A novel injectable formulation of 6-fluoro- l -DOPA imaging agent for diagnosis of neuroendocrine tumors and Parkinson’s disease

Trapani, Adriana; Tricarico, Domenico; Mele, Antonietta; Maqoud, Fatima; Mandracchia, Delia; Vitale, Paola; Capriati, Vito; Trapani, Giuseppe; Dimiccoli, Vincenzo; Tolomeo, Anna; Scilimati, Antonio

doi:10.1016/j.ijpharm.2017.01.038

Cited by 15 publications

(11 citation statements)

References 40 publications

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“…An autopsy with macroscopic observation of all organs was performed among the sacrificed subjects according to approved protocols [ 29 ]. After animal sacrifice, tissue samples were incorporated, frozen in liquid nitrogen at −80 °C, sectioned using a cryostat for ATPase and succinodehydrogenase (SDH) staining.…”

Section: Methodsmentioning

confidence: 99%

Consequences of SUR2[A478V] Mutation in Skeletal Muscle of Murine Model of Cantu Syndrome

Scala

Maqoud

Zizzo

et al. 2021

Cells

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(1) Background: Cantu syndrome (CS) arises from gain-of-function (GOF) mutations in the ABCC9 and KCNJ8 genes, which encode ATP-sensitive K+ (KATP) channel subunits SUR2 and Kir6.1, respectively. Most CS patients have mutations in SUR2, the major component of skeletal muscle KATP, but the consequences of SUR2 GOF in skeletal muscle are unknown. (2) Methods: We performed in vivo and ex vivo characterization of skeletal muscle in heterozygous SUR2[A478V] (SUR2wt/AV) and homozygous SUR2[A478V] (SUR2AV/AV) CS mice. (3) Results: In SUR2wt/AV and SUR2AV/AV mice, forelimb strength and diaphragm amplitude movement were reduced; muscle echodensity was enhanced. KATP channel currents recorded in Flexor digitorum brevis fibers showed reduced MgATP-sensitivity in SUR2wt/AV, dramatically so in SUR2AV/AV mice; IC50 for MgATP inhibition of KATP currents were 1.9 ± 0.5 × 10−5 M in SUR2wt/AV and 8.6 ± 0.4 × 10−6 M in WT mice and was not measurable in SUR2AV/AV. A slight rightward shift of sensitivity to inhibition by glibenclamide was detected in SUR2AV/AV mice. Histopathological and qPCR analysis revealed atrophy of soleus and tibialis anterior muscles and up-regulation of atrogin-1 and MuRF1 mRNA in CS mice. (4) Conclusions: SUR2[A478V] “knock-in” mutation in mice impairs KATP channel modulation by MgATP, markedly so in SUR2AV/AV, with atrophy and non-inflammatory edema in different skeletal muscle phenotypes.

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Section: Methodsmentioning

confidence: 99%

Consequences of SUR2[A478V] Mutation in Skeletal Muscle of Murine Model of Cantu Syndrome

Scala

Maqoud

Zizzo

et al. 2021

Cells

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“…Section analysis and the CSA evaluation of the fibers was performed by QWin software (Leica). Of the subjects sacrificed, a gross necropsy of all organs was also carried out (Trapani et al, 2017). Examination of cellular morphology as well as of intracellular structures was conducted and the severity of the observed lesions was assessed (Gibson-Corley et al, 2013), by animal pathologists blinded to mouse genotype.…”

Section: Histopathological Analysismentioning

confidence: 99%

Pathophysiological Consequences of KATP Channel Overactivity and Pharmacological Response to Glibenclamide in Skeletal Muscle of a Murine Model of Cantù Syndrome

et al. 2020

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Cantù syndrome (CS) arises from mutations in ABCC9 and KCNJ8 genes that lead to gain of function (GOF) of ATP-sensitive potassium (KATP) channels containing SUR2A and Kir6.1 subunits, respectively, of KATP channels. Pathological consequences of CS have been reported for cardiac and smooth muscle cells but consequences in skeletal muscle are unknown. Children with CS show muscle hypotonia and adult manifest fatigability. We analyzed muscle properties of Kir6.1[V65M] CS mice, by measurements of forelimb strength and ultrasonography of hind-limb muscles, as well as assessing KATP channel properties in native Flexor digitorum brevis (FDB) and Soleus (SOL) fibers by the patch-clamp technique in parallel with histopathological, immunohistochemical and Polymerase Chain Reaction (PCR) analysis. Forelimb strength was lower in Kir6.1wt/VM mice than in WT mice. Also, a significant enhancement of echodensity was observed in hind-limb muscles of Kir6.1wt/VM mice relative to WT, suggesting the presence of fibrous tissue. There was a higher KATP channel current amplitude in Kir6.1wt/VM FDB fibers relative to WT and a reduced response to glibenclamide. The IC50 of glibenclamide to block KATP channels in FDB fibers was 1.3 ± 0.2 × 10−7 M in WT and 1.2 ± 0.1 × 10−6 M in Kir6.1wt/VM mice, respectively; and it was 1.2 ± 0.4 × 10−7 M in SOL WT fibers but not measurable in Kir6.1wt/VM fibers. The sensitivity of the KATP channel to MgATP was not modified in Kir6.1wt/VM fibers. Histopathological/immunohistochemical analysis of SOL revealed degeneration plus regressive-necrotic lesions with regeneration, and up-regulation of Atrogin-1, MuRF1, and BNIP3 mRNA/proteins in Kir6.1wt/VM mice. Kir6.1wt/VM mutation in skeletal muscle leads to changes of the KATP channel response to glibenclamide in FDB and SOL fibers, and it is associated with histopathological and gene expression changes in slow-twitch muscle, suggesting marked atrophy and autophagy.

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“…In conclusion, (S)-ethyl 2-(tert-butoxycarbonylamino)-3-(2-iodo-4,5methylenedioxyphenyl)propanoate (2) has been successfully synthesized starting from commercially available L-DOPA and using CF 3 CO 2 Ag/I 2 as the iodinating reagent. The title compound is a suitable intermediate for the synthesis of 6-fluoro-L-DOPA and certain derivatives by cross-coupling reactions.…”

Section: Discussionmentioning

confidence: 98%

“…Other possible applications include psychiatric [5,6] and age-related neurodegenerative disorder diagnoses [7]. Figure 1)-is a positron emission tomography (PET) diagnostic radiotracer [1,2], useful to detect pathological loss of dopaminergic neuron terminals in the striatum. Thus, 6-[ 18 F]fluoro-L-DOPA is used for the diagnosis of Parkinson′s disease (PD) and distinction between essential tremor and parkinsonian syndromes (PS), especially at the PS onset [3].…”

mentioning

confidence: 99%

(S)-Ethyl 2-(tert-butoxycarbonylamino)-3-(2-iodo-4,5-methylenedioxyphenyl)propanoate

Lentini

Cavalluzzi

Degennaro

et al. 2019

Molbank

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A multistep gram-scale synthesis of (S)-ethyl 2-(tert-butoxycarbonylamino)-3-(2-iodo-4,5-methylenedioxyphenyl)propanoate (2) has been developed. The title compound was prepared starting from commercially available l-DOPA which was O- and N-protected before undergoing iodination by CF3CO2Ag/I2. The structure of the target compound was confirmed using IR, 1H-NMR, 13C-NMR, 2D (COSY, HSQC) NMR spectroscopy, as well as ESI-MS and HRMS.

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A novel injectable formulation of 6-fluoro- l -DOPA imaging agent for diagnosis of neuroendocrine tumors and Parkinson’s disease

Cited by 15 publications

References 40 publications

Consequences of SUR2[A478V] Mutation in Skeletal Muscle of Murine Model of Cantu Syndrome

Consequences of SUR2[A478V] Mutation in Skeletal Muscle of Murine Model of Cantu Syndrome

Pathophysiological Consequences of KATP Channel Overactivity and Pharmacological Response to Glibenclamide in Skeletal Muscle of a Murine Model of Cantù Syndrome

(S)-Ethyl 2-(tert-butoxycarbonylamino)-3-(2-iodo-4,5-methylenedioxyphenyl)propanoate

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