 publications

(37 citation statements)

References 19 publications

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“…Conceptually, low-molecular-weight probes can be advantageous over large proteins such as Annexin-V (MW=37 000 Da) in the aspects of radio-labeling, biodistribution and immunogenicity. Based on these considerations, we have developed and previously reported DDC [9][10][11] and NST-732 [12], which are members of the ApoSense family of recently developed small-molecule apoptosis probes. However, DDC or NST-732 do not comprise a Gla structural motif, which, as revealed in the present study, is unique in being the smallest structural motif for detection of apoptosis known to date.…”

Section: Discussionmentioning

confidence: 99%

“…Based on this hypothesis and on our previous experience in developing fluorescent small-molecule apoptosis probes of the ApoSense family, such as didansyl-Lcystine (DDC) [9,10,11] and NST-732 [12], we now present ML-10 (2-(5-fluoro-pentyl)-2-methyl-malonic acid), as a rationally designed molecule, with an amphipathic compact structure (MW=206 Da). We also describe the performance of this novel Gla-derived probe as a detector of apoptosis, and its mechanism of action.…”

Section: Introductionmentioning

confidence: 99%

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From the Gla domain to a novel small-molecule detector of apoptosis

Cohen¹,

Shirvan²,

Levin³

et al. 2009

Cell Res

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Apoptosis plays a pivotal role in the etiology or pathogenesis of numerous medical disorders, and thus, targeting of apoptotic cells may substantially advance patient care. In our quest for novel low-molecular-weight probes for apoptosis, we focused on the uncommon amino acid γ-carboxyglutamic acid (Gla), which plays a vital role in the binding of clotting factors to negatively charged phospholipid surfaces. Based on the alkyl-malonic acid motif of Gla, we have developed and now present ML-10 (2-(5-fluoro-pentyl)-2-methyl-malonic acid, MW=206 Da), the prototypical member of a novel family of small-molecule detectors of apoptosis. ML-10 was found to perform selective uptake and accumulation in apoptotic cells, while being excluded from either viable or necrotic cells. ML-10 uptake correlates with the apoptotic hallmarks of caspase activation, Annexin-V binding and disruption of mitochondrial membrane potential. The malonate moiety was found to be crucial for ML-10 function in apoptosis detection. ML-10 responds to a unique complex of features of the cell in early apoptosis, comprising irreversible loss of membrane potential, permanent acidification of cell membrane and cytoplasm, and preservation of membrane integrity. ML-10 is therefore the most compact apoptosis probe known to date. Due to its fluorine atom, ML-10 is amenable to radiolabeling with the 18 F isotope, towards its potential future use for clinical positron emission tomography imaging of apoptosis.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

From the Gla domain to a novel small-molecule detector of apoptosis

Cohen¹,

Shirvan²,

Levin³

et al. 2009

Cell Res

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“…It is a member of a family of small-molecule detectors of apoptosis (7)(8)(9). Apoptosis is characterized, from its early stages, by marked membrane alterations, comprising acidification of the outer membrane leaflet and permanent membrane depolarization.…”

Section: Discussionmentioning

confidence: 99%

“…Apoptosis is characterized, from its early stages, by marked membrane alterations, comprising acidification of the outer membrane leaflet and permanent membrane depolarization. The compounds are amphipathic, designed to respond to this unique set of membrane alterations by selectively binding to apoptotic cells from the early stages of the death process, crossing the cell membrane, and accumulating in the cytoplasm (7)(8)(9). On the basis of this mechanism, 18 F-ML-10 was designed to meet the challenge of clinical imaging of apoptosis by PET; achieving this goal required a very compact structure comprising an 18 F radioisotope.…”

Section: Discussionmentioning

confidence: 99%

“…After systemic administration, these compounds can detect apoptotic cells from the early stages of the death process, cross the intact plasma membrane, and accumulate in the cytoplasm (7)(8)(9). The performance of the fluorescent analogous compounds didansyl-L-cystine (DDC) and NST-732 in the detection of cell death after systemic administration in vivo was previously reported in various animal models (7)(8)(9) including, among others, monitoring of the tumor response to treatment, acute renal failure, and acute cerebral ischemia. In all of these models, the accumulation of the compounds in apoptotic cells in vivo was well correlated with the in vitro standard assessment of the death process.…”

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confidence: 99%

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Molecular Imaging of Neurovascular Cell Death in Experimental Cerebral Stroke by PET

Reshef

Shirvan²,

Waterhouse³

et al. 2008

J Nucl Med

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First use of ¹⁸F‐labeled ML‐10 PET to assess apoptosis change in a newly diagnosed glioblastoma multiforme patient before and early after therapy

et al. 2014

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ObjectivesThe authors present the first use of the novel positron emission tomography (PET) apoptosis tracer 18F-labeled 2-(5-fluoro-pentyl)-2-methyl-malonic acid (18F-ML-10) for early-therapy response assessment of a newly diagnosed glioblastoma multiforme (GBM) patient.Case reportA 71-year-old male with a newly diagnosed GBM received 18F-ML-10 PET scans prior to therapy initiation (baseline) and after completing 3 weeks of whole-brain radiation therapy with concomitant temozolomide chemotherapy (early-therapy assessment, ETA). The baseline 18F-ML-10 PET scan showed increased tracer uptake at the site of the GBM, with highest activity toward the central portion of the tumor. At the ETA time point, a new distribution of tracer uptake was observed compared to baseline. Normalized pixel-by-pixel subtraction of baseline from ETA was used to quantify change in tracer distribution between 18F-ML-10 PET imaging time points. Results of this analysis showed reduction in 18F-ML-10 uptake at the site of greatest baseline uptake, but increased uptake around the periphery of the tumor at the early-therapy time point.ConclusionThe changing patterns of 18F-ML-10 uptake between baseline and ETA are suggestive for therapy-induced tumor cellular apoptosis.

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Novel molecular imaging of cell death in experimental cerebral stroke

Cited by 36 publications

References 19 publications

From the Gla domain to a novel small-molecule detector of apoptosis

From the Gla domain to a novel small-molecule detector of apoptosis

Molecular Imaging of Neurovascular Cell Death in Experimental Cerebral Stroke by PET

First use of ¹⁸F‐labeled ML‐10 PET to assess apoptosis change in a newly diagnosed glioblastoma multiforme patient before and early after therapy

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Novel molecular imaging of cell death in experimental cerebral stroke

Cited by 36 publications

References 19 publications

From the Gla domain to a novel small-molecule detector of apoptosis

From the Gla domain to a novel small-molecule detector of apoptosis

Molecular Imaging of Neurovascular Cell Death in Experimental Cerebral Stroke by PET

First use of 18F‐labeled ML‐10 PET to assess apoptosis change in a newly diagnosed glioblastoma multiforme patient before and early after therapy

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First use of ¹⁸F‐labeled ML‐10 PET to assess apoptosis change in a newly diagnosed glioblastoma multiforme patient before and early after therapy