Tracers for metabolic imaging of brain and heart. Radiochemistry and radiopharmacology.
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Brain↗
Biomedical subjects
G Stöcklin
Publications and source records attributed to G Stöcklin.
11C-labelling of the analgesic tramadol and its major metabolites by selective O- and N-methylation.
For in vivo pharmacokinetic studies with PET, the analgesic Tramadol(1-(3-methoxyphenyl)-2-dimethylaminomethyl-cyclohexan-1-ol ) and its major O- and N-desmethylated metabolites M1 and M2 were labelled with carbon-11. Starting with the corresponding desmethyl precursors, (1R,2R)-(+), (1S,2S)-(-)-[O-methyl-11C]Tramadol and racemic-[N-methyl-11C]Tramadol were prepared by methylation with n.c.a. [11C]methyl iodide in DMSO with radiochemical yields of 85 and 90%, respectively. Specific n.c.a. N-methylation of bis-desmethyl-Tramadol (M5) was achieved without base obtaining 11C-labelled (1R,2R)-(+)- and (1S,2S)-(-)-M1 with 90% radiochemical yield. However, a selective O-methylation of (+)- and (-)-M5 was not possible even with an excess of NaOH, and only 70% of (1R,2R)-(+)- and (1S,2S)-(-)-[O-methyl-11C]M2 was obtained. Quaternization of Tramadol or M1 was greater than 15 times slower than O-methylation, and was only observed in the presence of added CH3I carrier.
Carbon Radioisotopes↗
[Applications of positron emission tomography (PET) to the measurement of regional cerebral pharmacokinetics].
Positron emission tomography (PET) has not only a variety of applications to functional diagnostics using methods of nuclear medicine and for the investigation of pathophysiological processes, it also offers new possibilities for pharmacology. As PET is able to quantitatively record "from outside" the regional concentration of a positron emitter in a living primate, the distribution and kinetics of a labelled drug at the site of action can be determined non-invasively. This is always the case if the research substance can be labelled practically carrier-free with a short-lived positron emitter such as 11C (T1/2 = 20 min) or if applicable 18F (T1/2 = 110 min). The quantities applied in this case are so small that pharmacodynamic effects do not occur. Therefore, this method is particularly suitable for measuring in vivo the regional cerebral pharmacokinetics of centrally acting drugs in humans.
Antipsychotic Agents↗
Noninvasive assessment of regional cardiac adenosine using positron emission tomography.
One of the early metabolic changes associated with myocardial ischemia is the breakdown of adenine nucleotides resulting in the enhanced production of adenosine. In order to image regional cardiac adenosine by positron emission tomography (PET) the enzymatic conversion of adenosine into [11C]-S-adenosylhomocysteine ([11C]SAH) was used in the presence of 11C-labeled homocysteine thiolactone (adenosine + [11C] - homocysteine-->[11C] - SAH + H2O). Following production of an experimental coronary constriction in anesthetized dogs carrier added 1-[11C]-D,L-homocysteine thiolactone (5-27 mCi, 30 mg/kg) was infused over 1 min. This intervention, while hemodynamically ineffective, increased the plasma homocysteine concentration from 2.5 to 306 microM, which thereafter declined with a T1/2 of 28 min to 97 microM after 60 min. During the first minutes following infusion of [11C] homocysteine, the radioactivity concentration in the blood pool, the nonischemic and the ischemic myocardium were similar. Between 20 and 60 min, however, the regional radioactivity concentration was highest in the perfusion area of the stenosed vessel: 6.6% compared to 5.2 and 5.2% of the injected dose per 1 I tissue. The elevated radioactivity concentration was strictly confined to the perfusion area of the occluded artery. Using [35S]-L-homocysteine (20 microCi; 30 mg/kg) chromatographic separation of SAH in tissue extracts confirmed that the radioactivity accumulation was due to trapping of adenosine in the cellular SAH-pool. These experiments provide first evidence that 1-[11C]homocysteine thiolactone can be successfully used to assess regional adenosine formation in the heart with PET via measurement of [11C] SAH accumulation.
Adenosine↗
Positron emission tomography with (18F)methylspiperone demonstrates D2 dopamine receptor binding differences of clozapine and haloperidol.
Four schizophrenic patients were investigated with dynamic positron emission tomography (PET) using (18F)fluorodeoxyglucose (FDG) and (18F)methylspiperone (MSP) as tracers. Two schizophrenics were on haloperidol therapy at the time of MSP PET. The other two schizophrenics were treated with clozapine, in one of them MSP PET was carried out twice with different daily doses (100 mg and 450 mg respectively). Neuroleptic serum levels were measured in all patients. Results were compared with MSP PET of two drug-free male control subjects and with a previous fluoroethylspiperone (FESP) study of normals. Three hours after tracer injection specific binding of MSP was observed in the striatum in all cases. The striatum to cerebellum ratio was used to estimate the degree of neuroleptic-caused striatal D2 dopamine receptor occupancy. In the haloperidol treated patients MSP binding was significantly decreased, whereas in the clozapine treated patients striatum to cerebellum ratio was normal. Even the increase of clozapine dose in the same patient had no influence on this ratio. Despite the smaller number of patients the study shows for the first time in humans that striatal MSP binding reflects the different D2 dopamine receptor affinities of clozapine and haloperidol.
Adult↗
Production of 6.5 h 82mRb via the 82Kr(p, n)-process at a low-energy cyclotron--a potential substitute for 82Rb.
The production of 6.5 h 82mRb, a potential substitute for generator-produced 1.2 min 82Rb in myocardial blood flow studies, is discussed. Using a 82Kr gas target and a low-energy cyclotron it is possible to obtain greater than 100 mCi (greater than 3.7 GBq) of high purity 82mRb. Results of radiation dose calculations for 81Rb/81mKr, 82Rb and 82mRb are reported.
Coronary Circulation↗
Estimation of local cerebral glucose utilization by positron emission tomography: comparison of [18F]2-fluoro-2-deoxy-D-glucose and [18F]2-fluoro-2-deoxy-D-mannose in patients with focal brain lesions.
A comparative PET study of [18F]2-fluoro-2-deoxy-D-glucose (FDG) and [18F]2-fluoro-2-deoxy-D-mannose (FDM) uptake was performed in 13 patients with focal brain lesions. Differences between FDG and FDM with respect to model rate constants, lumped constant, and estimated metabolic rate for glucose were determined on a regional basis. Across whole brain, the transport rate constant K1* was almost unchanged, whereas k2*, describing the transport back from tissue to plasma, was 6% higher, and the phosphorylation rate constant k3* was 9% lower for FDM compared to FDG. This implies a 20% lower lumped constant for FDM. No significant regional variability of this differential tracer behavior was observed in normal or in lesioned brain tissue. Thus, results from previous FDG studies, where the radiotracer was not 100% pure FDG but contained varying amounts of FDM, can easily be corrected by adjustment of the lumped constant employed in metabolic quantitation.
Adult↗
Increased amino acid transport into brain tumors measured by PET of L-(2-18F)fluorotyrosine.
The uptake of L-(2-18F)fluorotyrosine (F-Tyr), a newly synthetized amino acid tracer, was studied in 15 patients with various brain tumors by dynamic PET. The higher F-Tyr accumulation in tumors (mean 27% above contralateral tissue) was associated with two-fold transport rates into tumors, while the rate constants describing irreversible incorporation were decreased. The increased F-Tyr transport was not correlated to 68Ga-EDTA accumulation and cannot be explained by disruption of the blood-brain barrier. Kinetic analysis of 2-(18F)-fluoro-deoxy-glucose accumulation in the same patients demonstrated that increased metabolic rates in tumors are mainly caused by altered phosphorylation rates while transport of glucose is less affected. Since F-Tyr transport rates clearly separated tumors from normal tissue and since F-Tyr accumulation was related to tumor grade, PET studies of F-Tyr uptake are of clinical value for diagnosis and classification of brain tumors.
Adult↗
Brain and brain tumor uptake of L-3-[123I]iodo-alpha-methyl tyrosine: competition with natural L-amino acids.
SPECT studies with L-3-[123I]iodo-alpha-methyl tyrosine (IMT) were carried out in 10 patients with different types of brain tumors--first under fasting conditions (basal) and a week later during intravenous infusion of a mixture of naturally-occurring L-amino acids (AA load). An uptake index (UI) was calculated by dividing tissue count rates by the integral of plasma count rates. The UI decreased by 45.6% +/- 15.4% (n = 10, p less than 0.001) for normal brain and by 53.2% +/- 14.1% for gliomas (n = 5, p less than 0.01) during AA load compared to basal conditions, while two meningiomas and a metastasis showed only a minor decrease (23.9 +/- 5.7%, n.s.). Two pituitary adenomas could not be delineated on the SPECT scans. These data indicate that IMT competes with naturally-occurring L-amino acids for transport into normal brain and gliomas. Transport characteristics of IMT into tumors of nonglial origin appear to be different from those of gliomas. For both types of tumors, it is advisable to perform IMT-SPECT under fasting conditions.
Adult↗
PET studies of dopamine receptor distribution using [18F]fluoroethylspiperone: findings in disorders related to the dopaminergic system.
PET studies of dopamine D2-receptor binding were performed in thirty patients with various disorders related to the dopaminergic system and in six healthy controls. Uptake of [18F]fluoroethylspiperone in caudate over three hours was analyzed in terms of several indices of receptor binding:caudate-to-cerebellum activity ratio, concentration of ligand as percentage of injected dose, caudate-to-blood radioactivity ratio, slope of tracer uptake curves, binding potential, kinetic constants of a three compartment model. In 14 patients brain glucose metabolism was also measured. Data on medicated patients demonstrate that the average values of most of the above parameters indicate the decreased number of available D2-receptors whereby, besides an age dependent decline, the caudate-to-cerebellum ratio affords the relatively best distinction among diagnostic groups. In individual cases, large variability among subjects permits only the classification of severe pathologies. Morphological damage and neuronal loss in the striatum may also cause abnormal low values both for the indices of receptor binding and for glucose consumption, thus providing a possible pathogenetic link between receptor dysfunction and impaired energy metabolism.
Adolescent↗
SPECT studies of brain tumors with L-3-[123I] iodo-alpha-methyl tyrosine: comparison with PET, 124IMT and first clinical results.
L-3-[123I]iodo-alpha-methyltyrosine (123IMT) like tyrosine has been reported previously to have a high affinity for a transport system in the blood-brain-barrier (BBB). We examined the kinetic behavior of 124IMT in brain and plasma in two patients with glioblastoma using dynamic positron emission tomography (PET). 124IMT accumulated in brain and tumor tissue, reaching a maximum after 15 min, with a washout of 20% to 35% at 60 min postinjection. Animal experiments confirmed the accumulation of the intact tracer in murine brain, but there was no incorporation into proteins. SPECT studies with 123IMT in patients with different types of brain tumors showed increased uptake in 26 of 32 tumors. Although nonspecific uptake in tumors must be considered, the accumulation of IMT in normal brain and in some tumors with intact BBB suggests a specific uptake of IMT. As transport is the main determinant of initial amino acid uptake, 123IMT appears to be a suitable SPECT tracer of amino acid uptake although it is not incorporated into protein.
Animals↗
Imaging of brain tumors with L-3-[123I]iodo-alpha-methyl tyrosine and SPECT.
Carbon-11-labeled amino acids have been successfully used to image brain tumors by PET. This study was undertaken to evaluate the potential of L-3-[123I]-iodo-alpha-methyl tyrosine (123IMT) for metabolic imaging of brain tumors. Ten patients (glioblastoma, oligodendroglioma, lymphoma, and metastases) had early and delayed brain SPECT with a rotating gamma camera after i.v.-injection of 200-300 MBq 123IMT. In nine patients the tumors showed intense uptake of the radiotracer. Tumor-to-brain tissue ratios were between 1.4 and 2.6. 123IMT shows potentials for monitoring the effects of brain tumor therapy.
Brain Neoplasms↗
Cerebral metabolism of L-[2-18F]fluorotyrosine, a new PET tracer of protein synthesis.
L-[2-18F]fluorotyrosine (2-18FTyr) was evaluated as a tracer of cerebral protein synthesis for positron emission tomography (PET). Its metabolism in murine cerebrum was studied. The uptake in brain reaches a value of approximately 2% of the injected dose per gram tissue after 60 min. The incorporation of the tracer into tissue proteins was proven by discontinuous SDS gel electrophoresis. The protein bound fraction of tissue activity increased to 84% and 89% after 60 and 120 min p.i., respectively. High performance liquid chromatography analysis showed a concomitant decrease of free 2-18FTyr in tissue with time. The sum of free 2-18FTyr, tRNA-and protein-bound 2-18FTyr in cerebral tissue gave an almost quantitative activity balance of 96 +/- 4% at all times examined. A significant formation of fluorodopa or fluorodopamine must therefore be excluded. This shows that L-[2-18F]fluorotyrosine is a promising tracer for quantitation of protein synthesis rates with PET based on a three-compartment model.
Animals↗
PET measurement of D2 and S2 receptor binding of 3-N-[( 2'-18F]fluoroethyl)spiperone in baboon brain.
The regional pharmacokinetic behavior in baboon brain of 18F-fluoroethyl- and 18F-fluoropropylspiperone (18FESP, 18FPSP) at specific activities greater than or equal to 1000 Ci/mmol was studied with PET. Four hours after injection of 5-10 mCi 18FESP, uptake in striatum was 0.048% +/- 0.005% of injected dose per cm3, which is almost the same as with 18F- and 11C-methylspiperone. While 18FPSP was taken up in much smaller amounts than 18FESP, striatum to cerebellum activity ratios were quite similar for both ligands (about 9 to 10 at 4 h p.i.). Because of its higher striatal uptake, 18FESP seems to be better suited for PET. Furthermore, relative binding to S2 receptors was much smaller for FESP: competing cold S2 antagonists (ritanserin, ketanserin) did not alter 18FESP binding to striatum, concurrently reducing uptake in frontal cortex by only 15%-20%. With coinjection of increasing amounts of cold FESP, saturation of 18FESP binding to striatum occurred at doses exceeding 10 micrograms per kg. Quantitative analysis of radiolabelled ligand in arterial plasma (decrease to 8% at 4 h p.i.) demonstrated identical metabolic turnover for both ligands. Direct use of binding fractions from the saturation curve resulted in overestimation of the receptor density in striatum. Using the 18FESP plasma concentration time curve and the dynamic uptake data, k3 of a three compartment model could be determined by non linear regression. However, dramatic changes of the dependence of k3 on the specifically bound ligand concentration were observed even at small loading doses of FESP. Estimation of Bmax yielded a D2 receptor density of only 6 pmol per cm3 in baboon striatum.
Animals↗
Biochemical and autoradiographic study of cerebral protein synthesis with [18F]-and [14C]fluorophenylalanine.
Fluorine-18-labeled ortho or para isomers of L-fluorophenylalanine were used in double-label experiments together with L-[3H]phenylalanine for amino acid incorporation into cerebral proteins of Mongolian gerbil brain. It was demonstrated by qualitative regional comparison of the 18F and 3H autoradiographic images that L-p-[18F]fluorophenylalanine is incorporated into proteins and exhibits a regional cerebral protein synthesis pattern. To a minor extent, L-p-fluorophenyl[3-14C]alanine and L-o-[18F]fluorophenylalanine are hydroxylated in vivo to form labeled tyrosine or tyrosine analogues that are incorporated into cerebral proteins as well. The advantage and validity of the application of L-p-[18F]fluorophenylalanine with positron emission tomography for noninvasive studies of cerebral protein synthesis in humans are evaluated on the basis of an experimental animal approach.
Animals↗
Blood-brain transport and regional distribution of bromo-benzodiazepine.
The blood-brain transport and regional distribution of a tritium-labeled, brominated benzodiazepine (BFB) was determined for the rat brain in vivo. The unidirectional transport constant from blood to brain was measured by a graphical, integral method and was found to be 0.83 ml/g/min, a value which indicates that transport is essentially flow-dependent. The apparent volume of distribution increased linearly during the measurement period, suggesting that back transport from brain to blood was zero and that BFB was trapped in the tissue, possibly by specific receptors or acceptors. Under the conditions of these experiments, autoradiography of brain tissue sections indicated a regional distribution of [3H]BFB similar to that expected for regional cerebral blood flow. These results indicate that BFB is a useful blood flow tracer in brain and suggest that BFB radiobrominated with bromine-75 may, under appropriate conditions, be a suitable tracer for in vivo regional blood flow measurement or benzodiazepine receptor mapping by positron-emission tomography.
Animals↗
3-N-(2-[18F]-fluoroethyl)-spiperone: a novel ligand for cerebral dopamine receptor studies with pet.
3-N-(2-[18F]-fluoroethyl)-spiperone [( 18F]-FESP) was synthesized at high specific activity by condensation with 2-[18F]-fluoroethyltosylate (35 TBq/mmol). In vivo binding studies in baboons by positron emission tomography exhibited regio-selective uptake in the striatum which was saturable with the cold ligand and prevented by pretreatment with (+)-butaclamol. The pharmacokinetic behaviour, i.e. the absolute uptake in tissue and the striatum-to-cerebellum ratio, was very similar to that of methylspiperone. Analysis of the radioactivity in mouse brain after administration of [18F]-FESP indicated a high in-vivo stability (greater than 90% after 210 min in the striatum). Comparative distribution studies of other N-fluoroalkylspiperones in mice suggest that FESP and the N-fluoropropyl analogue are the most potent D2 receptor ligands.
Animals↗