We describe the use of molecules labeled with short-lived emitting radionuclides for molecular im... more We describe the use of molecules labeled with short-lived emitting radionuclides for molecular imaging in combination with the positron emission tomography technique. How to use molecular probes to visualize and quantitatively determine rates of specific biochemical events such as synaptic transmission, enzymatic processes and binding to specific receptor proteins is highlighted. The sensitivity of the PET technique and the ability to measure and validate relationships between molecular events and biological functions is a key factor for the successful application of PET in biomedical research. In specific applications, the opportunity of using molecules labeled in specific positions may be critical. Molecular imaging using PET is also gaining increasing interest as a tool in drug development, especially when applied to early proof of concept studies in man. In this chapter, the concept of molecular imaging is exemplified and the use of position-specific labeling of tracer molecules as a tool to gain understanding of complex biological processes will be discussed.
Positron emission tomography (PET) was applied to investigate the rate of turnover of pig brain M... more Positron emission tomography (PET) was applied to investigate the rate of turnover of pig brain MAO-B. For this purpose 11C-L-deprenyl was used as an irreversible ligand, which bind stoichiometrically to the enzyme. A tracer dose of 11C-L-deprenyl was injected and PET scans performed to obtain baseline deprenyl binding. A high dose of unlabelled deprenyl was then administered to inhibit the enzyme and tracer doses of 11C-L-deprenyl, with subsequent PET analyses, were given at 0, 2, 7, 21 and 42 days. The half-life for the turnover rate calculated was found to be 6.5 days.
Four enkephalin peptides Tyr-Gly-Gly-Phe-Met (Met-enkephalin), Tyr-D-Met-Gly-Phe-Pro-NH2(D-Met 2 ... more Four enkephalin peptides Tyr-Gly-Gly-Phe-Met (Met-enkephalin), Tyr-D-Met-Gly-Phe-Pro-NH2(D-Met 2 , Pro 5 -enkephalinamide), Tyr-D-Ala-Gly-Phe-Met-NH2 (DALA) and Tyr-D-Ala-D-Ala-Phe-Met-NH2 (TAAFM), Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2 (substance P) and one substance P-related octapeptide (Pro-Gln-Gln- Phe-Phe-Gly-Leu-Met-NH2) were labelled at the methyl group of methionine with 11C, which has a half-life of 20.4 minutes. The regional kinetics in the head, the brain and pituitary of Rhesus monkeys was followed with positron emission tomography after intravenous injection of each peptide. Total radioactivity in blood and urine was measured in a well counter and radiolabelled peptide fragments were analysed by liquid chromatography.
Positron emission tomography (PET) offers an unique opportunity to study regional distribution of... more Positron emission tomography (PET) offers an unique opportunity to study regional distribution of different compounds noninvasively. After i.v. injection of substances labelled with short-lived isotopes such as [11C], [13N], [15O], [18F] or [68Ga] the distribution of the radioactive label is measured as a function of time by means of a tomographic technique, based on the annihilation radiation produced during the process of positron emission.
Background: We previously demonstrated that radioligand binding to the 18 kDa translocator protei... more Background: We previously demonstrated that radioligand binding to the 18 kDa translocator protein (TSPO), a marker for inflammation, was greater in patients with Alzheimer’s disease (AD) than controls and correlated with clinical severity. We sought to determine the relationship between TSPO binding and progression of AD in a longitudinal study. Methods: Eleven patients with either AD or mild cognitive impairment and 8 age-matched controls underwent TSPO PET imaging with C-PBR28 at baseline and again after median follow up of 2.7 years. MRI, Pittsburgh Compound B (PIB) PET, and cognitive testing were also performed at baseline and follow up. PET images were corrected for partial volume effects. Regional C-PBR28 standardized uptake value ratios were determined using cerebellum as pseudo-reference region. PIB distribution volume ratios were determined using Logan graphical method with cerebellar reference. Results: Among patients, there was a significant correlation between increase in C-PBR28 binding and a decline in raw scores on Block Design, Trail Making part B, and Boston Naming Test. The strongest of such correlations occurred in prefrontal and parietal cortices (R > 0.68, P < 0.03). Percent change in C-PBR28 binding negatively correlated with %change in voxel count in prefrontal, parietal, and temporal cortices (R< -0.52, P< 0.03). Percent change in C-PBR28 correlated with %change in PIB binding in occipital cortex only (R 1⁄4 0.63, P 1⁄4 0.037). Controls showed no correlation between C-PBR28 binding and brain atrophy. Among patients, ApoE4 carriers (n 1⁄4 7) had greater increase in C-PBR28 binding than noncarriers (n1⁄4 4) in inferior temporal cortex (P1⁄4 0.042, Mann-Whitney U Test). Conclusions:TSPO increases with worsening clinical severity and cortical atrophy in AD. Larger studies are needed to better determine the relationship between TSPO, fibrillary amyloid load, and ApoE genotype. C-PBR28 PET has promise for monitoring AD progression.
Clinical efficacy of positron emission tomography, 1987
Positron emission tomography (PET) represents a new methodology of high research potential in cli... more Positron emission tomography (PET) represents a new methodology of high research potential in clinical neuropharmacology. It must be realised, however, that an effective utilization of the PET technique requires an interplay with the other approaches available in this area of research. Further, before introducing new applications of PET to man, preclinical studies in larger animals, particularly monkeys, is often a prerequisite.
To explore their potential use as in vivo tracers, the uptake of the amino acids glutamine, gluta... more To explore their potential use as in vivo tracers, the uptake of the amino acids glutamine, glutamate and aspartate, labeled with 11C or 14C, was evaluated in tumor cell aggregates, in vivo in rats and a few pilot studies with positron emission tomography (PET) in patients. The uptake in aggregates increased linearly with time, and was competitively inhibited by the same amino acids. The uptake of 14C-glutamate in carcinoid cells (BON) was inhibited by cystine but not by aspartate, contrary to the result in neuroblastoma (LAN). 6-Diazo-oxy-L-norleucine (a glutamine analogue) and Substance P had different effect on the uptake of glutamate in different cells. The metabolic fate of 14C-glutamate was evaluated with protein separation and with HPLC. The in vivo distribution in rats showed the highest uptake of 11C-glutamine and 11C-glutamate in pancreas and kidney, and of 11C-aspartate in the lung. In the human studies with PET, pancreas had the highest uptake followed by kidney with 11C...
We describe the use of molecules labeled with short-lived emitting radionuclides for molecular im... more We describe the use of molecules labeled with short-lived emitting radionuclides for molecular imaging in combination with the positron emission tomography technique. How to use molecular probes to visualize and quantitatively determine rates of specific biochemical events such as synaptic transmission, enzymatic processes and binding to specific receptor proteins is highlighted. The sensitivity of the PET technique and the ability to measure and validate relationships between molecular events and biological functions is a key factor for the successful application of PET in biomedical research. In specific applications, the opportunity of using molecules labeled in specific positions may be critical. Molecular imaging using PET is also gaining increasing interest as a tool in drug development, especially when applied to early proof of concept studies in man. In this chapter, the concept of molecular imaging is exemplified and the use of position-specific labeling of tracer molecules as a tool to gain understanding of complex biological processes will be discussed.
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 utilization as a measure of brain serotonin turnover, the selectivity of which was shown by pharmacological interventions in vivo.
Summary The in vivo dopamine precursor L-3,4-dihydroxyphenylalanine (L-DOPA) labelled with11 C in... more Summary The in vivo dopamine precursor L-3,4-dihydroxyphenylalanine (L-DOPA) labelled with11 C in the Β position has been used for positron emission tomography studies of L-DOPA utilization in the brain. The brain uptake and kinetics of L-[11 C]DOPA-derived radioactivity were studied in healthy male volunteers, and the specific utilization, i.e. decarboxylation rate of L-[11 C]DOPA in different brain areas, was quantified
We describe the use of molecules labeled with short-lived emitting radionuclides for molecular im... more We describe the use of molecules labeled with short-lived emitting radionuclides for molecular imaging in combination with the positron emission tomography technique. How to use molecular probes to visualize and quantitatively determine rates of specific biochemical events such as synaptic transmission, enzymatic processes and binding to specific receptor proteins is highlighted. The sensitivity of the PET technique and the ability to measure and validate relationships between molecular events and biological functions is a key factor for the successful application of PET in biomedical research. In specific applications, the opportunity of using molecules labeled in specific positions may be critical. Molecular imaging using PET is also gaining increasing interest as a tool in drug development, especially when applied to early proof of concept studies in man. In this chapter, the concept of molecular imaging is exemplified and the use of position-specific labeling of tracer molecules as a tool to gain understanding of complex biological processes will be discussed.
Positron emission tomography (PET) was applied to investigate the rate of turnover of pig brain M... more Positron emission tomography (PET) was applied to investigate the rate of turnover of pig brain MAO-B. For this purpose 11C-L-deprenyl was used as an irreversible ligand, which bind stoichiometrically to the enzyme. A tracer dose of 11C-L-deprenyl was injected and PET scans performed to obtain baseline deprenyl binding. A high dose of unlabelled deprenyl was then administered to inhibit the enzyme and tracer doses of 11C-L-deprenyl, with subsequent PET analyses, were given at 0, 2, 7, 21 and 42 days. The half-life for the turnover rate calculated was found to be 6.5 days.
Four enkephalin peptides Tyr-Gly-Gly-Phe-Met (Met-enkephalin), Tyr-D-Met-Gly-Phe-Pro-NH2(D-Met 2 ... more Four enkephalin peptides Tyr-Gly-Gly-Phe-Met (Met-enkephalin), Tyr-D-Met-Gly-Phe-Pro-NH2(D-Met 2 , Pro 5 -enkephalinamide), Tyr-D-Ala-Gly-Phe-Met-NH2 (DALA) and Tyr-D-Ala-D-Ala-Phe-Met-NH2 (TAAFM), Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2 (substance P) and one substance P-related octapeptide (Pro-Gln-Gln- Phe-Phe-Gly-Leu-Met-NH2) were labelled at the methyl group of methionine with 11C, which has a half-life of 20.4 minutes. The regional kinetics in the head, the brain and pituitary of Rhesus monkeys was followed with positron emission tomography after intravenous injection of each peptide. Total radioactivity in blood and urine was measured in a well counter and radiolabelled peptide fragments were analysed by liquid chromatography.
Positron emission tomography (PET) offers an unique opportunity to study regional distribution of... more Positron emission tomography (PET) offers an unique opportunity to study regional distribution of different compounds noninvasively. After i.v. injection of substances labelled with short-lived isotopes such as [11C], [13N], [15O], [18F] or [68Ga] the distribution of the radioactive label is measured as a function of time by means of a tomographic technique, based on the annihilation radiation produced during the process of positron emission.
Background: We previously demonstrated that radioligand binding to the 18 kDa translocator protei... more Background: We previously demonstrated that radioligand binding to the 18 kDa translocator protein (TSPO), a marker for inflammation, was greater in patients with Alzheimer’s disease (AD) than controls and correlated with clinical severity. We sought to determine the relationship between TSPO binding and progression of AD in a longitudinal study. Methods: Eleven patients with either AD or mild cognitive impairment and 8 age-matched controls underwent TSPO PET imaging with C-PBR28 at baseline and again after median follow up of 2.7 years. MRI, Pittsburgh Compound B (PIB) PET, and cognitive testing were also performed at baseline and follow up. PET images were corrected for partial volume effects. Regional C-PBR28 standardized uptake value ratios were determined using cerebellum as pseudo-reference region. PIB distribution volume ratios were determined using Logan graphical method with cerebellar reference. Results: Among patients, there was a significant correlation between increase in C-PBR28 binding and a decline in raw scores on Block Design, Trail Making part B, and Boston Naming Test. The strongest of such correlations occurred in prefrontal and parietal cortices (R > 0.68, P < 0.03). Percent change in C-PBR28 binding negatively correlated with %change in voxel count in prefrontal, parietal, and temporal cortices (R< -0.52, P< 0.03). Percent change in C-PBR28 correlated with %change in PIB binding in occipital cortex only (R 1⁄4 0.63, P 1⁄4 0.037). Controls showed no correlation between C-PBR28 binding and brain atrophy. Among patients, ApoE4 carriers (n 1⁄4 7) had greater increase in C-PBR28 binding than noncarriers (n1⁄4 4) in inferior temporal cortex (P1⁄4 0.042, Mann-Whitney U Test). Conclusions:TSPO increases with worsening clinical severity and cortical atrophy in AD. Larger studies are needed to better determine the relationship between TSPO, fibrillary amyloid load, and ApoE genotype. C-PBR28 PET has promise for monitoring AD progression.
Clinical efficacy of positron emission tomography, 1987
Positron emission tomography (PET) represents a new methodology of high research potential in cli... more Positron emission tomography (PET) represents a new methodology of high research potential in clinical neuropharmacology. It must be realised, however, that an effective utilization of the PET technique requires an interplay with the other approaches available in this area of research. Further, before introducing new applications of PET to man, preclinical studies in larger animals, particularly monkeys, is often a prerequisite.
To explore their potential use as in vivo tracers, the uptake of the amino acids glutamine, gluta... more To explore their potential use as in vivo tracers, the uptake of the amino acids glutamine, glutamate and aspartate, labeled with 11C or 14C, was evaluated in tumor cell aggregates, in vivo in rats and a few pilot studies with positron emission tomography (PET) in patients. The uptake in aggregates increased linearly with time, and was competitively inhibited by the same amino acids. The uptake of 14C-glutamate in carcinoid cells (BON) was inhibited by cystine but not by aspartate, contrary to the result in neuroblastoma (LAN). 6-Diazo-oxy-L-norleucine (a glutamine analogue) and Substance P had different effect on the uptake of glutamate in different cells. The metabolic fate of 14C-glutamate was evaluated with protein separation and with HPLC. The in vivo distribution in rats showed the highest uptake of 11C-glutamine and 11C-glutamate in pancreas and kidney, and of 11C-aspartate in the lung. In the human studies with PET, pancreas had the highest uptake followed by kidney with 11C...
We describe the use of molecules labeled with short-lived emitting radionuclides for molecular im... more We describe the use of molecules labeled with short-lived emitting radionuclides for molecular imaging in combination with the positron emission tomography technique. How to use molecular probes to visualize and quantitatively determine rates of specific biochemical events such as synaptic transmission, enzymatic processes and binding to specific receptor proteins is highlighted. The sensitivity of the PET technique and the ability to measure and validate relationships between molecular events and biological functions is a key factor for the successful application of PET in biomedical research. In specific applications, the opportunity of using molecules labeled in specific positions may be critical. Molecular imaging using PET is also gaining increasing interest as a tool in drug development, especially when applied to early proof of concept studies in man. In this chapter, the concept of molecular imaging is exemplified and the use of position-specific labeling of tracer molecules as a tool to gain understanding of complex biological processes will be discussed.
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 utilization as a measure of brain serotonin turnover, the selectivity of which was shown by pharmacological interventions in vivo.
Summary The in vivo dopamine precursor L-3,4-dihydroxyphenylalanine (L-DOPA) labelled with11 C in... more Summary The in vivo dopamine precursor L-3,4-dihydroxyphenylalanine (L-DOPA) labelled with11 C in the Β position has been used for positron emission tomography studies of L-DOPA utilization in the brain. The brain uptake and kinetics of L-[11 C]DOPA-derived radioactivity were studied in healthy male volunteers, and the specific utilization, i.e. decarboxylation rate of L-[11 C]DOPA in different brain areas, was quantified
Uploads
Papers by Bengt Långström