Molecular imaging and biology : MIB : the official publication of the Academy of Molecular Imaging, Jan 27, 2016
The plasma membrane P-glycoprotein (Pgp) is an efflux transporter involved in multidrug resistanc... more The plasma membrane P-glycoprotein (Pgp) is an efflux transporter involved in multidrug resistance and in the onset of neurodegenerative disease. Its function and most mechanisms of action are still under investigation. We developed a C-11-labeled 2-arylethylphenylamine-([(11)C]AEPH) derivative for positron emission tomography (PET), as a novel probe to better understand the activity and the function of Pgp in vivo. The synthetic procedure and the quality control of the selected lead compound, [(11)C]AEPH-1, were set up and optimized. The biodistribution and the dynamic extraction in target organs of [(11)C]AEPH-1 were studied in vivo by PET in healthy rats at baseline and after pre-treatment with a Pgp inhibitor (tariquidar). In vivo dynamic imaging was consistent with the results of ex vivo extraction on explanted organs. An adequate stability for in vivo studies, as well as a high activity of [(11)C]AEPH-1 in intestine and barrier tissues, has been demonstrated. Results of the bl...
A2B adenosine receptors (ARs) are commonly defined as &am... more A2B adenosine receptors (ARs) are commonly defined as "danger" sensors because they are triggered during cell injury when the endogenous molecule, adenosine, increases rapidly. These receptors, together with the other receptor subtypes (A1, A2A and A3), exert a wide variety of immunomodulating and (cyto)protective effects, thus representing a pivotal therapeutic target for different pathologies including diabetes, tumors, cardiovascular diseases, pulmonary fibrosis and others. The limited availability of potent and selective ligands for A2B ARs has prevented this receptor to emerge both as therapeutic and diagnostic target. Recently, a new class of potent A2B ARs antagonists was developed featuring the triazinobenzimidazole scaffold. Starting from this chemotype, we synthesized a new radiotracer, [(11)C]-4 (1-[(11)C]methyl-3-phenyl triazino[4,3-a]benzimidazol-4(1H)-one), and investigated the pharmacokinetics of this compound in vivo to define its potential use in the imaging of A2B AR with positron emission tomography. [(11)C]-4 showed a very high chemical and blood stability. Results of in vivo and ex vivo experiments underlined the ability of this molecule to bind the A2B AR and correlated with the A2B AR protein and gene expression data. Although further studies are necessary, these data suggest that [(11)C]-4 may represent a good lead compound for the development of novel selective and potent A2B AR radiotracers, and a new option for the clinical investigation of several pathophysiological processes and chronic diseases.
ABSTRACT Il rapporto tra numero di neutroni (N) e numero di protoni (Z) determina la stabilità di... more ABSTRACT Il rapporto tra numero di neutroni (N) e numero di protoni (Z) determina la stabilità di un nuclide: per gli elementi leggeri la condizione di stabilità è in generale raggiunta quando il numero di neutroni è uguale o appena superiore a quello dei protoni (N = Z o N = Z+1). I nuclidi che hanno un numero di neutroni inferiore rispetto a quello di protoni (N/Z
Scandinavian Journal of Clinical & Laboratory Investigation, 1997
We amplified and sequenced the rearranged immunoglobulin heavy chain VDJ genomic unit in B-leukem... more We amplified and sequenced the rearranged immunoglobulin heavy chain VDJ genomic unit in B-leukemias and used it as a clone-specific marker for the molecular monitoring of the patients during and after therapeutic treatment. The method described is patient-specific rather than disorder-specific, more sensitive and less time-consuming than other conventional techniques for the detection of minimal residual disease. We propose reproducible and quick procedures, from DNA extraction to Southern blotting, that can be easily performed in any clinical laboratory and also applied to other kinds of investigation.
To explore this issue, here we exploit AAV vectors to obtain the prolonged expression of VEGF and... more To explore this issue, here we exploit AAV vectors to obtain the prolonged expression of VEGF and angiopoietin-1 (Ang1) in rat skeletal muscle. Over a period of 6 months, muscle blood flow (MBF) and vascular permeability were measured by positron emission tomography and single-photon emission computed tomography, respectively. All measurements were performed under resting conditions and after electrically induced muscle exercise. Despite the potent angiogenic effect of VEGF, documented by vessel counting and intravascular volume assessment, the expression of this factor did not improve resting MBF, and it even decreased perfusion after exercise. This deleterious effect was related to the formation of leaky vascular lacunae, which accounted for the occurrence of arteriovenous shunts that excluded the downstream microcirculation. These effects were significantly counteracted by the coinjection of VEGF and Ang1, which determined a marked increase in resting MBF and, most notably, a significant improvement after exercise that persisted over time. Taken together, these results challenge the effectiveness of VEGF as a sole factor to induce angiogenesis and suggest the use of factor combinations to achieve competent vessel formation. 515
The production of pharmaceuticals is one of the most highly regulated fields in terms of quality.... more The production of pharmaceuticals is one of the most highly regulated fields in terms of quality. The body of good manufacturing practice (GMP) represents the standard required by law; GMP embraces the guidelines that regulate all activities related to the production and quality control of medicinal products for human and veterinary use. This paper deals with the implementation of a quality management system (QMS) in compliance with GMP and ISO 9001 standards for the production and distribution of radiopharmaceuticals in a public research institute. The production of 2-[18F]fluoro-2-deoxy-D-glucose has been implemented according to GMP standards and has been licensed by the national Authority in 2007. In 2010, a project to orient the system's GMP compliance to ISO 9001 standards has been approved. A QMS conforming to ISO 9001:2008 should be considered an important additional step in terms of quality, because ISO 9001 also takes into account economic and financial aspects, design and development aspects and introduces management review for measurement and analysis of the process with the aim of improving performances. The harmonization between GMP and ISO has been defined following the Pharmaceutical Quality System Q10 guideline developed by International Conference on Harmonization.
The aim of this work was to study the feasibility of using Positron Emission Tomography (PET) ima... more The aim of this work was to study the feasibility of using Positron Emission Tomography (PET) imaging as a new tool to detect transdermal penetration of topical drugs in human subjects. The compound used in the study is sodium 2-[(2,6-dichlorophenyl)amino]phenyl]acetate, better known as diclofenac sodium. This molecule belongs to the family of non-steroidal anti-inflammatory drugs and is considered one of the first choices among non-steroidal anti-inflammatory drugs for the treatment of inflammatory diseases; it is widely used and commercially present in a large number of pharmaceutical forms and formulations. 11C-labeled diclofenac has been synthesized and coformulated, as an internal indicator, with a proprietary preparation based on the use of a sprayer. The radiolabeled preparation was topically administered to healthy volunteers, and PET imaging was used to evaluate transdermal penetration. Results obtained have demonstrated the efficacy of PET and radiolabeled tracers for the evaluation of transdermal penetration of active pharmaceutical ingredients as topical formulations.
Molecular imaging and biology : MIB : the official publication of the Academy of Molecular Imaging, Jan 27, 2016
The plasma membrane P-glycoprotein (Pgp) is an efflux transporter involved in multidrug resistanc... more The plasma membrane P-glycoprotein (Pgp) is an efflux transporter involved in multidrug resistance and in the onset of neurodegenerative disease. Its function and most mechanisms of action are still under investigation. We developed a C-11-labeled 2-arylethylphenylamine-([(11)C]AEPH) derivative for positron emission tomography (PET), as a novel probe to better understand the activity and the function of Pgp in vivo. The synthetic procedure and the quality control of the selected lead compound, [(11)C]AEPH-1, were set up and optimized. The biodistribution and the dynamic extraction in target organs of [(11)C]AEPH-1 were studied in vivo by PET in healthy rats at baseline and after pre-treatment with a Pgp inhibitor (tariquidar). In vivo dynamic imaging was consistent with the results of ex vivo extraction on explanted organs. An adequate stability for in vivo studies, as well as a high activity of [(11)C]AEPH-1 in intestine and barrier tissues, has been demonstrated. Results of the bl...
A2B adenosine receptors (ARs) are commonly defined as &am... more A2B adenosine receptors (ARs) are commonly defined as "danger" sensors because they are triggered during cell injury when the endogenous molecule, adenosine, increases rapidly. These receptors, together with the other receptor subtypes (A1, A2A and A3), exert a wide variety of immunomodulating and (cyto)protective effects, thus representing a pivotal therapeutic target for different pathologies including diabetes, tumors, cardiovascular diseases, pulmonary fibrosis and others. The limited availability of potent and selective ligands for A2B ARs has prevented this receptor to emerge both as therapeutic and diagnostic target. Recently, a new class of potent A2B ARs antagonists was developed featuring the triazinobenzimidazole scaffold. Starting from this chemotype, we synthesized a new radiotracer, [(11)C]-4 (1-[(11)C]methyl-3-phenyl triazino[4,3-a]benzimidazol-4(1H)-one), and investigated the pharmacokinetics of this compound in vivo to define its potential use in the imaging of A2B AR with positron emission tomography. [(11)C]-4 showed a very high chemical and blood stability. Results of in vivo and ex vivo experiments underlined the ability of this molecule to bind the A2B AR and correlated with the A2B AR protein and gene expression data. Although further studies are necessary, these data suggest that [(11)C]-4 may represent a good lead compound for the development of novel selective and potent A2B AR radiotracers, and a new option for the clinical investigation of several pathophysiological processes and chronic diseases.
ABSTRACT The last decade has seen extraordinary growth in the clinical use of Positron Emission T... more ABSTRACT The last decade has seen extraordinary growth in the clinical use of Positron Emission Tomography (PET), an in vivo molecular imaging modality widely used in oncology that requires the use of radiopharmaceuticals labeled with short-lived radionuclides. These medicinal products have found widespread application in Nuclear Medicine departments equipped with PET scanners. Due to the great increase in radiopharmaceutical demand, their production has been centralized and moved to industrial manufacturing sites in which Good Manufacturing Practice (GMP) principles and guidelines for medicinal products are to be applied. The production of PET radiopharmaceuticals features particular aspects such as the use of the lot before the completion of all tests, the multiplicity of batches produced per single day and the absence of product stock due to radionuclide short half-life. In this context, the application of quality principles to all stages of the process and the implementation of a quality management system (QMS) are of primary importance. This paper reports on the development of a QMS applied to a GMP manufacturing site of an in vivo PET diagnostic product, and on how its application can describe the performance of the site. Data were collected over a 6-year period (2008-2013) and demonstrate the ability of Key Performance Indicators, strictly related to the structure and organization of the QMS, and quality tools (data analysis, internal audit, etc.) to monitor process performance in terms of effectiveness, efficacy and stability.
Journal of Radioanalytical and Nuclear Chemistry, 2013
The progress of positron emission tomography goes together with an increasing demand for new radi... more The progress of positron emission tomography goes together with an increasing demand for new radiopharmaceuticals: among these, the development of radiopharmaceuticals labelled with carbon-11 is particularly interesting because these compounds are biologically indistinguishable from their stable analogues. These radiotracers are prepared starting from [ 11 C]carbon dioxide, the most common and versatile primary labelling precursor, or from secondary labelling precursors such [ 11 C]methyl iodide produced by ''wet'' or ''gas-phase'' method. The gas-phase is the most used method and consists in the radical reaction of iodine vapours with [ 11 C]methane, produced in target or from [ 11 C]carbon dioxide by reduction with hydrogen on nickel catalyst at high temperature. This second approach is frequently adopted in commercial automatic methylation modules, such as the TRACERlab FX C. When not performed in target, [ 11 C]CH 4 production represents a key step for the [ 11 C]CH 3 I synthesis from which the outcome of the whole radiolabelling process depends. In order to improve the performance of the module, a new reduction catalyst made of a mixture of metallic Ni (nanopowder) and molecular sieves mixed in different ratios has been tested. Preliminary results demonstrated that not only the mixture of nanopowder-Ni and molecular sieves represents a valid reduction catalyst but also permits to trap [ 11 C]CO 2 and subsequently use it as labelling reagent, making TRACERlab FX C a module for both methylation and carboxylation.
The aim of this work was to study the feasibility of using Positron Emission Tomography (PET) ima... more The aim of this work was to study the feasibility of using Positron Emission Tomography (PET) imaging as a new tool to detect transdermal penetration of topical drugs in human subjects. The compound used in the study is sodium 2-[(2,6-dichlorophenyl)amino]phenyl]acetate, better known as diclofenac sodium. This molecule belongs to the family of non-steroidal anti-inflammatory drugs and is considered one of the first choices among non-steroidal anti-inflammatory drugs for the treatment of inflammatory diseases; it is widely used and commercially present in a large number of pharmaceutical forms and formulations. 11 C-labeled diclofenac has been synthesized and coformulated, as an internal indicator, with a proprietary preparation based on the use of a sprayer. The radiolabeled preparation was topically administered to healthy volunteers, and PET imaging was used to evaluate transdermal penetration. Results obtained have demonstrated the efficacy of PET and radiolabeled tracers for the evaluation of transdermal penetration of active pharmaceutical ingredients as topical formulations.
To explore this issue, here we exploit AAV vectors to obtain the prolonged expression of VEGF and... more To explore this issue, here we exploit AAV vectors to obtain the prolonged expression of VEGF and angiopoietin-1 (Ang1) in rat skeletal muscle. Over a period of 6 months, muscle blood flow (MBF) and vascular permeability were measured by positron emission tomography and single-photon emission computed tomography, respectively. All measurements were performed under resting conditions and after electrically induced muscle exercise. Despite the potent angiogenic effect of VEGF, documented by vessel counting and intravascular volume assessment, the expression of this factor did not improve resting MBF, and it even decreased perfusion after exercise. This deleterious effect was related to the formation of leaky vascular lacunae, which accounted for the occurrence of arteriovenous shunts that excluded the downstream microcirculation. These effects were significantly counteracted by the coinjection of VEGF and Ang1, which determined a marked increase in resting MBF and, most notably, a significant improvement after exercise that persisted over time. Taken together, these results challenge the effectiveness of VEGF as a sole factor to induce angiogenesis and suggest the use of factor combinations to achieve competent vessel formation. 515
Abstract: Co(II), Ni(II), and Cu(II) complexes with a tetradentate nitrogen donor [N4] macrocycli... more Abstract: Co(II), Ni(II), and Cu(II) complexes with a tetradentate nitrogen donor [N4] macrocyclic ligand, viz. 6,15-dimethyl-8,17diphenyl-7,16-dihyd-rodibenzo[b,i][1.4.8.11]tetraazacyclotetradecine , were synthesized. Their struc-tures were determined based on elemental analyses, ...
Journal of Radioanalytical and Nuclear Chemistry, 2012
Positron Emission Tomography has become increasingly relevant in clinical practice for diagnostic... more Positron Emission Tomography has become increasingly relevant in clinical practice for diagnostic purposes. A major concern regarding radiopharmaceuticals in general is how quality requirements can be guaranteed in nuclear medicine departments or in cases where marketing authorization has been granted. This article focuses on issues related to the small-volume preparation of radiopharmaceuticals by a Research Institute after Good Manufacturing Practice implementation.
The N, N-diethylcarbamato derivative of zirconium (IV), Zr (O2CNEt2) 4 has been studied by X-ray ... more The N, N-diethylcarbamato derivative of zirconium (IV), Zr (O2CNEt2) 4 has been studied by X-ray crystallography. Crystal data: C20H40Na4O8Zr, monoclinic, space group C2/c, a= 14.057 (1), b= 12.168 (1), c= 16.746 (2) Å, β= 108.071 (4)°, Z= 4, Dc= 1.356, F (000)= ...
European Journal of Nuclear Medicine and Molecular Imaging, 2013
Purpose The α v β 3 integrin is expressed in angiogenic vessels and is a potential target for mol... more Purpose The α v β 3 integrin is expressed in angiogenic vessels and is a potential target for molecular imaging of evolving pathological processes. Its expression is upregulated in cancer lesions and metastases as well as in acute myocardial infarction (MI) as part of the infarct healing process. The purpose of our study was to determine the feasibility of a new imaging approach with a novel 68 Ga-2,2′,2″-(1,4,7-triazonane-1,4,7-triyl)triacetic acid (NOTA)-arginine-glycine-aspartic acid (RGD) construct to assess integrin expression in the evolving MI. Methods A straightforward labelling chemistry to attach the radionuclide 68 Ga to a NOTA-based chelating agent conjugated with a cyclic RGD peptidomimetic is described. Affinity for α v β 3 integrin was assessed by in vitro receptor binding assay. The proof-of-concept in vivo studies combined the 68 Ga-NOTA-RGD with the flow tracer 13 N-NH 3 imaging in order to obtain positron emission tomography (PET)/CT imaging of both integrin expression and perfusion defect at 4 weeks after infarction. Hearts were then processed for immunostaining of integrin β 3 . Results NOTA-RGD conjugate displayed a binding affinity for α v β 3 integrin of 27.9±6.8 nM. 68 Ga-NOTA-RGD showed stability without detectable degradation or formation of byproducts in urine up to 2 h following injection in the rat. MI hearts exhibited 68 Ga-NOTA-RGD uptake in correspondence to infarcted and border zone regions. The tracer signal drew a parallel with vascular remodelling due to ischaemia-induced angiogenesis as assessed by immunohistochemistry.
The present study focuses on a micro-PET/CT application to be used for experimental Boron Neutron... more The present study focuses on a micro-PET/CT application to be used for experimental Boron Neutron Capture Therapy (BNCT), which integrates, in the same frame, micro-CT derived anatomy and PET radiotracer distribution. Preliminary results have demonstrated that (18)F-fluoroethyl-tyrosine (FET)/PET allows the identification of the extent of cerebral lesions in F98 tumor bearing rat. Neutron autoradiography and α-spectrometry on axial tissues slices confirmed the tumor localization and extraction, after the administration of fructose-boronophenylalanine (BPA). Therefore, FET-PET approach can be used to assess the transport, the net influx, and the accumulation of FET, as an aromatic amino acid analog of BPA, in experimental animal model. Coregistered micro-CT images allowed the accurate morphological localization of the radiotracer distribution and its potential use for experimental BNCT.
The production of pharmaceuticals is one of the most highly regulated fields in terms of quality.... more The production of pharmaceuticals is one of the most highly regulated fields in terms of quality. The body of good manufacturing practice (GMP) represents the standard required by law; GMP embraces the guidelines that regulate all activities related to the production and quality control of medicinal products for human and veterinary use. This paper deals with the implementation of a quality management system (QMS) in compliance with GMP and ISO 9001 standards for the production and distribution of radiopharmaceuticals in a public research institute. The production of 2-[18F]fluoro-2-deoxy-D-glucose has been implemented according to GMP standards and has been licensed by the national Authority in 2007. In 2010, a project to orient the system's GMP compliance to ISO 9001 standards has been approved. A QMS conforming to ISO 9001:2008 should be considered an important additional step in terms of quality, because ISO 9001 also takes into account economic and financial aspects, design and development aspects and introduces management review for measurement and analysis of the process with the aim of improving performances. The harmonization between GMP and ISO has been defined following the Pharmaceutical Quality System Q10 guideline developed by International Conference on Harmonization.
Molecular imaging and biology : MIB : the official publication of the Academy of Molecular Imaging, Jan 27, 2016
The plasma membrane P-glycoprotein (Pgp) is an efflux transporter involved in multidrug resistanc... more The plasma membrane P-glycoprotein (Pgp) is an efflux transporter involved in multidrug resistance and in the onset of neurodegenerative disease. Its function and most mechanisms of action are still under investigation. We developed a C-11-labeled 2-arylethylphenylamine-([(11)C]AEPH) derivative for positron emission tomography (PET), as a novel probe to better understand the activity and the function of Pgp in vivo. The synthetic procedure and the quality control of the selected lead compound, [(11)C]AEPH-1, were set up and optimized. The biodistribution and the dynamic extraction in target organs of [(11)C]AEPH-1 were studied in vivo by PET in healthy rats at baseline and after pre-treatment with a Pgp inhibitor (tariquidar). In vivo dynamic imaging was consistent with the results of ex vivo extraction on explanted organs. An adequate stability for in vivo studies, as well as a high activity of [(11)C]AEPH-1 in intestine and barrier tissues, has been demonstrated. Results of the bl...
A2B adenosine receptors (ARs) are commonly defined as &am... more A2B adenosine receptors (ARs) are commonly defined as "danger" sensors because they are triggered during cell injury when the endogenous molecule, adenosine, increases rapidly. These receptors, together with the other receptor subtypes (A1, A2A and A3), exert a wide variety of immunomodulating and (cyto)protective effects, thus representing a pivotal therapeutic target for different pathologies including diabetes, tumors, cardiovascular diseases, pulmonary fibrosis and others. The limited availability of potent and selective ligands for A2B ARs has prevented this receptor to emerge both as therapeutic and diagnostic target. Recently, a new class of potent A2B ARs antagonists was developed featuring the triazinobenzimidazole scaffold. Starting from this chemotype, we synthesized a new radiotracer, [(11)C]-4 (1-[(11)C]methyl-3-phenyl triazino[4,3-a]benzimidazol-4(1H)-one), and investigated the pharmacokinetics of this compound in vivo to define its potential use in the imaging of A2B AR with positron emission tomography. [(11)C]-4 showed a very high chemical and blood stability. Results of in vivo and ex vivo experiments underlined the ability of this molecule to bind the A2B AR and correlated with the A2B AR protein and gene expression data. Although further studies are necessary, these data suggest that [(11)C]-4 may represent a good lead compound for the development of novel selective and potent A2B AR radiotracers, and a new option for the clinical investigation of several pathophysiological processes and chronic diseases.
ABSTRACT Il rapporto tra numero di neutroni (N) e numero di protoni (Z) determina la stabilità di... more ABSTRACT Il rapporto tra numero di neutroni (N) e numero di protoni (Z) determina la stabilità di un nuclide: per gli elementi leggeri la condizione di stabilità è in generale raggiunta quando il numero di neutroni è uguale o appena superiore a quello dei protoni (N = Z o N = Z+1). I nuclidi che hanno un numero di neutroni inferiore rispetto a quello di protoni (N/Z
Scandinavian Journal of Clinical & Laboratory Investigation, 1997
We amplified and sequenced the rearranged immunoglobulin heavy chain VDJ genomic unit in B-leukem... more We amplified and sequenced the rearranged immunoglobulin heavy chain VDJ genomic unit in B-leukemias and used it as a clone-specific marker for the molecular monitoring of the patients during and after therapeutic treatment. The method described is patient-specific rather than disorder-specific, more sensitive and less time-consuming than other conventional techniques for the detection of minimal residual disease. We propose reproducible and quick procedures, from DNA extraction to Southern blotting, that can be easily performed in any clinical laboratory and also applied to other kinds of investigation.
To explore this issue, here we exploit AAV vectors to obtain the prolonged expression of VEGF and... more To explore this issue, here we exploit AAV vectors to obtain the prolonged expression of VEGF and angiopoietin-1 (Ang1) in rat skeletal muscle. Over a period of 6 months, muscle blood flow (MBF) and vascular permeability were measured by positron emission tomography and single-photon emission computed tomography, respectively. All measurements were performed under resting conditions and after electrically induced muscle exercise. Despite the potent angiogenic effect of VEGF, documented by vessel counting and intravascular volume assessment, the expression of this factor did not improve resting MBF, and it even decreased perfusion after exercise. This deleterious effect was related to the formation of leaky vascular lacunae, which accounted for the occurrence of arteriovenous shunts that excluded the downstream microcirculation. These effects were significantly counteracted by the coinjection of VEGF and Ang1, which determined a marked increase in resting MBF and, most notably, a significant improvement after exercise that persisted over time. Taken together, these results challenge the effectiveness of VEGF as a sole factor to induce angiogenesis and suggest the use of factor combinations to achieve competent vessel formation. 515
The production of pharmaceuticals is one of the most highly regulated fields in terms of quality.... more The production of pharmaceuticals is one of the most highly regulated fields in terms of quality. The body of good manufacturing practice (GMP) represents the standard required by law; GMP embraces the guidelines that regulate all activities related to the production and quality control of medicinal products for human and veterinary use. This paper deals with the implementation of a quality management system (QMS) in compliance with GMP and ISO 9001 standards for the production and distribution of radiopharmaceuticals in a public research institute. The production of 2-[18F]fluoro-2-deoxy-D-glucose has been implemented according to GMP standards and has been licensed by the national Authority in 2007. In 2010, a project to orient the system's GMP compliance to ISO 9001 standards has been approved. A QMS conforming to ISO 9001:2008 should be considered an important additional step in terms of quality, because ISO 9001 also takes into account economic and financial aspects, design and development aspects and introduces management review for measurement and analysis of the process with the aim of improving performances. The harmonization between GMP and ISO has been defined following the Pharmaceutical Quality System Q10 guideline developed by International Conference on Harmonization.
The aim of this work was to study the feasibility of using Positron Emission Tomography (PET) ima... more The aim of this work was to study the feasibility of using Positron Emission Tomography (PET) imaging as a new tool to detect transdermal penetration of topical drugs in human subjects. The compound used in the study is sodium 2-[(2,6-dichlorophenyl)amino]phenyl]acetate, better known as diclofenac sodium. This molecule belongs to the family of non-steroidal anti-inflammatory drugs and is considered one of the first choices among non-steroidal anti-inflammatory drugs for the treatment of inflammatory diseases; it is widely used and commercially present in a large number of pharmaceutical forms and formulations. 11C-labeled diclofenac has been synthesized and coformulated, as an internal indicator, with a proprietary preparation based on the use of a sprayer. The radiolabeled preparation was topically administered to healthy volunteers, and PET imaging was used to evaluate transdermal penetration. Results obtained have demonstrated the efficacy of PET and radiolabeled tracers for the evaluation of transdermal penetration of active pharmaceutical ingredients as topical formulations.
Molecular imaging and biology : MIB : the official publication of the Academy of Molecular Imaging, Jan 27, 2016
The plasma membrane P-glycoprotein (Pgp) is an efflux transporter involved in multidrug resistanc... more The plasma membrane P-glycoprotein (Pgp) is an efflux transporter involved in multidrug resistance and in the onset of neurodegenerative disease. Its function and most mechanisms of action are still under investigation. We developed a C-11-labeled 2-arylethylphenylamine-([(11)C]AEPH) derivative for positron emission tomography (PET), as a novel probe to better understand the activity and the function of Pgp in vivo. The synthetic procedure and the quality control of the selected lead compound, [(11)C]AEPH-1, were set up and optimized. The biodistribution and the dynamic extraction in target organs of [(11)C]AEPH-1 were studied in vivo by PET in healthy rats at baseline and after pre-treatment with a Pgp inhibitor (tariquidar). In vivo dynamic imaging was consistent with the results of ex vivo extraction on explanted organs. An adequate stability for in vivo studies, as well as a high activity of [(11)C]AEPH-1 in intestine and barrier tissues, has been demonstrated. Results of the bl...
A2B adenosine receptors (ARs) are commonly defined as &am... more A2B adenosine receptors (ARs) are commonly defined as "danger" sensors because they are triggered during cell injury when the endogenous molecule, adenosine, increases rapidly. These receptors, together with the other receptor subtypes (A1, A2A and A3), exert a wide variety of immunomodulating and (cyto)protective effects, thus representing a pivotal therapeutic target for different pathologies including diabetes, tumors, cardiovascular diseases, pulmonary fibrosis and others. The limited availability of potent and selective ligands for A2B ARs has prevented this receptor to emerge both as therapeutic and diagnostic target. Recently, a new class of potent A2B ARs antagonists was developed featuring the triazinobenzimidazole scaffold. Starting from this chemotype, we synthesized a new radiotracer, [(11)C]-4 (1-[(11)C]methyl-3-phenyl triazino[4,3-a]benzimidazol-4(1H)-one), and investigated the pharmacokinetics of this compound in vivo to define its potential use in the imaging of A2B AR with positron emission tomography. [(11)C]-4 showed a very high chemical and blood stability. Results of in vivo and ex vivo experiments underlined the ability of this molecule to bind the A2B AR and correlated with the A2B AR protein and gene expression data. Although further studies are necessary, these data suggest that [(11)C]-4 may represent a good lead compound for the development of novel selective and potent A2B AR radiotracers, and a new option for the clinical investigation of several pathophysiological processes and chronic diseases.
ABSTRACT The last decade has seen extraordinary growth in the clinical use of Positron Emission T... more ABSTRACT The last decade has seen extraordinary growth in the clinical use of Positron Emission Tomography (PET), an in vivo molecular imaging modality widely used in oncology that requires the use of radiopharmaceuticals labeled with short-lived radionuclides. These medicinal products have found widespread application in Nuclear Medicine departments equipped with PET scanners. Due to the great increase in radiopharmaceutical demand, their production has been centralized and moved to industrial manufacturing sites in which Good Manufacturing Practice (GMP) principles and guidelines for medicinal products are to be applied. The production of PET radiopharmaceuticals features particular aspects such as the use of the lot before the completion of all tests, the multiplicity of batches produced per single day and the absence of product stock due to radionuclide short half-life. In this context, the application of quality principles to all stages of the process and the implementation of a quality management system (QMS) are of primary importance. This paper reports on the development of a QMS applied to a GMP manufacturing site of an in vivo PET diagnostic product, and on how its application can describe the performance of the site. Data were collected over a 6-year period (2008-2013) and demonstrate the ability of Key Performance Indicators, strictly related to the structure and organization of the QMS, and quality tools (data analysis, internal audit, etc.) to monitor process performance in terms of effectiveness, efficacy and stability.
Journal of Radioanalytical and Nuclear Chemistry, 2013
The progress of positron emission tomography goes together with an increasing demand for new radi... more The progress of positron emission tomography goes together with an increasing demand for new radiopharmaceuticals: among these, the development of radiopharmaceuticals labelled with carbon-11 is particularly interesting because these compounds are biologically indistinguishable from their stable analogues. These radiotracers are prepared starting from [ 11 C]carbon dioxide, the most common and versatile primary labelling precursor, or from secondary labelling precursors such [ 11 C]methyl iodide produced by ''wet'' or ''gas-phase'' method. The gas-phase is the most used method and consists in the radical reaction of iodine vapours with [ 11 C]methane, produced in target or from [ 11 C]carbon dioxide by reduction with hydrogen on nickel catalyst at high temperature. This second approach is frequently adopted in commercial automatic methylation modules, such as the TRACERlab FX C. When not performed in target, [ 11 C]CH 4 production represents a key step for the [ 11 C]CH 3 I synthesis from which the outcome of the whole radiolabelling process depends. In order to improve the performance of the module, a new reduction catalyst made of a mixture of metallic Ni (nanopowder) and molecular sieves mixed in different ratios has been tested. Preliminary results demonstrated that not only the mixture of nanopowder-Ni and molecular sieves represents a valid reduction catalyst but also permits to trap [ 11 C]CO 2 and subsequently use it as labelling reagent, making TRACERlab FX C a module for both methylation and carboxylation.
The aim of this work was to study the feasibility of using Positron Emission Tomography (PET) ima... more The aim of this work was to study the feasibility of using Positron Emission Tomography (PET) imaging as a new tool to detect transdermal penetration of topical drugs in human subjects. The compound used in the study is sodium 2-[(2,6-dichlorophenyl)amino]phenyl]acetate, better known as diclofenac sodium. This molecule belongs to the family of non-steroidal anti-inflammatory drugs and is considered one of the first choices among non-steroidal anti-inflammatory drugs for the treatment of inflammatory diseases; it is widely used and commercially present in a large number of pharmaceutical forms and formulations. 11 C-labeled diclofenac has been synthesized and coformulated, as an internal indicator, with a proprietary preparation based on the use of a sprayer. The radiolabeled preparation was topically administered to healthy volunteers, and PET imaging was used to evaluate transdermal penetration. Results obtained have demonstrated the efficacy of PET and radiolabeled tracers for the evaluation of transdermal penetration of active pharmaceutical ingredients as topical formulations.
To explore this issue, here we exploit AAV vectors to obtain the prolonged expression of VEGF and... more To explore this issue, here we exploit AAV vectors to obtain the prolonged expression of VEGF and angiopoietin-1 (Ang1) in rat skeletal muscle. Over a period of 6 months, muscle blood flow (MBF) and vascular permeability were measured by positron emission tomography and single-photon emission computed tomography, respectively. All measurements were performed under resting conditions and after electrically induced muscle exercise. Despite the potent angiogenic effect of VEGF, documented by vessel counting and intravascular volume assessment, the expression of this factor did not improve resting MBF, and it even decreased perfusion after exercise. This deleterious effect was related to the formation of leaky vascular lacunae, which accounted for the occurrence of arteriovenous shunts that excluded the downstream microcirculation. These effects were significantly counteracted by the coinjection of VEGF and Ang1, which determined a marked increase in resting MBF and, most notably, a significant improvement after exercise that persisted over time. Taken together, these results challenge the effectiveness of VEGF as a sole factor to induce angiogenesis and suggest the use of factor combinations to achieve competent vessel formation. 515
Abstract: Co(II), Ni(II), and Cu(II) complexes with a tetradentate nitrogen donor [N4] macrocycli... more Abstract: Co(II), Ni(II), and Cu(II) complexes with a tetradentate nitrogen donor [N4] macrocyclic ligand, viz. 6,15-dimethyl-8,17diphenyl-7,16-dihyd-rodibenzo[b,i][1.4.8.11]tetraazacyclotetradecine , were synthesized. Their struc-tures were determined based on elemental analyses, ...
Journal of Radioanalytical and Nuclear Chemistry, 2012
Positron Emission Tomography has become increasingly relevant in clinical practice for diagnostic... more Positron Emission Tomography has become increasingly relevant in clinical practice for diagnostic purposes. A major concern regarding radiopharmaceuticals in general is how quality requirements can be guaranteed in nuclear medicine departments or in cases where marketing authorization has been granted. This article focuses on issues related to the small-volume preparation of radiopharmaceuticals by a Research Institute after Good Manufacturing Practice implementation.
The N, N-diethylcarbamato derivative of zirconium (IV), Zr (O2CNEt2) 4 has been studied by X-ray ... more The N, N-diethylcarbamato derivative of zirconium (IV), Zr (O2CNEt2) 4 has been studied by X-ray crystallography. Crystal data: C20H40Na4O8Zr, monoclinic, space group C2/c, a= 14.057 (1), b= 12.168 (1), c= 16.746 (2) Å, β= 108.071 (4)°, Z= 4, Dc= 1.356, F (000)= ...
European Journal of Nuclear Medicine and Molecular Imaging, 2013
Purpose The α v β 3 integrin is expressed in angiogenic vessels and is a potential target for mol... more Purpose The α v β 3 integrin is expressed in angiogenic vessels and is a potential target for molecular imaging of evolving pathological processes. Its expression is upregulated in cancer lesions and metastases as well as in acute myocardial infarction (MI) as part of the infarct healing process. The purpose of our study was to determine the feasibility of a new imaging approach with a novel 68 Ga-2,2′,2″-(1,4,7-triazonane-1,4,7-triyl)triacetic acid (NOTA)-arginine-glycine-aspartic acid (RGD) construct to assess integrin expression in the evolving MI. Methods A straightforward labelling chemistry to attach the radionuclide 68 Ga to a NOTA-based chelating agent conjugated with a cyclic RGD peptidomimetic is described. Affinity for α v β 3 integrin was assessed by in vitro receptor binding assay. The proof-of-concept in vivo studies combined the 68 Ga-NOTA-RGD with the flow tracer 13 N-NH 3 imaging in order to obtain positron emission tomography (PET)/CT imaging of both integrin expression and perfusion defect at 4 weeks after infarction. Hearts were then processed for immunostaining of integrin β 3 . Results NOTA-RGD conjugate displayed a binding affinity for α v β 3 integrin of 27.9±6.8 nM. 68 Ga-NOTA-RGD showed stability without detectable degradation or formation of byproducts in urine up to 2 h following injection in the rat. MI hearts exhibited 68 Ga-NOTA-RGD uptake in correspondence to infarcted and border zone regions. The tracer signal drew a parallel with vascular remodelling due to ischaemia-induced angiogenesis as assessed by immunohistochemistry.
The present study focuses on a micro-PET/CT application to be used for experimental Boron Neutron... more The present study focuses on a micro-PET/CT application to be used for experimental Boron Neutron Capture Therapy (BNCT), which integrates, in the same frame, micro-CT derived anatomy and PET radiotracer distribution. Preliminary results have demonstrated that (18)F-fluoroethyl-tyrosine (FET)/PET allows the identification of the extent of cerebral lesions in F98 tumor bearing rat. Neutron autoradiography and α-spectrometry on axial tissues slices confirmed the tumor localization and extraction, after the administration of fructose-boronophenylalanine (BPA). Therefore, FET-PET approach can be used to assess the transport, the net influx, and the accumulation of FET, as an aromatic amino acid analog of BPA, in experimental animal model. Coregistered micro-CT images allowed the accurate morphological localization of the radiotracer distribution and its potential use for experimental BNCT.
The production of pharmaceuticals is one of the most highly regulated fields in terms of quality.... more The production of pharmaceuticals is one of the most highly regulated fields in terms of quality. The body of good manufacturing practice (GMP) represents the standard required by law; GMP embraces the guidelines that regulate all activities related to the production and quality control of medicinal products for human and veterinary use. This paper deals with the implementation of a quality management system (QMS) in compliance with GMP and ISO 9001 standards for the production and distribution of radiopharmaceuticals in a public research institute. The production of 2-[18F]fluoro-2-deoxy-D-glucose has been implemented according to GMP standards and has been licensed by the national Authority in 2007. In 2010, a project to orient the system's GMP compliance to ISO 9001 standards has been approved. A QMS conforming to ISO 9001:2008 should be considered an important additional step in terms of quality, because ISO 9001 also takes into account economic and financial aspects, design and development aspects and introduces management review for measurement and analysis of the process with the aim of improving performances. The harmonization between GMP and ISO has been defined following the Pharmaceutical Quality System Q10 guideline developed by International Conference on Harmonization.
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Papers by Debora Petroni