The Experts below are selected from a list of 102 Experts worldwide ranked by ideXlab platform

Luigi G. Marzilli - One of the best experts on this subject based on the ideXlab platform.

  • PREPARATIONAND CRYSTAL STRUCTURE OFARHENIUMANALOGUE OFTHE CATIONIC Renal Agent, Tc-99mDIAMINOCYCLOHEXANE
    2020
    Co-Authors: Luigi G. Marzilli, Lory Hansen, Andrew Taylor, Rene J. Lachicotte
    Abstract:

    We report here a chemical study on a Re analogue of one of the few cationic Tc-99m tracers previously investigated as an Agent for effective Renal plasma flow (ERPF) measurement. Cationic Tc-99m tracers have the potential for overcoming problems associated with common anionic Tc-99m tracers in patients who have developed a uremic state. The Tc-99m-DACH tracer, prepared from 1,2diaminocyclohexane (I,2-DACH), is the only cationic Renal Agent tested in humans and has seven possible isomers. The complex isolated from the reaction of the racemic mixture, (+)-trans-l,2-DACH, and RelOz(PPh3)z after conversion to the BPh4 salt was found by X-ray crystallography to be the meso isomer, trans-[ReO(trans-R,R-l,2-DACH)(trans-S,S-l,2-DACH)][BPh4]oMeOHo2HzO (1). The structural parameters for 1 are normal. The complex is highly symmetrical, suggesting that the analogous meso Tc99m-DACH Agent is also symmetrical. Studies of other Tc-99m-DACH Agents that were made from cis-1,2DACH or individual trans-1,2-DACH enantiomers show that the biodistribution is not very dependent on the starting 1,2-DACH ligand stereochemistry; these Agents must be less symmetrical than the meso Tc-99mDACH Agent analogue of 1. Thus, the overall charge and lipophilicity (similar for all Tc-99m-DACH isomers) exert a greater influence on biodistribution than the specific structural features of the different Tc

  • Preparation and Crystal Structure of a Rhenium Analogue of the Cationic Renal Agent, Tc-99m Diaminocyclohexane
    Metal-based Drugs, 2020
    Co-Authors: Luigi G. Marzilli, Lory Hansen, Andrew M. Taylor, Rene J. Lachicotte
    Abstract:

    We report here a chemical study on a Re analogue of one of the few cationic Tc-99m tracers previously investigated as an Agent for effective Renal plasma flow (ERPF) measurement. Cationic Tc-99m tracers have the potential for overcoming problems associated with common anionic Tc-99m tracers in patients who have developed a uremic state. The Tc-99m-DACH tracer, prepared from 1,2-diaminocyclohexane (1,2-DACH), is the only cationic Renal Agent tested in humans and has seven possible isomers. The complex isolated from the reaction of the racemic mixture, (±)-trans-1,2-DACH, and ReIO2(PPh3)2 after conversion to the BPh4- salt was found by X-ray crystallography to be the meso isomer, trans-[ReO2 (trans-R,R-1,2-DACH)(trans-S,S-l,2-DACH)][BPh4]·MeOH·2H2O (1). The structural parameters for 1 are normal. The complex is highly symmetrical, suggesting that the analogous meso Tc-99m-DACH Agent is also symmetrical. Studies of other Tc-99m-DACH Agents that were made from cis-1,2-DACH or individual trans-1,2-DACH enantiomers show that the biodistribution is not very dependent on the starting 1,2-DACH ligand stereochemistry; these Agents must be less symmetrical than the meso Tc-99m-DACH Agent analogue of 1. Thus, the overall charge and lipophilicity (similar for all Tc-99m-DACH isomers) exert a greater influence on biodistribution than the specific structural features of the different Tc-99m-DACH isomers.

  • structure and properties of fac rei co 3 nta 2 nta3 trianion of nitrilotriacetic acid and fac rei co 3 l n analogues useful for assessing the excellent Renal clearance of the fac 99mtci co 3 nta 2 diagnostic Renal Agent
    Inorganic Chemistry, 2015
    Co-Authors: Jeffrey Klenc, Malgorzata Lipowska, Andrew M. Taylor, Pramuditha Abhayawardhana, Luigi G. Marzilli
    Abstract:

    We previously identified two new Agents based on the [99mTcVO]3+ core with Renal clearances in human volunteers 30% higher than that of the widely used clinical tracer 99mTc-MAG3 (MAG35– = penta-anion of mercaptoacetyltriglycine). However, Renal Agents with even higher clearances are needed. More recently, we changed our focus from the [99mTcVO]3+ core to the discovery of superior tracers based on the fac-[99mTcI(CO)3]+ core. Compared to 99mTc-MAG3, fac-[99mTcI(CO)3(NTA)]2– (NTA3– = trianion of nitrilotriacetic acid) holds great promise by virtue of its efficient Renal clearance via tubular secretion and the absence of hepatobiliary elimination, even in patients with severely reduced Renal function. We report here NMR, molecular (X-ray) structure, and solution data on fac-[ReI(CO)3(NTA)]2– with a −CH2CO2– dangling monoanionic chain and on two fac-[ReI(CO)3(L)]− analogues with either a −CH2CONH2 or a −CH2CH2OH dangling neutral chain. In these three fac-[ReI(CO)3(L)]n− complexes, the fac-[ReI(CO)3(N(CH2CO2)...

  • Structure and Properties of fac-[Re(I)(CO)3(NTA)](2-) (NTA(3-) = Trianion of Nitrilotriacetic Acid) and fac-[Re(I)(CO)3(L)](n-) Analogues Useful for Assessing the Excellent Renal Clearance of the fac-[(99m)Tc(I)(CO)3(NTA)](2-) Diagnostic Renal Agent.
    Inorganic Chemistry, 2015
    Co-Authors: Jeffrey Klenc, Malgorzata Lipowska, Andrew M. Taylor, Pramuditha Abhayawardhana, Luigi G. Marzilli
    Abstract:

    We previously identified two new Agents based on the [99mTcVO]3+ core with Renal clearances in human volunteers 30% higher than that of the widely used clinical tracer 99mTc-MAG3 (MAG35– = penta-anion of mercaptoacetyltriglycine). However, Renal Agents with even higher clearances are needed. More recently, we changed our focus from the [99mTcVO]3+ core to the discovery of superior tracers based on the fac-[99mTcI(CO)3]+ core. Compared to 99mTc-MAG3, fac-[99mTcI(CO)3(NTA)]2– (NTA3– = trianion of nitrilotriacetic acid) holds great promise by virtue of its efficient Renal clearance via tubular secretion and the absence of hepatobiliary elimination, even in patients with severely reduced Renal function. We report here NMR, molecular (X-ray) structure, and solution data on fac-[ReI(CO)3(NTA)]2– with a −CH2CO2– dangling monoanionic chain and on two fac-[ReI(CO)3(L)]− analogues with either a −CH2CONH2 or a −CH2CH2OH dangling neutral chain. In these three fac-[ReI(CO)3(L)]n− complexes, the fac-[ReI(CO)3(N(CH2CO2)...

  • Preclinical Evaluation of 99mTc(CO)3-Aspartic-N-Monoacetic Acid, a Renal Radiotracer with Pharmacokinetic Properties Comparable to 131I-o-Iodohippurate
    The Journal of Nuclear Medicine, 2012
    Co-Authors: Malgorzata Lipowska, Luigi G. Marzilli, Jeffrey Klenc, Andrew M. Taylor
    Abstract:

    Chronic kidney disease (CKD) has emerged as a serious health problem worldwide. In the US alone, an estimated 13% of the adult population have CKD (1) and this number is increasing yearly due to the rising prevalence of diabetes, hypertension, obesity, cardiovascular disease superimposed on an aging population (2–5). Moreover, the incidence of CKD in children has also steadily increased during the past two decades (6). Early detection and diagnosis can lead to treatment that will reduce the risk of kidney failure. The classification of CKD is currently based on the estimated GFR using a 4 variable algorithm which attempts to compensate for the fact that the serum creatinine may not become elevated until over 50% of the Renal function has been lost (7). Radionuclide imaging may detect unsuspected Renal disease in patients with a normal serum creatinine and continues to have an important role in evaluating suspected obstruction and renovascular hypertension and in monitoring Renal function through measurements of glomerular filtration and effective Renal plasma flow (ERPF). The gold standard for the determination of ERPF is p-aminohippurate (PAH). In practice, however, measurement of PAH clearance required a constant plasma infusion and time consuming analysis, limiting its use in a clinical setting. 131I-o-iodohippurate (131I-OIH) is a radioactive standard used as an imaging Agent and as a tracer to measure ERPF, although its clearance is still only 85–90% that of PAH (8). 131I-OIH commercial production has been discontinued in many countries because of the suboptimal characteristics of 131I (Emax = 364 keV) and the fact that its beta emission can result in a high radiation dose, particularly to the kidneys and thyroid in patients with impaired Renal function (9). Simple and rapid labeling methods with the 99mTc isotope have been developed for clinical applications (10, 11) because of the 99mTc highly favorable physical characteristics (t1/2 = 6 h, Emax = 140 keV), easy availability and low cost. Although a number of 99mTc complexes have been tested as potential alternatives for 131I-OIH (12–21), 99mTc-mercaptoacetyltriglycine (99mTc-MAG3) was shown to have favorable properties, has become commercially available, and is the most widely used 99mTc Renal tracer in the United States (22, 23). Nevertheless, 99mTc-MAG3 is not an ideal replacement for 131I-OIH because its clearance is only 50–60% that of 131I-OIH and it does not provide a direct measurement of effective Renal plasma flow (ERPF). Our recent studies showed that a new 99mTc Renal Agent based on the nitrilotriacetic acid ligand (Fig. 1), 99mTc(CO)3(NTA), and 131I-OIH had essentially identical pharmacokinetics in rats (24) and subjects with normal Renal function (21), suggesting that an anionic Renal tracer with a {99mTc(CO)3}+ core and an aminopolycarboxylate chelate is capable of providing a measurement of ERPF in humans equivalent to that of 131I-OIH. However, the promising biological properties of 99mTc(CO)3(NTA) still need to be confirmed in patients with impaired Renal function. Even if 99mTc(CO)3(NTA) proves to be equivalent to 131I-OIH in patients with Renal failure, 99mTc(CO)3(NTA) clearance is still likely to be inferior to that of PAH because the clearance of 131I-OIH is only 84% that of PAH (25). FIGURE 1 Structure of nitrilotriacetic acid (NTA) and aspartic-N-monoacetic acid (ASMA) ligands. The ellipse encloses the dangling carboxyl group and the asterisk indicates an asymmetric carbon. Our goal was to assess a new 99mTc(CO)3(NTA) isomer, 99mTc(CO)3(ASMA) (ASMA stands for aspartic-N-monoacetic acid, Fig. 1) in an animal model to determine if a change in ligand design could lead to a Renal tracer with improved pharmacokinetic properties.

Andrew M. Taylor - One of the best experts on this subject based on the ideXlab platform.

  • Preparation and Crystal Structure of a Rhenium Analogue of the Cationic Renal Agent, Tc-99m Diaminocyclohexane
    Metal-based Drugs, 2020
    Co-Authors: Luigi G. Marzilli, Lory Hansen, Andrew M. Taylor, Rene J. Lachicotte
    Abstract:

    We report here a chemical study on a Re analogue of one of the few cationic Tc-99m tracers previously investigated as an Agent for effective Renal plasma flow (ERPF) measurement. Cationic Tc-99m tracers have the potential for overcoming problems associated with common anionic Tc-99m tracers in patients who have developed a uremic state. The Tc-99m-DACH tracer, prepared from 1,2-diaminocyclohexane (1,2-DACH), is the only cationic Renal Agent tested in humans and has seven possible isomers. The complex isolated from the reaction of the racemic mixture, (±)-trans-1,2-DACH, and ReIO2(PPh3)2 after conversion to the BPh4- salt was found by X-ray crystallography to be the meso isomer, trans-[ReO2 (trans-R,R-1,2-DACH)(trans-S,S-l,2-DACH)][BPh4]·MeOH·2H2O (1). The structural parameters for 1 are normal. The complex is highly symmetrical, suggesting that the analogous meso Tc-99m-DACH Agent is also symmetrical. Studies of other Tc-99m-DACH Agents that were made from cis-1,2-DACH or individual trans-1,2-DACH enantiomers show that the biodistribution is not very dependent on the starting 1,2-DACH ligand stereochemistry; these Agents must be less symmetrical than the meso Tc-99m-DACH Agent analogue of 1. Thus, the overall charge and lipophilicity (similar for all Tc-99m-DACH isomers) exert a greater influence on biodistribution than the specific structural features of the different Tc-99m-DACH isomers.

  • structure and properties of fac rei co 3 nta 2 nta3 trianion of nitrilotriacetic acid and fac rei co 3 l n analogues useful for assessing the excellent Renal clearance of the fac 99mtci co 3 nta 2 diagnostic Renal Agent
    Inorganic Chemistry, 2015
    Co-Authors: Jeffrey Klenc, Malgorzata Lipowska, Andrew M. Taylor, Pramuditha Abhayawardhana, Luigi G. Marzilli
    Abstract:

    We previously identified two new Agents based on the [99mTcVO]3+ core with Renal clearances in human volunteers 30% higher than that of the widely used clinical tracer 99mTc-MAG3 (MAG35– = penta-anion of mercaptoacetyltriglycine). However, Renal Agents with even higher clearances are needed. More recently, we changed our focus from the [99mTcVO]3+ core to the discovery of superior tracers based on the fac-[99mTcI(CO)3]+ core. Compared to 99mTc-MAG3, fac-[99mTcI(CO)3(NTA)]2– (NTA3– = trianion of nitrilotriacetic acid) holds great promise by virtue of its efficient Renal clearance via tubular secretion and the absence of hepatobiliary elimination, even in patients with severely reduced Renal function. We report here NMR, molecular (X-ray) structure, and solution data on fac-[ReI(CO)3(NTA)]2– with a −CH2CO2– dangling monoanionic chain and on two fac-[ReI(CO)3(L)]− analogues with either a −CH2CONH2 or a −CH2CH2OH dangling neutral chain. In these three fac-[ReI(CO)3(L)]n− complexes, the fac-[ReI(CO)3(N(CH2CO2)...

  • Structure and Properties of fac-[Re(I)(CO)3(NTA)](2-) (NTA(3-) = Trianion of Nitrilotriacetic Acid) and fac-[Re(I)(CO)3(L)](n-) Analogues Useful for Assessing the Excellent Renal Clearance of the fac-[(99m)Tc(I)(CO)3(NTA)](2-) Diagnostic Renal Agent.
    Inorganic Chemistry, 2015
    Co-Authors: Jeffrey Klenc, Malgorzata Lipowska, Andrew M. Taylor, Pramuditha Abhayawardhana, Luigi G. Marzilli
    Abstract:

    We previously identified two new Agents based on the [99mTcVO]3+ core with Renal clearances in human volunteers 30% higher than that of the widely used clinical tracer 99mTc-MAG3 (MAG35– = penta-anion of mercaptoacetyltriglycine). However, Renal Agents with even higher clearances are needed. More recently, we changed our focus from the [99mTcVO]3+ core to the discovery of superior tracers based on the fac-[99mTcI(CO)3]+ core. Compared to 99mTc-MAG3, fac-[99mTcI(CO)3(NTA)]2– (NTA3– = trianion of nitrilotriacetic acid) holds great promise by virtue of its efficient Renal clearance via tubular secretion and the absence of hepatobiliary elimination, even in patients with severely reduced Renal function. We report here NMR, molecular (X-ray) structure, and solution data on fac-[ReI(CO)3(NTA)]2– with a −CH2CO2– dangling monoanionic chain and on two fac-[ReI(CO)3(L)]− analogues with either a −CH2CONH2 or a −CH2CH2OH dangling neutral chain. In these three fac-[ReI(CO)3(L)]n− complexes, the fac-[ReI(CO)3(N(CH2CO2)...

  • Preclinical Evaluation of 99mTc(CO)3-Aspartic-N-Monoacetic Acid, a Renal Radiotracer with Pharmacokinetic Properties Comparable to 131I-o-Iodohippurate
    The Journal of Nuclear Medicine, 2012
    Co-Authors: Malgorzata Lipowska, Luigi G. Marzilli, Jeffrey Klenc, Andrew M. Taylor
    Abstract:

    Chronic kidney disease (CKD) has emerged as a serious health problem worldwide. In the US alone, an estimated 13% of the adult population have CKD (1) and this number is increasing yearly due to the rising prevalence of diabetes, hypertension, obesity, cardiovascular disease superimposed on an aging population (2–5). Moreover, the incidence of CKD in children has also steadily increased during the past two decades (6). Early detection and diagnosis can lead to treatment that will reduce the risk of kidney failure. The classification of CKD is currently based on the estimated GFR using a 4 variable algorithm which attempts to compensate for the fact that the serum creatinine may not become elevated until over 50% of the Renal function has been lost (7). Radionuclide imaging may detect unsuspected Renal disease in patients with a normal serum creatinine and continues to have an important role in evaluating suspected obstruction and renovascular hypertension and in monitoring Renal function through measurements of glomerular filtration and effective Renal plasma flow (ERPF). The gold standard for the determination of ERPF is p-aminohippurate (PAH). In practice, however, measurement of PAH clearance required a constant plasma infusion and time consuming analysis, limiting its use in a clinical setting. 131I-o-iodohippurate (131I-OIH) is a radioactive standard used as an imaging Agent and as a tracer to measure ERPF, although its clearance is still only 85–90% that of PAH (8). 131I-OIH commercial production has been discontinued in many countries because of the suboptimal characteristics of 131I (Emax = 364 keV) and the fact that its beta emission can result in a high radiation dose, particularly to the kidneys and thyroid in patients with impaired Renal function (9). Simple and rapid labeling methods with the 99mTc isotope have been developed for clinical applications (10, 11) because of the 99mTc highly favorable physical characteristics (t1/2 = 6 h, Emax = 140 keV), easy availability and low cost. Although a number of 99mTc complexes have been tested as potential alternatives for 131I-OIH (12–21), 99mTc-mercaptoacetyltriglycine (99mTc-MAG3) was shown to have favorable properties, has become commercially available, and is the most widely used 99mTc Renal tracer in the United States (22, 23). Nevertheless, 99mTc-MAG3 is not an ideal replacement for 131I-OIH because its clearance is only 50–60% that of 131I-OIH and it does not provide a direct measurement of effective Renal plasma flow (ERPF). Our recent studies showed that a new 99mTc Renal Agent based on the nitrilotriacetic acid ligand (Fig. 1), 99mTc(CO)3(NTA), and 131I-OIH had essentially identical pharmacokinetics in rats (24) and subjects with normal Renal function (21), suggesting that an anionic Renal tracer with a {99mTc(CO)3}+ core and an aminopolycarboxylate chelate is capable of providing a measurement of ERPF in humans equivalent to that of 131I-OIH. However, the promising biological properties of 99mTc(CO)3(NTA) still need to be confirmed in patients with impaired Renal function. Even if 99mTc(CO)3(NTA) proves to be equivalent to 131I-OIH in patients with Renal failure, 99mTc(CO)3(NTA) clearance is still likely to be inferior to that of PAH because the clearance of 131I-OIH is only 84% that of PAH (25). FIGURE 1 Structure of nitrilotriacetic acid (NTA) and aspartic-N-monoacetic acid (ASMA) ligands. The ellipse encloses the dangling carboxyl group and the asterisk indicates an asymmetric carbon. Our goal was to assess a new 99mTc(CO)3(NTA) isomer, 99mTc(CO)3(ASMA) (ASMA stands for aspartic-N-monoacetic acid, Fig. 1) in an animal model to determine if a change in ligand design could lead to a Renal tracer with improved pharmacokinetic properties.

  • Initial evaluation of new 99mTc(CO)3 Renal imaging Agents having carboxyl-rich thioether ligands and chemical characterization of Re(CO)3 analogues
    Nuclear Medicine and Biology, 2007
    Co-Authors: Haiyang He, Luigi G. Marzilli, Malgorzata Lipowska, Anna Maria Christoforou, Andrew M. Taylor
    Abstract:

    Abstract Introduction The first human studies of a characterized radiopharmaceutical containing a { 99m Tc(CO) 3 } + core, Na[ 99m Tc(CO) 3 (LAN)], demonstrated that Na[ 99m Tc(CO) 3 (LAN)] was an excellent Renal imaging Agent; however, its clearance was less than that of 131 I-orthoiodohippurate ( 131 I-OIH), and it did not provide a direct measure of effective Renal plasma flow. In order to develop a 99m Tc Renal Agent with pharmacokinetic properties equivalent to those of 131 I-OIH, we investigated the 99m Tc(CO) 3 /Re(CO) 3 complexes formed from carboxymethylmercaptosuccinic acid (CMSAH 3 ) and thiodisuccinic acid (TDSAH 4 ). Once the ligand is bound to 99m Tc(CO) 3 through a thioether and two carboxyl groups, the complexes have at least one unbound carboxyl group, essential for the interaction with the Renal tubular transporter. Methods X-ray crystal structural analysis of [NMe 4 ][Re(CO) 3 (CMSAH)] was performed to interpret the nature of 99m Tc tracers. CMSAH 3 and TDSAH 4 were radiolabeled by incubating each ligand and the precursor [ 99m Tc(CO) 3 (H 2 O) 3 ] + at 70°C (pH 7) for 30 min. The products were purified by reversed-phase high-performance liquid chromatography, and biodistribution studies were performed in Sprague–Dawley rats, with 131 I-OIH as an internal control at 10 and 60 min. Results Radiolabeling CMSAH 3 and TDSAH 4 with the [ 99m Tc(CO) 3 (H 2 O) 3 ] + precursor gave products quantitatively. Analysis of the Re(CO) 3 complexes with the CMSAH 3 and TDSAH 4 ligands demonstrates that ligands are bound in 99m Tc/Re(CO) 3 complexes through a thioether and two deprotonated carboxyl groups (forming tridentate dianionic moieties, generally with two 5-membered chelate rings). Renal excretion at 60 min (activity in the urine as a percentage of 131 I-OIH) was 68±1% for Na 3 [ 99m Tc(CO) 3 (TDSA)] but was 98±1% for Na 2 [ 99m Tc(CO) 3 (CMSA)]. Conclusion In rats, Na 2 [ 99m Tc(CO) 3 (CMSA)] is extracted by the kidneys and eliminated in the urine almost as rapidly as 131 I-OIH; consequently, Na 2 [ 99m Tc(CO) 3 (CMSA)] may provide a direct measure of effective Renal plasma flow, and further evaluation in humans is warranted.

Hariprasad Gali - One of the best experts on this subject based on the ideXlab platform.

  • Primary radiation dosimetry of a novel PET radiopharmaceutical 68Ga-NODAGA-glycine in comparison with 99mTc-DTPA in Renal studies.
    Hellenic Journal of Nuclear Medicine, 2017
    Co-Authors: Mohsen Cheki, Hariprasad Gali
    Abstract:

    OBJECTIVE: In this study, we tried to estimate human absorbed dose of 68Ga-NODAGA-glycine as a new potential positron emission tomography (PET) Renal Agent based on the biodistribution data reported in healthy rats, and compare our estimation with the available absorbed dose data from technetium-99m-diethylenetriaminepentaacetic acid (99mTc-DTPA). SUBJECTS AND METHODS: The medical internal radiation dose (MIRD) formulation was applied to extrapolate from rats to human and to project the absorbed radiation dose for various organs in humans. S factor calculated by Monte-Carlo N-particle (MCNP) simulation and also this factor has been taken from the tables presented in MIRD pamphlet No.11. Hence, two radiation absorbed dose were calculated for organs. RESULTS: Our dose prediction shows that an 185MBq injection of gallium-68-1,4,7-triazacyclononane-1-γ-glutamylglycine-4,7-diacetic acid (68Ga-NODAGA-glycine) in humans might result in an estimated absorbed dose of 0.063mGy in the whole body when S factor calculated by MCNP simulation. The highest absorbed doses are observed in kidneys, lungs, spleen, liver, and red marrow with 3.510, 0.453, 0.335, 0.268, and 0.239mGy, respectively. In addition to, the estimated absorbed dose for total body after injection of 185MBq of 68Ga-NODAGA-glycine is 0.053mGy when S factor has been taken from MIRD pamphlet No.11. The highest absorbed doses are observed in kidneys, lungs, liver, spleen, and red marrow with 3.110, 0.438, 0.209, 0.203, and 0.203mGy, respectively. Comparison between human absorbed dose estimation for 68Ga-NODAGA-glycine and 99mTc-DTPA indicated that the absorbed dose of the most organs after injection of 99mTc-DTPA is higher than the amount after 68Ga-NODAGA-glycine. CONCLUSION: The results showed that 68Ga-NODAGA-glycine delivers lower dose to the patients. Also due to its application in PET (which offers higher sensitivity and spatial resolution compared to planar or SPET), 68Ga-NODAGA-glycine would be a superior choice than 99mTc-DTPA for renography and impose less radiation doses to patients.

  • single step radiosynthesis and in vivo evaluation of a novel fluorine 18 labeled hippurate for use as a pet Renal Agent
    Nuclear Medicine and Biology, 2012
    Co-Authors: Gopal Pathuri, Andria F Hedrick, Vibhudutta Awasthi, Hariprasad Gali
    Abstract:

    Abstract Objective The objective of this study was to investigate a new fluorine-18 labeled hippurate, m -cyano- p -[ 18 F]fluorohippurate ([ 18 F]CNPFH), as a potential radiopharmaceutical for evaluating Renal function by PET. Methods [ 18 F]CNPFH was synthesized by a direct one-step nucleophilic aromatic substitution using an 18 F-for-[N(CH 3 ) 3 ] + -reaction. In vivo stability was determined by HPLC analysis of urine collected from a healthy rat at 30min p.i. of [ 18 F]CNPFH. The plasma protein binding (PPB) and erythrocyte uptake of [ 18 F]CNPFH were determined using blood collected from healthy rats at 5min p.i. Biodistribution studies were conducted in healthy rats at 10min and 1h p.i. of [ 18 F]CNPFH. Dynamic PET/CT imaging data were acquired in normal rats. For comparison, the same rats underwent an identical imaging study using the previously reported p -[ 18 F]fluorohippurate ([ 18 F]PFH) Renal Agent. Results [ 18 F]CNPFH demonstrated high in vivo stability with no metabolic degradation. The in vivo PPB and erythrocyte uptake of [ 18 F]CNPFH were found to be comparable to those of [ 18 F]PFH. Biodistribution and dynamic PET/CT imaging studies revealed a rapid clearance of [ 18 F]CNPFH primarily through the Renal–urinary pathway. However, unlike [ 18 F]PFH, a minor (about 12%) fraction was eliminated via the hepatobiliary route. The PET-derived [ 18 F]CNPFH renograms revealed an average time-to-peak (T max ) of 3.2±0.4min which was similar to [ 18 F]PFH, but the average time-to-half-maximal activity (11.4±2.8min) was found to be higher than that of [ 18 F]PFH (7.1±1.3min). Conclusions Our in vivo results indicate that [ 18 F]CNPFH has renogram characteristics similar to those of [ 18 F]PFH, however, the unexpected hepatobiliary elimination is adding undesirable background signal in the PET images.

  • Renogram comparison of p-[18F]fluorohippurate with o-[125I]iodohippurate and [99mTc]MAG3 in normal rats
    Nuclear Medicine Communications, 2011
    Co-Authors: Gopal Pathuri, Vibhudutta Awasthi, Kaustuv Sahoo, Hariprasad Gali
    Abstract:

    ObjectiveWe recently identified p-[18F]fluorohippurate ([18F]PFH) as a potential positron emission tomography (PET) Renal Agent. The objective of this study was to compare renogram parameters of [18F]PFH with o-[125I]iodohippurate ([125I]OIH) as a surrogate for the Renal imaging gold standard 131I-O

  • Synthesis and In Vivo Evaluation of p-18F-Fluorohippurate as a New Radiopharmaceutical for Assessment of Renal Function by PET
    The Journal of Nuclear Medicine, 2010
    Co-Authors: Vibhudutta Awasthi, Gopal Pathuri, Hrushikesh Agashe, Hariprasad Gali
    Abstract:

    UNLABELLED: The molecular structure of p-18F-fluorohippurate (18F-PFH) is similar to that of p-aminohippurate, a gold standard for the measurement of effective Renal plasma flow. The objective of this study was to investigate 18F-PFH as a new PET Renal Agent. METHODS: 18F-PFH was synthesized by reacting N-succinimidyl-4-18F-fluorobenzoate (18F-SFB) with glycine at 90°C (pH 8) for 20 min. In vitro stability was determined by incubating 18F-PFH in fresh human plasma at 37°C for 60 min. In vivo stability was determined by high-performance liquid chromatography analysis of urine collected from a normal rat at 40 min after injection of 18F-PFH. The plasma protein binding and erythrocyte uptake were determined using plasma collected from a normal rat at 5 min after injection of 18F-PFH. The plasma clearance of 18F-PFH was determined using a single-injection clearance method in normal and probenecid-treated rats. Biodistribution studies were conducted in normal rats at 10 min and 1 h after injection of 18F-PFH. Dynamic PET/CT studies were conducted in normal rats injected with 18F-PFH. RESULTS: In normal rats, the plasma clearance of 18F-PFH was 4.11±1.09 mL/min/100 g, which reduced by approximately 50% (P=0.03) to 2.01±0.08 mL/min/100 g in probenecid-treated rats. About 45.3% of 18F-PFH was found to associate with plasma proteins in vivo in normal rats. Biodistribution studies of 18F-PFH in normal rats showed 72.1±6.4 percentage injected dose and 88.6±6.2 percentage injected dose, respectively, in urine at 10 min and 1 h after injection. The uptake in other organs was negligible. High-performance liquid chromatography analysis of urine collected from a rat at 40 min after injection of 18F-PFH indicated that it was excreted intact, with no metabolic products. Dynamic PET revealed a rapid clearance of 18F-PFH through the Renal-urinary pathway. The PET-derived renograms revealed a time to peak activity of 3.0±1.0 min. CONCLUSION: These combined results warrant further investigation of 18F-PFH as a radiopharmaceutical for the assessment of Renal function by PET.

Malgorzata Lipowska - One of the best experts on this subject based on the ideXlab platform.

  • structure and properties of fac rei co 3 nta 2 nta3 trianion of nitrilotriacetic acid and fac rei co 3 l n analogues useful for assessing the excellent Renal clearance of the fac 99mtci co 3 nta 2 diagnostic Renal Agent
    Inorganic Chemistry, 2015
    Co-Authors: Jeffrey Klenc, Malgorzata Lipowska, Andrew M. Taylor, Pramuditha Abhayawardhana, Luigi G. Marzilli
    Abstract:

    We previously identified two new Agents based on the [99mTcVO]3+ core with Renal clearances in human volunteers 30% higher than that of the widely used clinical tracer 99mTc-MAG3 (MAG35– = penta-anion of mercaptoacetyltriglycine). However, Renal Agents with even higher clearances are needed. More recently, we changed our focus from the [99mTcVO]3+ core to the discovery of superior tracers based on the fac-[99mTcI(CO)3]+ core. Compared to 99mTc-MAG3, fac-[99mTcI(CO)3(NTA)]2– (NTA3– = trianion of nitrilotriacetic acid) holds great promise by virtue of its efficient Renal clearance via tubular secretion and the absence of hepatobiliary elimination, even in patients with severely reduced Renal function. We report here NMR, molecular (X-ray) structure, and solution data on fac-[ReI(CO)3(NTA)]2– with a −CH2CO2– dangling monoanionic chain and on two fac-[ReI(CO)3(L)]− analogues with either a −CH2CONH2 or a −CH2CH2OH dangling neutral chain. In these three fac-[ReI(CO)3(L)]n− complexes, the fac-[ReI(CO)3(N(CH2CO2)...

  • Structure and Properties of fac-[Re(I)(CO)3(NTA)](2-) (NTA(3-) = Trianion of Nitrilotriacetic Acid) and fac-[Re(I)(CO)3(L)](n-) Analogues Useful for Assessing the Excellent Renal Clearance of the fac-[(99m)Tc(I)(CO)3(NTA)](2-) Diagnostic Renal Agent.
    Inorganic Chemistry, 2015
    Co-Authors: Jeffrey Klenc, Malgorzata Lipowska, Andrew M. Taylor, Pramuditha Abhayawardhana, Luigi G. Marzilli
    Abstract:

    We previously identified two new Agents based on the [99mTcVO]3+ core with Renal clearances in human volunteers 30% higher than that of the widely used clinical tracer 99mTc-MAG3 (MAG35– = penta-anion of mercaptoacetyltriglycine). However, Renal Agents with even higher clearances are needed. More recently, we changed our focus from the [99mTcVO]3+ core to the discovery of superior tracers based on the fac-[99mTcI(CO)3]+ core. Compared to 99mTc-MAG3, fac-[99mTcI(CO)3(NTA)]2– (NTA3– = trianion of nitrilotriacetic acid) holds great promise by virtue of its efficient Renal clearance via tubular secretion and the absence of hepatobiliary elimination, even in patients with severely reduced Renal function. We report here NMR, molecular (X-ray) structure, and solution data on fac-[ReI(CO)3(NTA)]2– with a −CH2CO2– dangling monoanionic chain and on two fac-[ReI(CO)3(L)]− analogues with either a −CH2CONH2 or a −CH2CH2OH dangling neutral chain. In these three fac-[ReI(CO)3(L)]n− complexes, the fac-[ReI(CO)3(N(CH2CO2)...

  • Preclinical Evaluation of 99mTc(CO)3-Aspartic-N-Monoacetic Acid, a Renal Radiotracer with Pharmacokinetic Properties Comparable to 131I-o-Iodohippurate
    The Journal of Nuclear Medicine, 2012
    Co-Authors: Malgorzata Lipowska, Luigi G. Marzilli, Jeffrey Klenc, Andrew M. Taylor
    Abstract:

    Chronic kidney disease (CKD) has emerged as a serious health problem worldwide. In the US alone, an estimated 13% of the adult population have CKD (1) and this number is increasing yearly due to the rising prevalence of diabetes, hypertension, obesity, cardiovascular disease superimposed on an aging population (2–5). Moreover, the incidence of CKD in children has also steadily increased during the past two decades (6). Early detection and diagnosis can lead to treatment that will reduce the risk of kidney failure. The classification of CKD is currently based on the estimated GFR using a 4 variable algorithm which attempts to compensate for the fact that the serum creatinine may not become elevated until over 50% of the Renal function has been lost (7). Radionuclide imaging may detect unsuspected Renal disease in patients with a normal serum creatinine and continues to have an important role in evaluating suspected obstruction and renovascular hypertension and in monitoring Renal function through measurements of glomerular filtration and effective Renal plasma flow (ERPF). The gold standard for the determination of ERPF is p-aminohippurate (PAH). In practice, however, measurement of PAH clearance required a constant plasma infusion and time consuming analysis, limiting its use in a clinical setting. 131I-o-iodohippurate (131I-OIH) is a radioactive standard used as an imaging Agent and as a tracer to measure ERPF, although its clearance is still only 85–90% that of PAH (8). 131I-OIH commercial production has been discontinued in many countries because of the suboptimal characteristics of 131I (Emax = 364 keV) and the fact that its beta emission can result in a high radiation dose, particularly to the kidneys and thyroid in patients with impaired Renal function (9). Simple and rapid labeling methods with the 99mTc isotope have been developed for clinical applications (10, 11) because of the 99mTc highly favorable physical characteristics (t1/2 = 6 h, Emax = 140 keV), easy availability and low cost. Although a number of 99mTc complexes have been tested as potential alternatives for 131I-OIH (12–21), 99mTc-mercaptoacetyltriglycine (99mTc-MAG3) was shown to have favorable properties, has become commercially available, and is the most widely used 99mTc Renal tracer in the United States (22, 23). Nevertheless, 99mTc-MAG3 is not an ideal replacement for 131I-OIH because its clearance is only 50–60% that of 131I-OIH and it does not provide a direct measurement of effective Renal plasma flow (ERPF). Our recent studies showed that a new 99mTc Renal Agent based on the nitrilotriacetic acid ligand (Fig. 1), 99mTc(CO)3(NTA), and 131I-OIH had essentially identical pharmacokinetics in rats (24) and subjects with normal Renal function (21), suggesting that an anionic Renal tracer with a {99mTc(CO)3}+ core and an aminopolycarboxylate chelate is capable of providing a measurement of ERPF in humans equivalent to that of 131I-OIH. However, the promising biological properties of 99mTc(CO)3(NTA) still need to be confirmed in patients with impaired Renal function. Even if 99mTc(CO)3(NTA) proves to be equivalent to 131I-OIH in patients with Renal failure, 99mTc(CO)3(NTA) clearance is still likely to be inferior to that of PAH because the clearance of 131I-OIH is only 84% that of PAH (25). FIGURE 1 Structure of nitrilotriacetic acid (NTA) and aspartic-N-monoacetic acid (ASMA) ligands. The ellipse encloses the dangling carboxyl group and the asterisk indicates an asymmetric carbon. Our goal was to assess a new 99mTc(CO)3(NTA) isomer, 99mTc(CO)3(ASMA) (ASMA stands for aspartic-N-monoacetic acid, Fig. 1) in an animal model to determine if a change in ligand design could lead to a Renal tracer with improved pharmacokinetic properties.

  • Initial evaluation of new 99mTc(CO)3 Renal imaging Agents having carboxyl-rich thioether ligands and chemical characterization of Re(CO)3 analogues
    Nuclear Medicine and Biology, 2007
    Co-Authors: Haiyang He, Luigi G. Marzilli, Malgorzata Lipowska, Anna Maria Christoforou, Andrew M. Taylor
    Abstract:

    Abstract Introduction The first human studies of a characterized radiopharmaceutical containing a { 99m Tc(CO) 3 } + core, Na[ 99m Tc(CO) 3 (LAN)], demonstrated that Na[ 99m Tc(CO) 3 (LAN)] was an excellent Renal imaging Agent; however, its clearance was less than that of 131 I-orthoiodohippurate ( 131 I-OIH), and it did not provide a direct measure of effective Renal plasma flow. In order to develop a 99m Tc Renal Agent with pharmacokinetic properties equivalent to those of 131 I-OIH, we investigated the 99m Tc(CO) 3 /Re(CO) 3 complexes formed from carboxymethylmercaptosuccinic acid (CMSAH 3 ) and thiodisuccinic acid (TDSAH 4 ). Once the ligand is bound to 99m Tc(CO) 3 through a thioether and two carboxyl groups, the complexes have at least one unbound carboxyl group, essential for the interaction with the Renal tubular transporter. Methods X-ray crystal structural analysis of [NMe 4 ][Re(CO) 3 (CMSAH)] was performed to interpret the nature of 99m Tc tracers. CMSAH 3 and TDSAH 4 were radiolabeled by incubating each ligand and the precursor [ 99m Tc(CO) 3 (H 2 O) 3 ] + at 70°C (pH 7) for 30 min. The products were purified by reversed-phase high-performance liquid chromatography, and biodistribution studies were performed in Sprague–Dawley rats, with 131 I-OIH as an internal control at 10 and 60 min. Results Radiolabeling CMSAH 3 and TDSAH 4 with the [ 99m Tc(CO) 3 (H 2 O) 3 ] + precursor gave products quantitatively. Analysis of the Re(CO) 3 complexes with the CMSAH 3 and TDSAH 4 ligands demonstrates that ligands are bound in 99m Tc/Re(CO) 3 complexes through a thioether and two deprotonated carboxyl groups (forming tridentate dianionic moieties, generally with two 5-membered chelate rings). Renal excretion at 60 min (activity in the urine as a percentage of 131 I-OIH) was 68±1% for Na 3 [ 99m Tc(CO) 3 (TDSA)] but was 98±1% for Na 2 [ 99m Tc(CO) 3 (CMSA)]. Conclusion In rats, Na 2 [ 99m Tc(CO) 3 (CMSA)] is extracted by the kidneys and eliminated in the urine almost as rapidly as 131 I-OIH; consequently, Na 2 [ 99m Tc(CO) 3 (CMSA)] may provide a direct measure of effective Renal plasma flow, and further evaluation in humans is warranted.

  • Comparison of technetium-99m-ll-EC isomers in rats and humans.
    The Journal of Nuclear Medicine, 1997
    Co-Authors: Andrew M. Taylor, Lory Hansen, Dennis Eshima, Eugene Malveaux, Russell D. Folks, L. A. Shattuck, Malgorzata Lipowska, Luigi G. Marzilli
    Abstract:

    Technetium-99m-L,L-ethylenedicysteine ( 99m Tc-LL-EC) is a new Renal imaging Agent with pharmacokinetic properties reported to be slightly superior to those of 99m Tc-mercaptoacetyltriglycine ( 99m Tc-MAG3) ; however, to better define the potential of the enantiomer 99m Tc-DD-EC and the diastereomer 99m Tc-DL-EC as Renal imaging Agents, we compared the three EC stereoisomers with 131 I-orthoiodohippurate (OIH) in a series of rats and humans. Methods: Each 99m Tc-EC stereoisomer was coinjected with OIH in six Sprague-Dawley rats for measurements of clearance and extraction fraction. Each stereoisomer was also coinjected with OIH in three human volunteers followed by sequential imaging, plasma clearance measurements and timed urine collections. Results: Technetium-99m-DD-EC had the highest clearance and extraction efficiency in rats (p ≤ 0.02). In humans, image quality was good with all three Agents. The clearance ratio (EC/OIH) was 82% ± 8% for 99m Tc-DD-EC compared to 70% ± 3% and 40% ± 5% for 99m Tc-LL-EC and 99m Tc-DL-EC, respectively. Technetium-99m-DD and 99m Tc-LL-EC were excreted more rapidly than 99m Tc-DL-EC. Conclusion: Technetium-99m-DD-EC has excellent imaging properties and the data suggest that its clearance may approach that of OIH more closely than any other 99m Tc Renal Agent. A potential limitation is the fact that both 99m Tc-DD and LL-EC exist in dianionic (80%) and monoanionic (20%) forms at physiological pH and it is unlikely that these two forms have the same clearance or protein binding affinity.

Dennis Eshima - One of the best experts on this subject based on the ideXlab platform.

  • Comparison of technetium-99m-ll-EC isomers in rats and humans.
    The Journal of Nuclear Medicine, 1997
    Co-Authors: Andrew M. Taylor, Lory Hansen, Dennis Eshima, Eugene Malveaux, Russell D. Folks, L. A. Shattuck, Malgorzata Lipowska, Luigi G. Marzilli
    Abstract:

    Technetium-99m-L,L-ethylenedicysteine ( 99m Tc-LL-EC) is a new Renal imaging Agent with pharmacokinetic properties reported to be slightly superior to those of 99m Tc-mercaptoacetyltriglycine ( 99m Tc-MAG3) ; however, to better define the potential of the enantiomer 99m Tc-DD-EC and the diastereomer 99m Tc-DL-EC as Renal imaging Agents, we compared the three EC stereoisomers with 131 I-orthoiodohippurate (OIH) in a series of rats and humans. Methods: Each 99m Tc-EC stereoisomer was coinjected with OIH in six Sprague-Dawley rats for measurements of clearance and extraction fraction. Each stereoisomer was also coinjected with OIH in three human volunteers followed by sequential imaging, plasma clearance measurements and timed urine collections. Results: Technetium-99m-DD-EC had the highest clearance and extraction efficiency in rats (p ≤ 0.02). In humans, image quality was good with all three Agents. The clearance ratio (EC/OIH) was 82% ± 8% for 99m Tc-DD-EC compared to 70% ± 3% and 40% ± 5% for 99m Tc-LL-EC and 99m Tc-DL-EC, respectively. Technetium-99m-DD and 99m Tc-LL-EC were excreted more rapidly than 99m Tc-DL-EC. Conclusion: Technetium-99m-DD-EC has excellent imaging properties and the data suggest that its clearance may approach that of OIH more closely than any other 99m Tc Renal Agent. A potential limitation is the fact that both 99m Tc-DD and LL-EC exist in dianionic (80%) and monoanionic (20%) forms at physiological pH and it is unlikely that these two forms have the same clearance or protein binding affinity.

  • Evaluation of technetium-99m-triamide-mercaptide complexes designed to identify properties favoring Renal tubular transport.
    The Journal of Nuclear Medicine, 1994
    Co-Authors: Lory Hansen, Luigi G. Marzilli, Dennis Eshima, Eugene Malveaux, Russell D. Folks, Andrew M. Taylor
    Abstract:

    To aid in the design of an improved {sup 99m}Tc-labeled Renal Agent, several new [{sup 99m}TcO(MAG{sub 3})]{sup 2{minus}} analogs were synthesized to determine the effects of varying the position and chemical form of the terminal charged group on Renal clearance. Clearance, extraction efficiency and plasma protein binding were measured in six Sprague-Dawley rats per complex for ortho, meta and para isomers of [{sup 99m}TcO(MAG{sub 2{minus}}ABA)]{sup 2{minus}}, with MAG{sub 2{minus}} = mercaptoacetylglycylglycyl- and ABA = aminobenzoate; [{sup 99m}TcO(MAG{sub 2{minus}}pASA)]{sup 2{minus}}, with pASA = p-aminosalicylate; [{sup 99m}TcO(MAG{sub 2{minus}}AMS)]{sup 3{minus}}, with AMP = aminomethylphosphonate. For Agents with relatively poor clearances, hepatobiliary excretion was evaluated by using a camera-based method. The clearances of the ortho, meta and para isomers of [{sup 22m}TcO(MAG{sub 2{minus}}ABA)]{sup 2{minus}} were 17%, 20% and 59% of those of OIH, respectively. The clearances of [{sup 99m}TcO(MAG{sub 2{minus}}pASA)]{sup 2{minus}}, [{sup 99m}TcO(MAG{sub 2{minus}}AMS)]{sup 2{minus}} and [{sup 99m}TcO(MAG{sub 2{minus}}AMP)]{sup 3{minus}} were 32%, 46% and 39% those of OIH, respectively. Optimal tubular transport appears to require a terminal anionic group; a planar carboxylate is preferred over nonplanar -SO{sup {minus}}{sub 3} or -PO{sup 2{minus}}{sub 3} substituents, suggesting that the smaller size and/or planar shape of the carboxylate group are probably more important than the total chargemore » or charge distribution. Optimal transport also appears to depend on the oxo-carboxylate conformation (syn or anti) and the oxo-carboxylate distance, although these relationships can be modulated by steric interactions. These structure-distribution relationships are important factors to consider in the future design of Renal radiopharmaceuticals. 25 refs., 2 figs., 4 tabs.« less

  • Comparison of Tc-99m MAG3 and Tc-99m DTPA in Renal transplant patients with impaired Renal function.
    Clinical Nuclear Medicine, 1990
    Co-Authors: Andrew M. Taylor, Jack A. Ziffer, Dennis Eshima
    Abstract:

    : Tc-99m mercaptoacetyltriglycine (MAG3) is a new Tc-99m Renal Agent that compares favorably to I-131 Hippuran in animal models, normal volunteers, and patients. Based on the fact that Tc-99m MAG3 has a much more rapid clearance than Tc-99m DTPA and a smaller volume of distribution, it was postulated that the image quality of Tc-99m MAG3 studies should be superior to scans obtained using Tc-99m DTPA, particularly in patients with impaired Renal function. To test this hypothesis, Tc-99m DTPA and MAG3 images were obtained in three transplant patients during periods of stable but impaired Renal function. In one study, the Tc-99m DTPA study was potentially misleading, whereas the Tc-99m MAG3 examination assessed the clinical situation correctly. In all three cases, the Tc-99m MAG3 images were superior.