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Biomedical subjects

G Stöcklin

Publications and source records attributed to G Stöcklin.

At least 55 records · Page 3Linked to original sources
PubMed1986

Regional cerebral pharmacokinetics of the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine as examined by positron emission tomography in a baboon is altered by tranylcypromine.

The selective dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) has chemical and metabolic characteristics which allow its in vivo tissue distribution to be studied using positron emission tomography (PET). The cerebral pharmacokinetics of [11C]MPTP labelled at the N-methyl position was quantitatively traced in the living brain of an anesthetized baboon using PET, and the effect of administration of the monoamine oxidase (MAO) inhibitor tranylcypromine on this regional cerebral distribution was determined in the same animal. Following injection of [1C]MPTP, radioactivity rapidly concentrated in the basal ganglia of the primate's brain. This in vivo localization was prevented by prior administration of tranylcypromine, suggesting that it is oxidized metabolites of MPTP which are sequestered by dopaminergic neurons. Radioactivity rapidly localized preferentially in the basal ganglia of the primate brain, and this in vivo localization was blocked by prior administration of the MAO inhibitor tranylcypromine.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1986

Evaluation of 75Br-labelled butyrophenone neuroleptics for imaging cerebral dopaminergic receptor areas using positron emission tomography.

A comparative evaluation of three radiobrominated butyrophenone neuroleptics--bromospiperone (BSP), brombenperidol (BBP), and bromperidol (BP)--was made to assess the applicability of these compounds as radiopharmaceuticals labelled with the positron emitter 75Br (T1/2 = 1.6 h) for mapping cerebral dopaminergic receptor areas non-invasively with positron emission tomography (PET). BSP, BBP, and BP were prepared in high specific activities with high radiochemical yields, using electrophilic reactions with no-carrier-added 77Br- or 75Br-. Screening tests in rats using 77Br-labelled compounds indicated D2-specific localization for 77Br-BSP and 77Br-BBP, whereas PET experiments in baboons showed that only 75Br-BSP preferentially localized in cerebral tissues rich in dopaminergic receptors. The data suggest an inverse relationship between cerebral uptake and receptor-specific localization, which was attributed to a complicated interplay between the D2 receptor binding affinity, lipophilicity, % ionization and molecular weight of the radioligand, and the binding capacity of the cerebral tissues. 75Br-BSP gave a striatum-to-cerebellum ratio of 3 in baboon brain 5 h post-injection, which allowed visualization of dopaminergic-receptor-containing areas of the living brain using PET.

Animals↗
PubMed1986

Efficient stereospecific synthesis of no-carrier-added 2-[18F]-fluoro-2-deoxy-D-glucose using aminopolyether supported nucleophilic substitution.

An aminopolyether mediated synthesis of fluorine-18 (18F) 2-fluoro-2-deoxy-D-glucose (FDG) has been developed. The nucleophilic fluorination with accelerator-produced [18F]fluoride works at the no-carrier-added level and gives epimerically pure 2-18FDG with an uncorrected radiochemical yield of a maximum 50% in a synthesis time of approximately 50 min from EOB.

Chemical Phenomena↗
PubMed1985

In vivo determination of the kinetic parameters of glucose transport in the human brain using 11C-methyl-D-glucose (CMG) and dynamic positron emission tomography (dPET).

A method was developed to measure simultaneously the rate constants for glucose influx and glucose efflux, and the Michaelis-Menten constant (KM) and maximal velocity (Vmax) for glucose transport across the blood-brain barrier (BBB) in any selected brain area. Moreover, on the basis of a mathematical model, the local perfusion rate (LPR) and local unidirectional glucose transport rate (LUGTR) are calculated in terms of parameters of the time-activity curves registered over different brain regions; 11C-methyl-D-glucose (CMG) is used as an indicator. The transaxial distribution of activity in the organism is registered using dynamic positron-emission tomography (dPET). The method was used in 4 normal subjects and 50 patients with ischemic brain disease. In normals, the rate constant for CMG efflux was found to be 0.25 +/- 0.04 min-1 in the cortex and 0.12 +/- 0.02 min-1 in white matter. In the cortex, the KM was found to be 6.42 mumol/g and the Vmax was 2.46 mumol/g per minute. The LUGTR ranged from 0.43 to 0.6 mumol/g per minute in the cortex, and from 0.09 to 0.12 mumol/g per minute in white matter. The LPR was calculated to be 0.80-0.98 ml/g per minute for the cortex and 0.2-0.4 ml/g per minute for white matter. In patients with stroke, the ischemic defects appeared to be larger in CMG scans than in computed x-ray tomography (CT) scans. Prolonged reversible ischemic neurological deficit was associated with a significant fall in the LUGTR but no change in the LPR in the corresponding cerebral cortex. Normal LUGTR and significantly decreased LPR were registered in a patient with progressive occlusion of the middle cerebral artery. In a patient with transient ischemic attacks, a slightly reduced LPR and a disproportionally reduced LUGTR were observed before operation. After extra- and intracranial bypass surgery, the LPR became normal, whereas the LUGTR increased but did not achieve normal values.

3-O-Methylglucose↗
PubMed1985

Effect of lipophilicity on the in vivo localization of radiolabelled spiperone analogues.

A series of N-alkylated and para-brominated analogues of spiperone were synthesized to ascertain the effect of lipophilicity on the in vivo localization of neuroleptics. While the IC50 for D2 receptor binding was within the same order of magnitude for these compounds, the calculated octanol-water partition coefficients varied 300-fold. When the in vivo distribution data for 77Br-labelled compounds were compared with previous data for 18F- and 11C-labelled analogues it was seen that the highest cerebral uptake was for bromospiperone, but the optimum striatum-to-cerebellum and brain-to-blood concentrations were achieved by N-methyl spiperone. The implications of these results for radiopharmaceutical design or medicinal chemistry are discussed.

Animals↗
PubMed1985

Chemical and biological consequences of the radioactive decay of iodine-125 in plasmid DNA.

Doubly labeled [U-14C, 5-125I]iododeoxycytidine (IdC) triphosphate was synthesized and incorporated enzymatically into defined positions of the plasmid pBR322. After storage under various conditions, the stable end products were analyzed using radio-GC, radio-HPLC, and electron microscopy. In addition, solutions of 14C-IdC-labeled DNA containing Na125I as an internal radiation source were studied to investigate the influence of internal radiolysis. Transmutation of the covalently bound 125I leads to complete destruction of the labeled nucleotide, giving rise to 14CO2 and 14CO as major products. Fragmentation of the pyrimidine base is independent of solvent and DNA configuration. Internal radiolysis caused by Na125I leads to only minor damage. Electron microscopy studies reveal that decay-induced double strand breaks (dsb) occur both at the site of decay and in areas as far as hundreds of base pairs apart from that site. Number and distribution of the breaks is strongly dependent on solvent and DNA configuration. A direct correlation exists between the extent of fragmentation of the nucleotide and the mean number of dsb.

Bromodeoxycytidine↗
PubMed1984

Specific in vivo binding of 77Br-brombenperidol in rat brain.

The in vivo binding of the radiobrominated neuroleptic brombenperidol in rat brain was studied. The accumulation of the radiolabeled neuroleptic was high in the striatum and relatively low in the cerebellum, cortex, and blood. Striatal binding of brombenperidol was saturable and displaced by subsequent administration of benperidol. The rationale for the development of 75Br-brombenperidol as a radiopharmaceutical for the non-invasive imaging of cerebral dopamine receptor areas is presented.

Animals↗
PubMed1984

Omega-halofatty acids: a probe for mitochondrial membrane integrity. In vitro investigations in normal and ischaemic myocardium.

Long-chain omega-halofatty acids, especially omega-123I-iodoheptadecanoic acid (IHA), are widely used clinically as radiopharmaceuticals for functional heart imaging. The metabolic interpretation of the various elimination rates, however, remains in dispute. It has been previously shown (Kloster and Stöcklin 1982) that in isolated perfused guinea-pig hearts halide diffusion from the mitochondrion to the blood is the rate-determining step of IHA pharmacokinetics in normal myocardium. We have now extended these in vitro experiments to normal and globally ischaemic isolated perfused rabbit hearts. Again, in normal hearts a single phase iodide elimination half-time (14.3 +/- 2.1 min) was observed. In hearts made globally ischaemic for 90 min, the iodide elimination was biphasic with a first fast phase (T 1/2 = 3.8 +/- 0.49 min) and a late slow phase (T 1/2 = 60.5 +/- 14.0 min). The first fast phase is attributed to iodide ion released by residual beta-oxidation (more rapid than in normal hearts due to damaged membranes in ischaemia), while the late slow phase is explained by beta-oxidation of IHA slowly released by hydrolysis of intracellular lipid stores. These data were compared with published data from investigations in patients which seem to support our interpretation.

Animals↗
PubMed1984

Effect of iloprost (ZK 36 374) on membrane integrity in ischemic rabbit hearts.

The hypothesis that prostacyclins exert a membrane stabilizing action on the ischemic myocardium was examined in isolated rabbit hearts by measuring the elimination half-time of labelled catabolites after injection of 17-(131I)-heptadecanoic acid. During normoxia, a rapid washout of labelled lipids was observed along with a slower exponential elimination of I- from beta-oxidation. After 90 min of ischemia, lipid washout was increased over 6-fold. Infusion of iloprost (1.1 nmol/min) significantly reduced the lipid washout half-time. Iloprost preserved functional myocardial integrity as evidenced by a greater recovery of left ventricular pressure and attenuation of the increase in coronary resistance after reperfusion. These results indicate that the poor recovery of the heart after ischemia is associated with significant changes in membrane integrity and permeability. These data support the hypothesis that the biochemical and functional myocardial preservation by prostacyclin(s) is by a membrane stabilizing mechanism.

Animals↗
PubMed1983

75,77Br- and 123I-analogues of D-glucose as potential tracers for glucose utilisation in heart and brain.

A number of D-glucose analogues labelled with either the positron emitter 75Br (T 1/2 = 1.6 h) or the single photon emitter 123I (T 1/2 = 13.3 h) were studied as potential tracers for glucose utilisation in heart and brain. Of these, 3-deoxy-3-bromo-D-glucose, 3-deoxy-3-iodo-D-glucose, methyl 2-deoxy-2-bromo-beta-D-glucoside and methyl 2-deoxy-2-iodo-beta-D-glucoside showed little uptake of radioactivity into brain and an unfavourable ratio of heart-to-blood and heart-to-lung concentrations. In contrast, methyl 3,4,6-tri-O-acetyl-2-deoxy-2-iodo-beta-D-glucoside (MTIG) and methyl 3,4,6-tri-O-acetyl-2-deoxy-2-bromo-beta-D-glucoside (MTBG) showed promising brain uptake (160% MBC for MTBG) with a good brain-to-blood concentration ratio of 0.8. MTBG is not metabolically altered in the brain. Thus, this compound may be a promising tracer for measuring glucose transport if it proves to be a substrate for the hexose carrier at the blood-brain-barrier.

Animals↗
PubMed1983

Bromine-75-labeled 1,4-benzodiazepines: potential agents for the mapping of benzodiazepine receptors in vivo: concise communication.

We have prepared four different 1,4-benzodiazepines, labeled at C-7 with the 1.6-hr positron emitter Br-75 or the 57-hr gamma emitter Br-77, as potential radio-pharmaceuticals for the mapping of cerebral benzodiazepine receptor areas. The triazene method was used and optimized. Yields at the no-carrier-added level were 20%. 7-[75Br]-5-(2-fluorophenyl)-1-methyl-1,3-dihydro-2H-1,4-benzodiazepine-2-one (Br-75 BFB) was isolated with a minimum specific activity of 20,000 Ci/mmole. Biodistribution in mice shows that BFB is taken up rapidly by the brain and is retained there at useful concentrations for significant periods of time. The maximum uptake is observed at 0.25 min. Brain-to-blood concentration ratios are larger than 2 during the interval (0.25 to 10 min) investigated.

Animals↗
PubMed1982

Excitation functions for 3He-Particle induced nuclear reactions on 76Se, 77Se and natSe: possibilities of production of 77Kr.

Thin selenium films were prepared by cathodic deposition on aluminium foils. The Al-Se-Al sandwich stacks were used for measurement of the excitation functions of the 76Se(3He,2n)77Kr, 77Se(3He,3n)77Kr and natSe(3He,xn)77Kr reactions up to 3He-particle energy of 36 MeV. Excitation functions were also measured for the competing reactions 76Se(3H,3n)76Kr, 76Se(3He,pn)77Br, 76Se(3He,p2n)76Br, 76Se(3He,p3n)75Br, 76Se(3He, alpha)75Se, 77Se(3He,n)79Kr, 77Se(3He,4n)76Kr, 77Se(3He,pn)78Br, 77Se(3He,p2n)77Br, 77Se(3He,p3n)76Br, 77Se(3He, alpha n)75Se, natSe(3He,xn)79Kr and natSe(3He,xn)76Kr. Thick target yields were calculated for the formation of krypton and bromine isotopes in 3He-induced reactions on 76Se and 77Se and for krypton isotopes in reactions on natural selenium. The possibilities of production of 77Kr using 3He-particle induced reactions on 76Se, 77Se and natSe were investigated. From the viewpoint of yield and purity, for the production of 77Kr the reactions 76Se(3He,2n)77Kr and 77Se(3He,3n)77Kr were found to be very suitable, the former at low energies and the latter at relatively higher energies. In the case of 76Se(3He,2n)77Kr reaction, a target thickness corresponding to E3Hc = 25 leads to 15 MeV leads to a theoretical thick target yield of 7.5 mCi 77Kr/micro Ah; the 76Kr impurity at EOB amounts to 0.45%. In the case of 77Se(3He,3n)77Kr reaction, on the other hand, for a target thickness corresponding to E3Hc = 36 leads to 15 MeV the calculated thick target yield of 77Kr is 11.5 mCi/micro Ah and the levels of impurities 79Kr and 76Kr at EOB amount to 0.35 and 0.36% respectively.

Helium↗
PubMed1981

[Studies of cardiac metabolism with 123I-labelled fatty acids and 11C-methylglucose (author's transl)].

To characterize externally detectable changes in the myocardial metabolism of free fatty acids (FFA) and glucose, which are associated with ischemia and cardiomyopathy, omega-123I-heptadecanoic acid (stearic acid analogue), 75Br-phenylpentadecanoic acid, and 3-0-11C-methyl-D-glucose were used as indicators. It could be demonstrated that in the metabolism of free fatty acids at least two different patho-physiological situations may exist. Disturbances in the mechanism of the accumulation of free fatty acids lead to a decrease of the amount of the free fatty acids which are available for energy production (these disturbances can be recognized as indicator accumulation defects). Disturbances associated with the mechanism of free fatty acid catabolism lead to a decrease of the ability of the myocardial cell to utilize the free fatty acids (these disturbances can be recognized as changes in indicator elimination rates). Whereas in ischaemic heart disease, the areas with altered FFA accumulation correlate with the areas of altered FFA-elimination, no correlation was found in the case of cardiomyopathy. The 11C-methylglucose seems to be an excellent indicator for the in-vivo assessment of the function of transport system in the myocardial cell membrane.

Animals↗
PubMed1981

15-(p[75Br]bromophenyl)pentadecanoic acid: pharmacokinetics and potential as heart agent.

Preparation, quality control, and pharmacokinetics of 15-(p-[75Br]bromophenyl)pentadecanoic acid (BPPA) were studied, with particular emphasis on the fate of the label and the usefulness of BPPA as a heart agent. BPPA labeled with the positron emitter Br-75 (T 1/2 = 98 min) was prepared in 55% radiochemical yield with a specific activity of greater than or equal to 1000 Ci/mmol. While the uptake of BPPA in the heart muscle is as fast and efficient as that of aliphatic omega-halofatty acids, its elimination is delayed, owing mainly to an inhibited beta oxidation and the formation of lipophilic catabolites. The blood activity and its time course are identical to those of omega-halofatty acids, but no free bromide appears in any body fluid or organ. The complex pharmacokinetic behavior of stable lipophilic catabolites prevents a quantitative background correction. In contrast to aliphatic omega-halofatty acids, a quantitative evaluation of myocardial metabolism is not possible. Br-75 BPPA, however, is well suited for positron emission tomography of the heart.

Animals↗