Monoclonal antibody 38S1 was radiobrominated with the positron emitter 76Br (T1/2 = 16.2 h). Indi... more Monoclonal antibody 38S1 was radiobrominated with the positron emitter 76Br (T1/2 = 16.2 h). Indirect labeling was performed using N-succinimidyl para-(tri-methylstannyl)benzoate (SPMB) as the precursor molecule. SPMB was labeled using Chloramine-T yielding N-succinimidyl para-[76Br]bromobenzoate, which was then conjugated to the antibody. Optimization of the labeling conditions and further conjugation gave a total yield ( mean±maxerror) of 49±2%. The immunoreactivity of the antibodies was retained after labeling. Thus, antibodies intended for positron emission tomography can be labeled with 76Br, which gives high yields and preserved immunoreactivity when using the SPMB technique described.
... 7. Lundqvist H, Nordberg A, Hartvig R Lfingstr6m B. Nicotine binding assessed by a dual trace... more ... 7. Lundqvist H, Nordberg A, Hartvig R Lfingstr6m B. Nicotine binding assessed by a dual tracer model evaluated in the rhe-sus ... A. Notghi, LK Harding, NR Williams Department of Physics and Nuclear Medicine City Hospital NHS Trust Dudley Road, Birmingham, B 18 7QH, UK ...
Alzheimer Disease and Associated Disorders, Oct 1, 1998
A dual tracer model, consisting of the administration of 15O-water and (S)-(-)-[11C]nicotine in c... more A dual tracer model, consisting of the administration of 15O-water and (S)-(-)-[11C]nicotine in close succession, is suggested to assess nicotine binding in the brain. Regional cerebral blood flow (rCBF) determined by 15O-water was used to flow compensate two nicotine model parameters, k1 and k2, obtained in a two-compartment kinetic model. In the present study, this dual tracer approach was evaluated in the rhesus monkey by altering the rCBF or by administering (S)-(-)-[11C]nicotine at either high or low specific radioactivity. The model parameter, k2' = k2/rCBF, was found to be independent of rCBF in different regions of interest in the monkey brain. The parameter, k2', increased significantly when (S)-(-)-[11C]nicotine was given at low specific radioactivity, indicating lower nicotine binding in the brain. Thus, this observation implies an influence on specific receptor binding on the corrected efflux rate constant. This dual tracer model may be useful in evaluating nicotine binding changes in the human brain and the effect of drug treatment in neurodegenerative disorders such as Alzheimer disease.
Radiolabelled DNA-binding compounds can be used to increase the efficiency of radionuclide cancer... more Radiolabelled DNA-binding compounds can be used to increase the efficiency of radionuclide cancer therapy of disseminated disease. In this work, the aminoacridine compound N-[3-(acridine-9-ylamino)-propyl]-3-iodobenzamide (A3) labelled with the Auger-emitting nuclide 125I using Chloramine-T was studied. Optimal labelling conditions of 125I-A3 were investigated and the interaction with DNA was studied using a novel cell-free in vitro assay with naked human genomic DNA in agarose plugs. This novel assay showed to be simple and reliable. The results verify that 125I-A3 specifically binds DNA with low dissociation and is potent in causing double-strand breaks, yielding 1.0-1.4 breaks per decay. In conclusion, 125I-A3 is a most suitable DNA-binding compound for future therapeutic studies of Auger-electron emitters like 125I.
ABSTRACT Background Gadolinium (Gd) neutron capture therapy (GdNCT) is based on a neutron capture... more ABSTRACT Background Gadolinium (Gd) neutron capture therapy (GdNCT) is based on a neutron capture reaction (NCR) that involves emission of both short and long range products. The aim of this study was to investigate both the microscopic and macroscopic contributions of the absorbed dose involved in GdNCT. Methods Cylindrical containers with diameters 1–30 mm filled with a solution of Gd were irradiated with epithermal neutrons. The background neutron dose as well as the prompt gamma dose has been calculated and measured by means of film dosimetry for the largest cylinder. Monte Carlo codes MCNP5(b) and GEANT4 have been utilized for calculation the absorbed dose. Results and discussion Results from the film dosimetry are in agreement with the calculations for high doses while for low doses the measured values are higher than the calculated results. For the largest cylinder, the prompt gamma dose from GdNCR neutron is at least five times higher than the background dose. For a cell cluster model, in the first 0.1 mm the major contribution to the absorbed dose is from IC electrons. If Gd atoms were homogeneously distributed in the nuclei of all tumour cells, capture events between neutron and Gd atoms close to DNA could kill the tumour cells and give cross-fire dose from IC electrons to the cells located in the 0.1 mm range. Conclusions For a correct GdNCT dosimetry both microscopic part of the dose delivered by short-range low energy electrons and macroscopic part delivered by the prompt gamma should be considered.
Monoclonal antibody (MAb) A33 was labeled with the positron emitter 76Br (T(1/2) = 16.2 h). Direc... more Monoclonal antibody (MAb) A33 was labeled with the positron emitter 76Br (T(1/2) = 16.2 h). Direct labeling was done using the conventional chloramine-T method. After optimization of the labeling conditions, a maximum yield (mean +/- max error) of 77 +/- 2% was obtained at pH 6.8. In vitro binding of 76Br-A33 to SW1222 colonic cancer cells showed that the immunoreactivity was retained. Also, the MAbs 38S1 and 3S193 and the peptide hEGF were 76Br-labeled, resulting in labeling yields (mean +/- max error) of 75 +/- 3%, 63 +/- 4%, and 73 +/- 0.1%, respectively. We conclude that antibodies and peptides can be labeled conveniently with 76Br for the purpose of whole-body tumour imaging by positron emission tomography.
A conjugate with specific binding to the epidermal growth factor receptor, EGFR, and of interest ... more A conjugate with specific binding to the epidermal growth factor receptor, EGFR, and of interest for clinical tests was prepared using mouse epidermal growth factor, mEGF, and dextran. The mEGF was first coupled to dextran by reductive amination in which the free amino group on the N-terminal of mEGF was reacted with the aldehyde group on the reductive end of the dextran chain. The end-end coupled intermediate was further activated by the cyanopyridinium agent CDAP and tyrosines introduced to the dextran part of the conjugate. The mEGF-dextran-tyrosine conjugate was, with high efficiency, iodinated with the chloramine-T method. Approximately 25-35% of the radioactivity could be removed from the conjugate after exposure to protease K while 65-75% of the radioactivity could be removed after exposure to dextranase. Thus, the largest amount of the iodine was on the dextran part of the conjugate. The iodinated mEGF-dextran-tyrosine had EGFR specific binding since the binding to an EGFR r...
International journal of radiation applications and instrumentation. Part B, Nuclear medicine and biology, 1988
The uptake of various labeled compounds by tumors was studied by double-tracer whole-body autorad... more The uptake of various labeled compounds by tumors was studied by double-tracer whole-body autoradiography (DTWBA) in rats. Each animal carried two types of tumors: mammary carcinomas and the Walker 256 carcinosarcomas. The markers used were [18F]- and [3H]fluorodeoxyglucose (glucose utilization), [3H]thymidine (cell proliferation), [11C]methionine (amino acid metabolism) and [11C]- and [3H]toremifene (estrogen-receptor-avid agents). In each experiment, the distribution of a substance labeled with short-lived radionuclide (11C or 18F) was compared with that of another substance labeled with a long-lived nuclide (3H). Quantification was done by combining computerized image analysis of the autoradiograms with liquid scintillation counting of punched tissue pieces obtained from the cryosections. The relationships between the uptakes of the various radiopharmaceuticals were recorded in tumors and normal tissues. The dynamics of [18F]fluorodeoxyglucose and [11C]methionine were determined ...
The immediate precursor in the serotonin synthetic route, 5-hydroxytryptophan (5-HTP), labeled wi... more The immediate precursor in the serotonin synthetic route, 5-hydroxytryptophan (5-HTP), labeled with 11C in the beta position, has become available for studies using positron emission tomography (PET) to examine serotonin formation in human brain. Normalized uptake and intracerebral utilization of tracer amounts of [beta-11C]5-HTP were studied twice in six healthy male volunteers, three of them before and after pharmacological pretreatments. The kinetic model defines regional utilization as the relative regional radioactivity accumulation rate. Repeat studies showed good reproducibility. Pretreatments with benserazide, p-chlorophenylalanine (PCPA), and unlabeled 5-HTP all significantly increased uptake of [beta-11C]5-HTP. The utilization rates in both striatal and frontal cortex were higher than those in the surrounding brain, indicating that PET studies using [beta-11C]5-HTP as a ligand quantitate selective processes in the utilization of 5-HTP. We tentatively interpret uptake and u...
Knowledge on the physical and biological aspects of Auger-electron emission is described and the ... more Knowledge on the physical and biological aspects of Auger-electron emission is described and the major attempts to use such emitters in cancer therapy are discussed. Focus is on the need for nuclear localization of the Auger-electron emitters, i.e. preferably targeting the nuclear DNA, to have a good therapy effect. Delivery of Auger-electron emitters using nucleoside analogues, DNA-intercalators, minor groove binders,
An animal model has been developed in the Rhesus monkey for noninvasive monitoring of CSF transpo... more An animal model has been developed in the Rhesus monkey for noninvasive monitoring of CSF transport of drugs by external detectors i.e. positron emission tomography. The model compromises the cannulation of the subarachnoid space (with a spinal needle), and has been used without any damage to the monkey. With the method it was shown that injection rate had a major influence on the transport rate of 68GaCl3 in the CSF. Injection of 0.5 ml over 60 sec gave the highest radioactivity near the injection site, whereas an injection rate of this volume over 10 sec resulted in high radioactivity more rostrally shortly after injection. This method have been of value for the determination of drug kinetics after spinal administration.
Monoclonal antibody 38S1 was radiobrominated with the positron emitter 76Br (T1/2 = 16.2 h). Indi... more Monoclonal antibody 38S1 was radiobrominated with the positron emitter 76Br (T1/2 = 16.2 h). Indirect labeling was performed using N-succinimidyl para-(tri-methylstannyl)benzoate (SPMB) as the precursor molecule. SPMB was labeled using Chloramine-T yielding N-succinimidyl para-[76Br]bromobenzoate, which was then conjugated to the antibody. Optimization of the labeling conditions and further conjugation gave a total yield ( mean±maxerror) of 49±2%. The immunoreactivity of the antibodies was retained after labeling. Thus, antibodies intended for positron emission tomography can be labeled with 76Br, which gives high yields and preserved immunoreactivity when using the SPMB technique described.
... 7. Lundqvist H, Nordberg A, Hartvig R Lfingstr6m B. Nicotine binding assessed by a dual trace... more ... 7. Lundqvist H, Nordberg A, Hartvig R Lfingstr6m B. Nicotine binding assessed by a dual tracer model evaluated in the rhe-sus ... A. Notghi, LK Harding, NR Williams Department of Physics and Nuclear Medicine City Hospital NHS Trust Dudley Road, Birmingham, B 18 7QH, UK ...
Alzheimer Disease and Associated Disorders, Oct 1, 1998
A dual tracer model, consisting of the administration of 15O-water and (S)-(-)-[11C]nicotine in c... more A dual tracer model, consisting of the administration of 15O-water and (S)-(-)-[11C]nicotine in close succession, is suggested to assess nicotine binding in the brain. Regional cerebral blood flow (rCBF) determined by 15O-water was used to flow compensate two nicotine model parameters, k1 and k2, obtained in a two-compartment kinetic model. In the present study, this dual tracer approach was evaluated in the rhesus monkey by altering the rCBF or by administering (S)-(-)-[11C]nicotine at either high or low specific radioactivity. The model parameter, k2' = k2/rCBF, was found to be independent of rCBF in different regions of interest in the monkey brain. The parameter, k2', increased significantly when (S)-(-)-[11C]nicotine was given at low specific radioactivity, indicating lower nicotine binding in the brain. Thus, this observation implies an influence on specific receptor binding on the corrected efflux rate constant. This dual tracer model may be useful in evaluating nicotine binding changes in the human brain and the effect of drug treatment in neurodegenerative disorders such as Alzheimer disease.
Radiolabelled DNA-binding compounds can be used to increase the efficiency of radionuclide cancer... more Radiolabelled DNA-binding compounds can be used to increase the efficiency of radionuclide cancer therapy of disseminated disease. In this work, the aminoacridine compound N-[3-(acridine-9-ylamino)-propyl]-3-iodobenzamide (A3) labelled with the Auger-emitting nuclide 125I using Chloramine-T was studied. Optimal labelling conditions of 125I-A3 were investigated and the interaction with DNA was studied using a novel cell-free in vitro assay with naked human genomic DNA in agarose plugs. This novel assay showed to be simple and reliable. The results verify that 125I-A3 specifically binds DNA with low dissociation and is potent in causing double-strand breaks, yielding 1.0-1.4 breaks per decay. In conclusion, 125I-A3 is a most suitable DNA-binding compound for future therapeutic studies of Auger-electron emitters like 125I.
ABSTRACT Background Gadolinium (Gd) neutron capture therapy (GdNCT) is based on a neutron capture... more ABSTRACT Background Gadolinium (Gd) neutron capture therapy (GdNCT) is based on a neutron capture reaction (NCR) that involves emission of both short and long range products. The aim of this study was to investigate both the microscopic and macroscopic contributions of the absorbed dose involved in GdNCT. Methods Cylindrical containers with diameters 1–30 mm filled with a solution of Gd were irradiated with epithermal neutrons. The background neutron dose as well as the prompt gamma dose has been calculated and measured by means of film dosimetry for the largest cylinder. Monte Carlo codes MCNP5(b) and GEANT4 have been utilized for calculation the absorbed dose. Results and discussion Results from the film dosimetry are in agreement with the calculations for high doses while for low doses the measured values are higher than the calculated results. For the largest cylinder, the prompt gamma dose from GdNCR neutron is at least five times higher than the background dose. For a cell cluster model, in the first 0.1 mm the major contribution to the absorbed dose is from IC electrons. If Gd atoms were homogeneously distributed in the nuclei of all tumour cells, capture events between neutron and Gd atoms close to DNA could kill the tumour cells and give cross-fire dose from IC electrons to the cells located in the 0.1 mm range. Conclusions For a correct GdNCT dosimetry both microscopic part of the dose delivered by short-range low energy electrons and macroscopic part delivered by the prompt gamma should be considered.
Monoclonal antibody (MAb) A33 was labeled with the positron emitter 76Br (T(1/2) = 16.2 h). Direc... more Monoclonal antibody (MAb) A33 was labeled with the positron emitter 76Br (T(1/2) = 16.2 h). Direct labeling was done using the conventional chloramine-T method. After optimization of the labeling conditions, a maximum yield (mean +/- max error) of 77 +/- 2% was obtained at pH 6.8. In vitro binding of 76Br-A33 to SW1222 colonic cancer cells showed that the immunoreactivity was retained. Also, the MAbs 38S1 and 3S193 and the peptide hEGF were 76Br-labeled, resulting in labeling yields (mean +/- max error) of 75 +/- 3%, 63 +/- 4%, and 73 +/- 0.1%, respectively. We conclude that antibodies and peptides can be labeled conveniently with 76Br for the purpose of whole-body tumour imaging by positron emission tomography.
A conjugate with specific binding to the epidermal growth factor receptor, EGFR, and of interest ... more A conjugate with specific binding to the epidermal growth factor receptor, EGFR, and of interest for clinical tests was prepared using mouse epidermal growth factor, mEGF, and dextran. The mEGF was first coupled to dextran by reductive amination in which the free amino group on the N-terminal of mEGF was reacted with the aldehyde group on the reductive end of the dextran chain. The end-end coupled intermediate was further activated by the cyanopyridinium agent CDAP and tyrosines introduced to the dextran part of the conjugate. The mEGF-dextran-tyrosine conjugate was, with high efficiency, iodinated with the chloramine-T method. Approximately 25-35% of the radioactivity could be removed from the conjugate after exposure to protease K while 65-75% of the radioactivity could be removed after exposure to dextranase. Thus, the largest amount of the iodine was on the dextran part of the conjugate. The iodinated mEGF-dextran-tyrosine had EGFR specific binding since the binding to an EGFR r...
International journal of radiation applications and instrumentation. Part B, Nuclear medicine and biology, 1988
The uptake of various labeled compounds by tumors was studied by double-tracer whole-body autorad... more The uptake of various labeled compounds by tumors was studied by double-tracer whole-body autoradiography (DTWBA) in rats. Each animal carried two types of tumors: mammary carcinomas and the Walker 256 carcinosarcomas. The markers used were [18F]- and [3H]fluorodeoxyglucose (glucose utilization), [3H]thymidine (cell proliferation), [11C]methionine (amino acid metabolism) and [11C]- and [3H]toremifene (estrogen-receptor-avid agents). In each experiment, the distribution of a substance labeled with short-lived radionuclide (11C or 18F) was compared with that of another substance labeled with a long-lived nuclide (3H). Quantification was done by combining computerized image analysis of the autoradiograms with liquid scintillation counting of punched tissue pieces obtained from the cryosections. The relationships between the uptakes of the various radiopharmaceuticals were recorded in tumors and normal tissues. The dynamics of [18F]fluorodeoxyglucose and [11C]methionine were determined ...
The immediate precursor in the serotonin synthetic route, 5-hydroxytryptophan (5-HTP), labeled wi... more The immediate precursor in the serotonin synthetic route, 5-hydroxytryptophan (5-HTP), labeled with 11C in the beta position, has become available for studies using positron emission tomography (PET) to examine serotonin formation in human brain. Normalized uptake and intracerebral utilization of tracer amounts of [beta-11C]5-HTP were studied twice in six healthy male volunteers, three of them before and after pharmacological pretreatments. The kinetic model defines regional utilization as the relative regional radioactivity accumulation rate. Repeat studies showed good reproducibility. Pretreatments with benserazide, p-chlorophenylalanine (PCPA), and unlabeled 5-HTP all significantly increased uptake of [beta-11C]5-HTP. The utilization rates in both striatal and frontal cortex were higher than those in the surrounding brain, indicating that PET studies using [beta-11C]5-HTP as a ligand quantitate selective processes in the utilization of 5-HTP. We tentatively interpret uptake and u...
Knowledge on the physical and biological aspects of Auger-electron emission is described and the ... more Knowledge on the physical and biological aspects of Auger-electron emission is described and the major attempts to use such emitters in cancer therapy are discussed. Focus is on the need for nuclear localization of the Auger-electron emitters, i.e. preferably targeting the nuclear DNA, to have a good therapy effect. Delivery of Auger-electron emitters using nucleoside analogues, DNA-intercalators, minor groove binders,
An animal model has been developed in the Rhesus monkey for noninvasive monitoring of CSF transpo... more An animal model has been developed in the Rhesus monkey for noninvasive monitoring of CSF transport of drugs by external detectors i.e. positron emission tomography. The model compromises the cannulation of the subarachnoid space (with a spinal needle), and has been used without any damage to the monkey. With the method it was shown that injection rate had a major influence on the transport rate of 68GaCl3 in the CSF. Injection of 0.5 ml over 60 sec gave the highest radioactivity near the injection site, whereas an injection rate of this volume over 10 sec resulted in high radioactivity more rostrally shortly after injection. This method have been of value for the determination of drug kinetics after spinal administration.
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