Gunnar Antoni | Uppsala University (original) (raw)
Papers by Gunnar Antoni
European Neuropsychopharmacology, 2009
BL-1020 is a potentially novel antipsychotic, which comprises the typical antipsychotic perphenaz... more BL-1020 is a potentially novel antipsychotic, which comprises the typical antipsychotic perphenazine linked by an ester bound to γ-aminobutyric acid (GABA), intending a simultaneous dopamine-2 (D 2 ) receptor blockade and GABA facilitation in the brain. This positron emission tomography (PET) study, using [ 11 C]raclopride, assessed the extent and duration of D 2 receptor occupancy (D 2 RO) and safety for single doses of BL-1020 in healthy male subjects. Overall, this study did not raise any safety concern. Single doses of 16-32 mg BL-1020 caused a dose dependent striatal D 2 RO. The 32 mg dose of BL-1020 resulted in an average D 2 RO of 44% at 4-6 h post dosing (pd), which declined to 33% at 24 h pd. Equimolar doses of BL-1020 and perphenazine resulted in similar D 2 RO at 24 h pd. Pharmacokinetic-pharmacodynamic analysis predicted that oral once daily administration of 32 mg BL-1020 would result in D 2 ROs ranging from 52 to 66% at a steady state.
Psychopharmacology, 2014
BMS-820836 is a novel antidepressant that selectively inhibits the reuptake of serotonin, norepin... more BMS-820836 is a novel antidepressant that selectively inhibits the reuptake of serotonin, norepinephrine, and dopamine. This Phase I study assessed safety, tolerability, and pharmacokinetics of multiple daily doses of BMS-820836 in healthy subjects. Central serotonin transporter (SERT) and dopamine transporter (DAT) occupancy were assessed using positron emission tomography and [(11)C]MADAM or [(11)C]PE2I, respectively. Fifty-seven healthy volunteers were enrolled in this double-blind, placebo-controlled, ascending multiple-dose study (ClincalTrials.gov identifier: NCT00892840). Eight participants in seven dose cohorts received oral doses of BMS-820836 (0.1-4 mg) or placebo for 14 days to assess safety, tolerability, and pharmacokinetics. Additionally, SERT and DAT occupancies were evaluated in 4-8 subjects per cohort at 8 h post-dose on Day 10 and 24 h post-dose on Day 15 at anticipated steady-state conditions. Most adverse events were mild to moderate; there were no serious safety concerns. Median maximum concentrations of BMS-820836 were observed at 4.0-5.5 h post-dose; estimated elimination half-life was 44-74 h. About 80 % striatal SERT occupancy was achieved after multiple doses of 0.5 mg BMS-820836 at both 8 and 24 h post-dose. Striatal DAT occupancy ranged between 14 % and 35 % at 8 h post-dose with a slight decline at 24 h post-dose. Multiple daily doses of up to 4 mg BMS-820836 appeared to be generally safe and well tolerated in a healthy population. SERT and DAT occupancies were in a range associated with therapeutic efficacy of antidepressants. Together with the pharmacokinetic profile of BMS-820836, the occupancy data support once-daily administration.
![Research paper thumbnail of Autoradiographic Mapping of 5-HT(1B/1D) Binding Sites in the Rhesus Monkey Brain Using [carbonyl-C]zolmitriptan](https://attachments.academia-assets.com/43580528/thumbnails/1.jpg)
](International journal of molecular imaging, 2011
Zolmitriptan is a serotonin 5-HT(1B/1D) receptor agonist that is an effective and well-tolerated ... more Zolmitriptan is a serotonin 5-HT(1B/1D) receptor agonist that is an effective and well-tolerated drug for migraine treatment. In a human positron emission tomography study, [(11)C]zolmitriptan crossed the blood-brain barrier but no clear pattern of regional uptake was discernable. The objective of this study was to map the binding of [(11)C]zolmitriptan in Rhesus monkey brain using whole hemisphere in vitro autoradiography with [(11)C]zolmitriptan as a radioligand. In saturation studies, [(11)C]zolmitriptan showed specific (90%) binding to a population of high-affinity binding sites (Kd 0.95-5.06 nM). There was regional distribution of binding sites with the highest density in the ventral pallidum, followed by the external globus pallidus, substantia nigra, visual cortex, and nucleus accumbens. In competitive binding studies with 5-HT(1) receptor antagonists, [(11)C]zolmitriptan binding was blocked by selective 5-HT(1B) and 5-HT(1D) ligands in all target areas. There was no apprecia...
Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 2014
Phosphodiesterase 10A (PDE10A) plays a key role in the regulation of brain striatal signaling, an... more Phosphodiesterase 10A (PDE10A) plays a key role in the regulation of brain striatal signaling, and several pharmaceutical companies currently investigate PDE10A inhibitors in clinical trials for various central nervous system diseases. A PDE10A PET ligand may provide evidence that a clinical drug candidate reaches and binds to the target. Here we describe the successful discovery and initial validation of the novel radiolabeled PDE10A ligand 5,8-dimethyl-2-[2-((1-(11)C-methyl)-4-phenyl-1H-imidazol-2-yl)-ethyl]-[1,2,4]triazolo[1,5-a]pyridine ((11)C-Lu AE92686) and its tritiated analog (3)H-Lu AE92686. Initial in vitro experiments suggested Lu AE92686 as a promising radioligand, and the corresponding tritiated and (11)C-labeled compounds were synthesized. (3)H-Lu AE92686 was evaluated as a ligand for in vivo occupancy studies in mice and rats, and (11)C-Lu AE92686 was evaluated as a PET tracer candidate in cynomolgus monkeys and in humans. (11)C-Lu AE92686 displayed high specificity a...
Journal of Computer Assisted Tomography, 1986
Two patients with pituitary tumors were examined with positron emission tomography (PET) after in... more Two patients with pituitary tumors were examined with positron emission tomography (PET) after intravenous administration of 11C-N-methylspiperone. In repeat studies the patients were given 1 mg of intravenous haloperidol prior to the administration of the radioligand to block the dopamine receptors. High uptakes of the radiolabeled ligand were seen in one of the tumors. With haloperidol pretreatment the uptake was lower, probably mainly showing the remaining unspecific binding. The most marked uptake and the largest effect of haloperidol pretreatment was seen in a patient with a hormonally active prolactinoma. Dopamine receptor binding in pituitary tumors can be demonstrated in vivo with PET, and quantification of this binding is possible using a compartmental model. This technique may be useful in improving our understanding of the variable response to medical treatment of prolactinomas with dopamine agonists as well as in the prediction of the effect of such treatment.
Acta Chemica Scandinavica, 1990
Anticancer research
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...
Acta chemica Scandinavica (Copenhagen, Denmark : 1989), 1999
Some examples of recent development of the synthesis of compounds labelled with short-lived beta(... more Some examples of recent development of the synthesis of compounds labelled with short-lived beta(+)-emitting radionuclides will be discussed with an emphasis on the importance of time in selecting a synthetic strategy. Furthermore the use of such labelled compounds to monitor certain processes in areas within the field of analytical chemistry and in various applications in drug development will be presented.
Aprepitant is a highly selective substance P (neurokinin 1 [NK(1)] receptor) antagonist that sign... more Aprepitant is a highly selective substance P (neurokinin 1 [NK(1)] receptor) antagonist that significantly improves the pharmacotherapy of acute and delayed highly emetogenic chemotherapy-induced nausea and vomiting, probably through an action in the brain stem region of the central nervous system. Here, we report the use of positron emission tomography imaging with the NK(1) receptor binding-selective tracer [(18)F]SPA-RQC to determine the levels of central NK(1) receptor occupancy achieved by therapeutically relevant doses of aprepitant in healthy humans. Two single-blind, randomized, placebo-controlled studies in healthy subjects were performed. The first study evaluated the plasma concentration-occupancy relationships for aprepitant dosed orally at 10, 30, 100, or 300 mg, or placebo (n = 12). The second study similarly evaluated oral aprepitant 30 mg and placebo (n = 4). In each study, dosing was once daily for 14 consecutive days. Data from both studies were combined for analyses. The ratio of striatal/cerebellar [(18)F]SPA-RQ (high receptor density region/reference region lacking receptors) was used to calculate trough receptor occupancy 24 hours after the last dose of aprepitant. Brain NK(1) receptor occupancy increased after oral aprepitant dosing in both a plasma concentration-related (r =.97; 95% confidence interval [CI] =.94-1.00, p <.001) and a dose-related (r =.94; 95% CI =.86-1.00, p <.001) fashion. High (> or =90%) receptor occupancy was achieved at doses of 100 mg/day or greater. The plasma concentrations of aprepitant that achieved 50% and 90% occupancy were estimated as approximately 10 ng/mL and approximately 100 ng/mL, respectively. Positron emission tomography imaging with [(18)F]SPA-RQ allows brain NK(1) receptor occupancy by aprepitant to be predicted from plasma drug concentrations and can be used to guide dose selection for clinical trials of NK(1) receptor antagonists in central therapeutic indications.
Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 2014
Phosphodiesterase 10A (PDE10A) plays a key role in the regulation of brain striatal signaling, an... more Phosphodiesterase 10A (PDE10A) plays a key role in the regulation of brain striatal signaling, and several pharmaceutical companies currently investigate PDE10A inhibitors in clinical trials for various central nervous system diseases. A PDE10A PET ligand may provide evidence that a clinical drug candidate reaches and binds to the target. Here we describe the successful discovery and initial validation of the novel radiolabeled PDE10A ligand 5,8-dimethyl-2-[2-((1-(11)C-methyl)-4-phenyl-1H-imidazol-2-yl)-ethyl]-[1,2,4]triazolo[1,5-a]pyridine ((11)C-Lu AE92686) and its tritiated analog (3)H-Lu AE92686. Initial in vitro experiments suggested Lu AE92686 as a promising radioligand, and the corresponding tritiated and (11)C-labeled compounds were synthesized. (3)H-Lu AE92686 was evaluated as a ligand for in vivo occupancy studies in mice and rats, and (11)C-Lu AE92686 was evaluated as a PET tracer candidate in cynomolgus monkeys and in humans. (11)C-Lu AE92686 displayed high specificity a...
![Research paper thumbnail of Positron emission tomography ligand [11C]5-hydroxy-tryptophan can be used as a surrogate marker for the human endocrine pancreas](https://attachments.academia-assets.com/43879572/thumbnails/1.jpg)
](Diabetes, 2014
In humans, a well-developed serotonin system is localized to the pancreatic islets while being ab... more In humans, a well-developed serotonin system is localized to the pancreatic islets while being absent in exocrine pancreas. Assessment of pancreatic serotonin biosynthesis could therefore be used to estimate the human endocrine pancreas. Proof of concept was tested in a prospective clinical trial by comparisons of type 1 diabetic (T1D) patients, with extensive reduction of β-cells, with healthy volunteers (HVs). C-peptide-negative (i.e., insulin-deficient) T1D subjects (n = 10) and HVs (n = 9) underwent dynamic positron emission tomography with the radiolabeled serotonin precursor [(11)C]5-hydroxy-tryptophan ([(11)C]5-HTP). A significant accumulation of [(11)C]5-HTP was obtained in the pancreas of the HVs, with large interindividual variation. A substantial and highly significant reduction (66%) in the pancreatic uptake of [(11)C]5-HTP in T1D subjects was observed, and this was most evident in the corpus and caudal regions of the pancreas where β-cells normally are the major constit...
Acta Chemica Scandinavica, 1992
Plasma concentrations, maximum regional brain concentrations, and specific regional binding in th... more Plasma concentrations, maximum regional brain concentrations, and specific regional binding in the brain after administration of 0, 0.1, and 0.2 mg/kg doses of (S)-ketamine were measured in a randomized, double-blind, crossover study in five volunteers and were related to induced effects such as analgesia, amnesia, and mood changes. Specific binding in the brain was assessed by simultaneous administration of (S)-[N-methyl-11C]ketamine quantified by positron emission tomography. High radioactivities in the brain corresponded to regional distribution of N-methyl-D-aspartate receptor complexes. A significant and dose-dependent reduction of binding was measured as a result of displacement of (S)-[N-methyl-11C]ketamine. Memory impairment and psychotomimetic effects were related to dose, plasma concentration 4 minutes after administration, and decreased regional binding of (S)-ketamine in the brain and were consistently seen at plasma and maximum regional brain (S)-ketamine concentrations higher than 70 and 500 ng/ml, respectively. The magnitude of specific binding of (S)-ketamine, measured with positron emission tomography, can be related directly to drug effects.
Clinical Pharmacology & Therapeutics, 1995
The deposition of 11C-nicotine in the respiratory tract from a nicotine vapor inhaler was studied... more The deposition of 11C-nicotine in the respiratory tract from a nicotine vapor inhaler was studied by means of positron emission tomography (PET) in an intrasubject comparison of six healthy smokers using two modes of inhalation: one with shallow, frequent inhalations ("buccal mode") and one with deep inhalations ("pulmonary mode"). An average of 15% of the radioactivity was released from the vapor inhaler after 5 minutes of inhalation. Approximately 45% of the dose released was found in the oral cavity. A significant amount of radioactivity, 10%, was observed in the esophagus, suggesting transfer of a major fraction of the dose to the stomach. Only a minor fraction, 5%, was found in the lungs, followed by 2% in the bronchi and 1% in the trachea. The deposition in the oral cavity closely followed a linear pattern during the 5 minutes of inhalation and was followed by a rapid elimination from the oral cavity, with an average half-life of 18 minutes. Only 8% of the dose released remained in the oral cavity 45 minutes after the end of inhalation. On the other hand, the dose fraction of about 14% distributed into the body tissue compartment at the end of inhalation had risen to 60% at that late time point. No statistically or clinically important differences were observed between the buccal and the pulmonary mode of inhalation in either deposition pattern or elimination rates.
Acta Chemica Scandinavica, 1999
![Research paper thumbnail of [11C]Carbon Monoxide Has Become a Versatile Precursor](https://attachments.academia-assets.com/43879556/thumbnails/1.jpg)
](ChemInform, 2003
Organic chemistry Z 0200 [ 11 C]Carbon Monoxide Has Become a Versatile Precursor -[17 refs.]. -(K... more Organic chemistry Z 0200 [ 11 C]Carbon Monoxide Has Become a Versatile Precursor -[17 refs.]. -(KIHLBERG, T.; ANTONI, G.; BJORKMAN, M.; KARIMI, F.; RAHMAN, O.; OGREN, M.; LANGSTROM, B.; Synth.
![Research paper thumbnail of Organ biodistribution of Germanium-68 in rat in the presence and absence of [(68)Ga]Ga-DOTA-TOC for the extrapolation to the human organ and whole-body radiation dosimetry](https://attachments.academia-assets.com/43879571/thumbnails/1.jpg)
](American journal of nuclear medicine and molecular imaging, 2013
Positron Emission Tomography (PET) and in particular gallium-68 ((68)Ga) applications are growing... more Positron Emission Tomography (PET) and in particular gallium-68 ((68)Ga) applications are growing exponentially worldwide contributing to the expansion of nuclear medicine and personalized management of patients. The significance of (68)Ga utility is reflected in the implementation of European Pharmacopoeia monographs. However, there is one crucial point in the monographs that might limit the use of the generators and consequently expansion of (68)Ga applications and that is the limit of 0.001% of Germanium-68 ((68)Ge(IV)) radioactivity content in a radiopharmaceutical. We have investigated the organ distribution of (68)Ge(IV) in rat and estimated human dosimetry parameters in order to provide experimental evidence for the determination and justification of the (68)Ge(IV) limit. Male and female rats were injected in the tail vein with formulated [(68)Ge]GeCl4 in the absence or presence of [(68)Ga]Ga-DOTA-TOC. The tissue radioactivity distribution data was extrapolated for the estima...
Journal of Nuclear Medicine, 2014
Serotonergic biosynthesis in the endocrine pancreas, of which the islets of Langerhans is the maj... more Serotonergic biosynthesis in the endocrine pancreas, of which the islets of Langerhans is the major constituent, has been implicated in insulin release and β cell proliferation. In this study, we investigated the feasibility of quantitative noninvasive imaging of the serotonergic metabolism in the pancreas using the PET tracer 11 C-5-hydroxy-Ltryptophan ( 11 C-5-HTP). Methods: Uptake of 11 C-5-HTP, and its specificity for key enzymes in the serotonergic metabolic pathway, was assessed in vitro (INS-1 and PANC1 cells and human islet and exocrine preparations) and in vivo (nonhuman primates and healthy and diabetic rats). Results: In vitro tracer uptake in endocrine cells (INS-1 and human islets), but not PANC1 and exocrine cells, was mediated specifically by intracellular conversion into serotonin. Pancreatic uptake of 11 C-5-HTP in nonhuman primates was markedly decreased by inhibition of the enzyme dopa decarboxylase, which converts 11 C-5-HTP to 11 C-serotonin and increased after inhibition of monoamine oxidase-A, the main enzyme responsible for serotonin degradation. Uptake in the rat pancreas was similarly modulated by inhibition of monoamine oxidase-A and was reduced in animals with induced diabetes. Conclusion: The PET tracer 11 C-5-HTP can be used for quantitative imaging of the serotonergic system in the endocrine pancreas.
Journal of Labelled Compounds and Radiopharmaceuticals, 2004
Summary A method is presented for preparing [1-11C]ethyl iodide from [11C]carbon monoxide. The me... more Summary A method is presented for preparing [1-11C]ethyl iodide from [11C]carbon monoxide. The method utilizes methyl iodide and [11C]carbon monoxide in a palladium-mediated carbonylation reaction to form a mixture of [1-11C]acetic acid and [1-11C]methyl acetate. ...
European Neuropsychopharmacology, 2009
BL-1020 is a potentially novel antipsychotic, which comprises the typical antipsychotic perphenaz... more BL-1020 is a potentially novel antipsychotic, which comprises the typical antipsychotic perphenazine linked by an ester bound to γ-aminobutyric acid (GABA), intending a simultaneous dopamine-2 (D 2 ) receptor blockade and GABA facilitation in the brain. This positron emission tomography (PET) study, using [ 11 C]raclopride, assessed the extent and duration of D 2 receptor occupancy (D 2 RO) and safety for single doses of BL-1020 in healthy male subjects. Overall, this study did not raise any safety concern. Single doses of 16-32 mg BL-1020 caused a dose dependent striatal D 2 RO. The 32 mg dose of BL-1020 resulted in an average D 2 RO of 44% at 4-6 h post dosing (pd), which declined to 33% at 24 h pd. Equimolar doses of BL-1020 and perphenazine resulted in similar D 2 RO at 24 h pd. Pharmacokinetic-pharmacodynamic analysis predicted that oral once daily administration of 32 mg BL-1020 would result in D 2 ROs ranging from 52 to 66% at a steady state.
Psychopharmacology, 2014
BMS-820836 is a novel antidepressant that selectively inhibits the reuptake of serotonin, norepin... more BMS-820836 is a novel antidepressant that selectively inhibits the reuptake of serotonin, norepinephrine, and dopamine. This Phase I study assessed safety, tolerability, and pharmacokinetics of multiple daily doses of BMS-820836 in healthy subjects. Central serotonin transporter (SERT) and dopamine transporter (DAT) occupancy were assessed using positron emission tomography and [(11)C]MADAM or [(11)C]PE2I, respectively. Fifty-seven healthy volunteers were enrolled in this double-blind, placebo-controlled, ascending multiple-dose study (ClincalTrials.gov identifier: NCT00892840). Eight participants in seven dose cohorts received oral doses of BMS-820836 (0.1-4 mg) or placebo for 14 days to assess safety, tolerability, and pharmacokinetics. Additionally, SERT and DAT occupancies were evaluated in 4-8 subjects per cohort at 8 h post-dose on Day 10 and 24 h post-dose on Day 15 at anticipated steady-state conditions. Most adverse events were mild to moderate; there were no serious safety concerns. Median maximum concentrations of BMS-820836 were observed at 4.0-5.5 h post-dose; estimated elimination half-life was 44-74 h. About 80 % striatal SERT occupancy was achieved after multiple doses of 0.5 mg BMS-820836 at both 8 and 24 h post-dose. Striatal DAT occupancy ranged between 14 % and 35 % at 8 h post-dose with a slight decline at 24 h post-dose. Multiple daily doses of up to 4 mg BMS-820836 appeared to be generally safe and well tolerated in a healthy population. SERT and DAT occupancies were in a range associated with therapeutic efficacy of antidepressants. Together with the pharmacokinetic profile of BMS-820836, the occupancy data support once-daily administration.
International journal of molecular imaging, 2011
Zolmitriptan is a serotonin 5-HT(1B/1D) receptor agonist that is an effective and well-tolerated ... more Zolmitriptan is a serotonin 5-HT(1B/1D) receptor agonist that is an effective and well-tolerated drug for migraine treatment. In a human positron emission tomography study, [(11)C]zolmitriptan crossed the blood-brain barrier but no clear pattern of regional uptake was discernable. The objective of this study was to map the binding of [(11)C]zolmitriptan in Rhesus monkey brain using whole hemisphere in vitro autoradiography with [(11)C]zolmitriptan as a radioligand. In saturation studies, [(11)C]zolmitriptan showed specific (90%) binding to a population of high-affinity binding sites (Kd 0.95-5.06 nM). There was regional distribution of binding sites with the highest density in the ventral pallidum, followed by the external globus pallidus, substantia nigra, visual cortex, and nucleus accumbens. In competitive binding studies with 5-HT(1) receptor antagonists, [(11)C]zolmitriptan binding was blocked by selective 5-HT(1B) and 5-HT(1D) ligands in all target areas. There was no apprecia...
Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 2014
Phosphodiesterase 10A (PDE10A) plays a key role in the regulation of brain striatal signaling, an... more Phosphodiesterase 10A (PDE10A) plays a key role in the regulation of brain striatal signaling, and several pharmaceutical companies currently investigate PDE10A inhibitors in clinical trials for various central nervous system diseases. A PDE10A PET ligand may provide evidence that a clinical drug candidate reaches and binds to the target. Here we describe the successful discovery and initial validation of the novel radiolabeled PDE10A ligand 5,8-dimethyl-2-[2-((1-(11)C-methyl)-4-phenyl-1H-imidazol-2-yl)-ethyl]-[1,2,4]triazolo[1,5-a]pyridine ((11)C-Lu AE92686) and its tritiated analog (3)H-Lu AE92686. Initial in vitro experiments suggested Lu AE92686 as a promising radioligand, and the corresponding tritiated and (11)C-labeled compounds were synthesized. (3)H-Lu AE92686 was evaluated as a ligand for in vivo occupancy studies in mice and rats, and (11)C-Lu AE92686 was evaluated as a PET tracer candidate in cynomolgus monkeys and in humans. (11)C-Lu AE92686 displayed high specificity a...
Journal of Computer Assisted Tomography, 1986
Two patients with pituitary tumors were examined with positron emission tomography (PET) after in... more Two patients with pituitary tumors were examined with positron emission tomography (PET) after intravenous administration of 11C-N-methylspiperone. In repeat studies the patients were given 1 mg of intravenous haloperidol prior to the administration of the radioligand to block the dopamine receptors. High uptakes of the radiolabeled ligand were seen in one of the tumors. With haloperidol pretreatment the uptake was lower, probably mainly showing the remaining unspecific binding. The most marked uptake and the largest effect of haloperidol pretreatment was seen in a patient with a hormonally active prolactinoma. Dopamine receptor binding in pituitary tumors can be demonstrated in vivo with PET, and quantification of this binding is possible using a compartmental model. This technique may be useful in improving our understanding of the variable response to medical treatment of prolactinomas with dopamine agonists as well as in the prediction of the effect of such treatment.
Acta Chemica Scandinavica, 1990
Anticancer research
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...
Acta chemica Scandinavica (Copenhagen, Denmark : 1989), 1999
Some examples of recent development of the synthesis of compounds labelled with short-lived beta(... more Some examples of recent development of the synthesis of compounds labelled with short-lived beta(+)-emitting radionuclides will be discussed with an emphasis on the importance of time in selecting a synthetic strategy. Furthermore the use of such labelled compounds to monitor certain processes in areas within the field of analytical chemistry and in various applications in drug development will be presented.
Aprepitant is a highly selective substance P (neurokinin 1 [NK(1)] receptor) antagonist that sign... more Aprepitant is a highly selective substance P (neurokinin 1 [NK(1)] receptor) antagonist that significantly improves the pharmacotherapy of acute and delayed highly emetogenic chemotherapy-induced nausea and vomiting, probably through an action in the brain stem region of the central nervous system. Here, we report the use of positron emission tomography imaging with the NK(1) receptor binding-selective tracer [(18)F]SPA-RQC to determine the levels of central NK(1) receptor occupancy achieved by therapeutically relevant doses of aprepitant in healthy humans. Two single-blind, randomized, placebo-controlled studies in healthy subjects were performed. The first study evaluated the plasma concentration-occupancy relationships for aprepitant dosed orally at 10, 30, 100, or 300 mg, or placebo (n = 12). The second study similarly evaluated oral aprepitant 30 mg and placebo (n = 4). In each study, dosing was once daily for 14 consecutive days. Data from both studies were combined for analyses. The ratio of striatal/cerebellar [(18)F]SPA-RQ (high receptor density region/reference region lacking receptors) was used to calculate trough receptor occupancy 24 hours after the last dose of aprepitant. Brain NK(1) receptor occupancy increased after oral aprepitant dosing in both a plasma concentration-related (r =.97; 95% confidence interval [CI] =.94-1.00, p <.001) and a dose-related (r =.94; 95% CI =.86-1.00, p <.001) fashion. High (> or =90%) receptor occupancy was achieved at doses of 100 mg/day or greater. The plasma concentrations of aprepitant that achieved 50% and 90% occupancy were estimated as approximately 10 ng/mL and approximately 100 ng/mL, respectively. Positron emission tomography imaging with [(18)F]SPA-RQ allows brain NK(1) receptor occupancy by aprepitant to be predicted from plasma drug concentrations and can be used to guide dose selection for clinical trials of NK(1) receptor antagonists in central therapeutic indications.
Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 2014
Phosphodiesterase 10A (PDE10A) plays a key role in the regulation of brain striatal signaling, an... more Phosphodiesterase 10A (PDE10A) plays a key role in the regulation of brain striatal signaling, and several pharmaceutical companies currently investigate PDE10A inhibitors in clinical trials for various central nervous system diseases. A PDE10A PET ligand may provide evidence that a clinical drug candidate reaches and binds to the target. Here we describe the successful discovery and initial validation of the novel radiolabeled PDE10A ligand 5,8-dimethyl-2-[2-((1-(11)C-methyl)-4-phenyl-1H-imidazol-2-yl)-ethyl]-[1,2,4]triazolo[1,5-a]pyridine ((11)C-Lu AE92686) and its tritiated analog (3)H-Lu AE92686. Initial in vitro experiments suggested Lu AE92686 as a promising radioligand, and the corresponding tritiated and (11)C-labeled compounds were synthesized. (3)H-Lu AE92686 was evaluated as a ligand for in vivo occupancy studies in mice and rats, and (11)C-Lu AE92686 was evaluated as a PET tracer candidate in cynomolgus monkeys and in humans. (11)C-Lu AE92686 displayed high specificity a...
Diabetes, 2014
In humans, a well-developed serotonin system is localized to the pancreatic islets while being ab... more In humans, a well-developed serotonin system is localized to the pancreatic islets while being absent in exocrine pancreas. Assessment of pancreatic serotonin biosynthesis could therefore be used to estimate the human endocrine pancreas. Proof of concept was tested in a prospective clinical trial by comparisons of type 1 diabetic (T1D) patients, with extensive reduction of β-cells, with healthy volunteers (HVs). C-peptide-negative (i.e., insulin-deficient) T1D subjects (n = 10) and HVs (n = 9) underwent dynamic positron emission tomography with the radiolabeled serotonin precursor [(11)C]5-hydroxy-tryptophan ([(11)C]5-HTP). A significant accumulation of [(11)C]5-HTP was obtained in the pancreas of the HVs, with large interindividual variation. A substantial and highly significant reduction (66%) in the pancreatic uptake of [(11)C]5-HTP in T1D subjects was observed, and this was most evident in the corpus and caudal regions of the pancreas where β-cells normally are the major constit...
Acta Chemica Scandinavica, 1992
Plasma concentrations, maximum regional brain concentrations, and specific regional binding in th... more Plasma concentrations, maximum regional brain concentrations, and specific regional binding in the brain after administration of 0, 0.1, and 0.2 mg/kg doses of (S)-ketamine were measured in a randomized, double-blind, crossover study in five volunteers and were related to induced effects such as analgesia, amnesia, and mood changes. Specific binding in the brain was assessed by simultaneous administration of (S)-[N-methyl-11C]ketamine quantified by positron emission tomography. High radioactivities in the brain corresponded to regional distribution of N-methyl-D-aspartate receptor complexes. A significant and dose-dependent reduction of binding was measured as a result of displacement of (S)-[N-methyl-11C]ketamine. Memory impairment and psychotomimetic effects were related to dose, plasma concentration 4 minutes after administration, and decreased regional binding of (S)-ketamine in the brain and were consistently seen at plasma and maximum regional brain (S)-ketamine concentrations higher than 70 and 500 ng/ml, respectively. The magnitude of specific binding of (S)-ketamine, measured with positron emission tomography, can be related directly to drug effects.
Clinical Pharmacology & Therapeutics, 1995
The deposition of 11C-nicotine in the respiratory tract from a nicotine vapor inhaler was studied... more The deposition of 11C-nicotine in the respiratory tract from a nicotine vapor inhaler was studied by means of positron emission tomography (PET) in an intrasubject comparison of six healthy smokers using two modes of inhalation: one with shallow, frequent inhalations ("buccal mode") and one with deep inhalations ("pulmonary mode"). An average of 15% of the radioactivity was released from the vapor inhaler after 5 minutes of inhalation. Approximately 45% of the dose released was found in the oral cavity. A significant amount of radioactivity, 10%, was observed in the esophagus, suggesting transfer of a major fraction of the dose to the stomach. Only a minor fraction, 5%, was found in the lungs, followed by 2% in the bronchi and 1% in the trachea. The deposition in the oral cavity closely followed a linear pattern during the 5 minutes of inhalation and was followed by a rapid elimination from the oral cavity, with an average half-life of 18 minutes. Only 8% of the dose released remained in the oral cavity 45 minutes after the end of inhalation. On the other hand, the dose fraction of about 14% distributed into the body tissue compartment at the end of inhalation had risen to 60% at that late time point. No statistically or clinically important differences were observed between the buccal and the pulmonary mode of inhalation in either deposition pattern or elimination rates.
Acta Chemica Scandinavica, 1999
ChemInform, 2003
Organic chemistry Z 0200 [ 11 C]Carbon Monoxide Has Become a Versatile Precursor -[17 refs.]. -(K... more Organic chemistry Z 0200 [ 11 C]Carbon Monoxide Has Become a Versatile Precursor -[17 refs.]. -(KIHLBERG, T.; ANTONI, G.; BJORKMAN, M.; KARIMI, F.; RAHMAN, O.; OGREN, M.; LANGSTROM, B.; Synth.
American journal of nuclear medicine and molecular imaging, 2013
Positron Emission Tomography (PET) and in particular gallium-68 ((68)Ga) applications are growing... more Positron Emission Tomography (PET) and in particular gallium-68 ((68)Ga) applications are growing exponentially worldwide contributing to the expansion of nuclear medicine and personalized management of patients. The significance of (68)Ga utility is reflected in the implementation of European Pharmacopoeia monographs. However, there is one crucial point in the monographs that might limit the use of the generators and consequently expansion of (68)Ga applications and that is the limit of 0.001% of Germanium-68 ((68)Ge(IV)) radioactivity content in a radiopharmaceutical. We have investigated the organ distribution of (68)Ge(IV) in rat and estimated human dosimetry parameters in order to provide experimental evidence for the determination and justification of the (68)Ge(IV) limit. Male and female rats were injected in the tail vein with formulated [(68)Ge]GeCl4 in the absence or presence of [(68)Ga]Ga-DOTA-TOC. The tissue radioactivity distribution data was extrapolated for the estima...
Journal of Nuclear Medicine, 2014
Serotonergic biosynthesis in the endocrine pancreas, of which the islets of Langerhans is the maj... more Serotonergic biosynthesis in the endocrine pancreas, of which the islets of Langerhans is the major constituent, has been implicated in insulin release and β cell proliferation. In this study, we investigated the feasibility of quantitative noninvasive imaging of the serotonergic metabolism in the pancreas using the PET tracer 11 C-5-hydroxy-Ltryptophan ( 11 C-5-HTP). Methods: Uptake of 11 C-5-HTP, and its specificity for key enzymes in the serotonergic metabolic pathway, was assessed in vitro (INS-1 and PANC1 cells and human islet and exocrine preparations) and in vivo (nonhuman primates and healthy and diabetic rats). Results: In vitro tracer uptake in endocrine cells (INS-1 and human islets), but not PANC1 and exocrine cells, was mediated specifically by intracellular conversion into serotonin. Pancreatic uptake of 11 C-5-HTP in nonhuman primates was markedly decreased by inhibition of the enzyme dopa decarboxylase, which converts 11 C-5-HTP to 11 C-serotonin and increased after inhibition of monoamine oxidase-A, the main enzyme responsible for serotonin degradation. Uptake in the rat pancreas was similarly modulated by inhibition of monoamine oxidase-A and was reduced in animals with induced diabetes. Conclusion: The PET tracer 11 C-5-HTP can be used for quantitative imaging of the serotonergic system in the endocrine pancreas.
Journal of Labelled Compounds and Radiopharmaceuticals, 2004
Summary A method is presented for preparing [1-11C]ethyl iodide from [11C]carbon monoxide. The me... more Summary A method is presented for preparing [1-11C]ethyl iodide from [11C]carbon monoxide. The method utilizes methyl iodide and [11C]carbon monoxide in a palladium-mediated carbonylation reaction to form a mixture of [1-11C]acetic acid and [1-11C]methyl acetate. ...