Current status of clinical PET.
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Contrast Media↗
Biomedical subjects
M S Berridge
Publications and source records attributed to M S Berridge.
Design and synthesis of 18F-labeled neurotoxic analogs of MPTP.
We report on the synthesis of two fluorine-18 labeled analogs of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). A piperidyl triazene was fluorinated to produce [18F]-1-methyl-4-(2-fluorophenyl)-1,2,3,6-tetrahydropyridine (2'-F-MPTP, 12) in very low yield, and 1-methyl-4-[2-(fluoromethyl)phenyl]-1,2,3,6-tetrahydropyridine (2'-FCH2-MPTP, 11) was labeled with 18F by nucleophilic displacement of the corresponding chloride in 60% yield. The biodistribution in mice of the latter radiotracer and its oxidation to 1-methyl-4-[2-(fluoromethyl)phenyl]pyridinium (2'-FCH2-MPP+, 6) is also reported. The kinetics of oxidation of 2'-FCH2-MPTP and its solvolysis products (the corresponding 2'-hydroxymethyl and 2'-chloromethyl analogs) by rat liver monoamine oxidase were investigated. 2'-FCH2-MPTP accumulated to a useful degree in the brain, was oxidized by monoamine oxidase in vitro, was converted to the oxidation product in brain in vivo, and had a neurotoxic potency similar to that of MPTP. We feel it may be useful as an 18F-labeled radiopharmaceutical for positron tomographic studies of the mechanisms of MPTP toxicity.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
In-target production of [13N]ammonia: target design, products, and operating parameters.
[13N]Ammonia, commonly used in PET, has been prepared in good yield in the target. Up to 800 mCi of radiopharmaceutical was obtained by in-line processing of the irradiated water. Relatively low hydrogen pressure was used to control the target chemistry. Target designs and the product dependence on beam dose, dose rate and pressure are reported. Ethanol as a target additive was also investigated. Hydrogen and ethanol together were more effective than either alone at high beam dose. Parameters are reported for production needs from single doses to synthetic applications. An incidental method for production of [13N]nitrogen gas is also reported.
Ammonia↗
An efficient radiosynthesis of [18F]fluoromisonidazole.
An efficient preparation of the hypoxic cell tracer [18F]3-fluoro-1-(2'-nitro-1'-imidazolyl)-2-propanol ([18F]fluoromisonidazole) is reported. This radiopharmaceutical is of interest to probe hypoxic tissue in infarcts and tumors. One-step radiolabeling and rapid protection group removal provided 55-80% yield in 50 min. The process is similar to common fluorine labeling procedures, simplifying the procedure for most laboratories, and offers an improvement over more difficult previous methods. The labeling precursor was prepared in five steps from readily available materials in a straightforward reaction scheme.
Fluorine Radioisotopes↗
Development of fluorinated 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine analogs with potent nigrostriatal toxicity for potential use in positron emission tomography studies.
The discovery of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity stimulated intense interest in neurotoxicology and in the possible toxic etiology of Parkinson's disease. Better understanding of MPTP neurotoxicity may be achieved by studies using 18F-radiolabeled MPTP analogs and positron emission tomography in nonhuman primates. We synthesized three fluorinated analogs of MPTP: 1-methyl-4-(2-fluorophenyl)-1,2,3,6-tetrahydropyridine (2'-F-MPTP), 1-methyl-4-[2-(trifluoromethyl)phenyl]-1,2,3,6-tetrahydropyridine (2'-CF3-MPTP) and 1-methyl-4-[2-(fluoromethyl)phenyl]-1,2,3,6-tetrahydropyridine (2'-CH2F-MPTP), and developed a method for preparing the latter in 18F-labeled form. We now studied the suitability of 2'-CH2F-MPTP and its hydrolysis products as substrates for monoamine oxidase (MAO) from mouse and monkey brain preparations, and investigated the neurotoxic effect of 2'-CH2F-MPTP and 2'-F-MPTP on the nigrostriatal dopaminergic system in mice. We found that 2'-CH2F-MPTP is a better substrate for MAO and that both 2'-CH2F-MPTP and 2'-F-MPTP were more potent neurotoxins than MPTP. Like MPTP, 2'-F-MPTP was exclusively oxidized by MAO-B and its toxicity blocked by pargyline or deprenyl but not by clorgyline. In contrast, 2'-CH2F-MPTP was oxidized by both MAO-A and MAO-B, and its toxicity was not blocked by pargyline, clorgyline or deprenyl when given separately, but required clorgyline and deprenyl together.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
Preparation and in vivo binding of [11C]carazolol, a radiotracer for the beta-adrenergic receptor.
Carazolol is a high affinity beta-adrenergic receptor antagonist which is relatively non-specific for the receptor subtypes. The labeling of the two enantiomers of this compound with carbon-11, including the synthesis of the required labeling precursors, is reported. The yield and specific activity are sufficient for use in positron tomography. Biodistribution and specific receptor binding studies show the labeled material to be of interest for further investigation as a radiopharmaceutical for positron tomography.
Adrenergic beta-Antagonists↗
Comparative assessment of the effect of lomefloxacin, ciprofloxacin, and placebo on cerebral blood flow, and glucose and oxygen metabolism in healthy subjects by positron emission tomography.
The mechanism by which the fluorinated quinolones produce central nervous system (CNS) effects is currently unknown. We measured the effect of lomefloxacin on cerebral blood flow and metabolism using positron emission tomography. Eighteen healthy, nonsmoking volunteers were randomized to receive lomefloxacin 400 mg, ciprofloxacin 750 mg, or placebo given in a single-blind fashion every 12 hours for 72 hours, the time window for maximum lomefloxacin CNS effects. Subjects receiving lomefloxacin had a mean (+/- SEM) cerebral blood flow (CBF) of 46 (2.9) ml/min/100 g, glucose metabolism (FDG) 4.7 (0.4) mg/min/100 g, oxygen metabolism (OM) 3.3 (0.3) ml/min/100 g, and oxygen extraction (%OM) 0.4 (0.04). Posttreatment values were 43 (3.6) ml/min/100 g, 4.2 (0.4) mg/min/100 g, 2.6 (0.3) ml/min/100 g, and 0.4 (0.03), respectively. Values for subjects receiving ciprofloxacin were CBF 44.8 (1.6) ml/min/100 g, FDG 4.9 (0.7) mg/min/100 g, OM 4.1 (0.4) ml/min/100 g, and %OM 0.6 (0.03) at baseline, and 40.3 (3.5), 4.5 (0.6), 3.4 (0.4), and 0.5 (0.09), respectively, after treatment. For placebo-treated subjects, baseline values were CBF 41.4 (1.9) ml/min/100 g, FDG 4.9 (0.5) mg/min/100 g, OM 3.3 (0.4) ml/min/100 g, and %OM 0.5 (0.07), and respective posttreatment values were 42.1 (2.3), 5.0 (0.6), 3.5 (0.3), and 0.5 (0.02). No effect was observed on visual (qualitative), blinded reading of the scans. No significant effect on cerebral blood flow or metabolism was detected. We conclude that short-term administration of lomefloxacin or ciprofloxacin to healthy volunteers does not have a significant effect on cerebral blood flow, or on oxygen or glucose metabolism.(ABSTRACT TRUNCATED AT 250 WORDS)
Adolescent↗
Comparison of the effect of temafloxacin, ciprofloxacin, or placebo on cerebral blood flow, glucose, and oxygen metabolism in healthy subjects by means of positron emission tomography.
STUDY OBJECTIVE: To determine the cause of the central nervous system effect of the fluorinated quinolones temafloxacin and ciprofloxacin by measuring cerebral blood flow and metabolism by use of positron emission tomography. DESIGN: This was a prospective, randomized, double-blind, placebo-controlled study. PATIENTS: The patients were 13 healthy, nonsmoking volunteers whose ages ranged from 18 to 40 years. RESULTS: We measured brain blood flow and metabolism by use of positron emission tomography before and after a five-dose course of 750 mg ciprofloxacin, 600 mg temafloxacin, or placebo given every 12 hours. Quinolone administration produced no significant effect on visual (qualitative) reading of the positron emission tomography scans. CONCLUSIONS: We conclude that short-term administration of temafloxacin, ciprofloxacin, or placebo does not significantly alter cerebral glucose or oxygen metabolism. Subjects treated with ciprofloxacin demonstrated a significant decrease in brain blood flow compared with baseline and with temafloxacin- or placebo-treated subjects.
Adolescent↗
Measurement of human cerebral blood flow with [15O]butanol and positron emission tomography.
Although H2(15)O is widely used for CBF measurement by positron tomography, it underestimates CBF, especially at elevated flow rates. Several tracers, including butanol, overcome this problem, but the short half-life of 15O provides advantages that cause water to remain the tracer of choice. We report the first use and evaluation of 15O-labeled butanol for CBF measurement. Flow measurements made in a similar fashion with water and butanol at 10-min intervals were compared in normal volunteers under resting and hypercapnic conditions. Regional analysis showed good agreement between the tracers at low flows, and significant underestimation of flow by water relative to butanol in regions of elevated flow. The observed relationship between the tracers and the curve-fitted permeability-surface area product for water (133 ml.100 g-1.min-1) follow the known relationship between water and true flow. These observations indicate that [15O]-butanol provided accurate measurements of human regional CBF under conditions of elevated perfusion. We conclude that butanol is a convenient and accurate method for routine CBF determination by positron emission tomography.
Adult↗
A routine, automated synthesis of oxygen-15-labeled butanol for positron tomography.
The use of labeled butanol for autoradiographic and positron tomographic measurement of cerebral blood flow has been well established using radiocarbon labels. The advantages of the short half-life of oxygen-15 (15O) in doing sequential flow studies are also recognized. An automated procedure has been developed for the routine rapid and sequential synthesis of 15O-labeled butanol in amounts and with purity suitable for use in positron tomography. Butanol can now replace 15O-labeled water, which is commonly used for routine applications. The 14N(d,n)15O reaction is used, with 8 MeV deuterons on a nitrogen target containing 0.2% oxygen. Labeled oxygen is reacted with tri-n-butyl-borane by passing the gas over an alumina support which holds the reagent. Washing with water through small C18-bonded phase silica cartridges eliminates labeled water and the majority of boron-containing impurities. Injectable labeled butanol is collected at 2.5 min after the end of bombardment. The yield is 6 mCi per microampere of saturated bombardment, measured at the end of synthesis. Injectable product up to 250 mCi can be obtained at 10-min intervals.
Butanols↗
Chemistry of fluorine-18 radiopharmaceuticals.
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Fluorine↗
Noninvasive assessment of coronary stenoses by myocardial perfusion imaging during pharmacologic coronary vasodilation. VIII. Clinical feasibility of positron cardiac imaging without a cyclotron using generator-produced rubidium-82.
The purpose of this study was to determine the clinical feasibility of diagnosing significant coronary artery disease by positron imaging of myocardial perfusion without a cyclotron, using generator-produced rubidium-82 (82Rb). Fifty patients underwent positron emission tomography of the entire heart using a multislice positron camera and intravenous 82Rb or nitrogen-13 ammonia (13NH3) before and after intravenous dipyridamole combined with handgrip stress. Images were read by two observers blinded as to clinical or arteriographic data. Automated quantitative coronary arteriography was obtained for the arteriographic determination of coronary flow reserve, previously demonstrated to be a single integrated measure of stenosis severity accounting for all its geometric dimensions of length, absolute diameter, percent narrowing and asymmetry by quantitative analysis of cine films. Significant coronary artery disease was defined as an arteriographically determined coronary flow reserve of less than 3.0 based on all stenosis dimensions. Any single geometric measure of stenosis severity alone was an inadequate reference standard for comparison with perfusion images. Sensitivity of identifying patients with coronary artery disease having an arteriographically determined coronary flow reserve of less than 3.0 was 95% by positron imaging with a specificity of 100%. The single case that was missed, studied with 13NH3, had a 43% diameter narrowing of a small ramus intermedius off the left coronary artery with no significant narrowing of the major coronary arteries. Positron emission tomography of myocardial perfusion before and after intravenous dipyridamole combined with handgrip stress utilizing generator-produced 82Rb provides sensitive and specific diagnosis of reduced coronary flow reserve due to coronary artery disease in humans.
Coronary Angiography↗
Preparation of oxygen-15 butanol for positron tomography.
Butanol was labeled with 15O using the reaction of tri-n-butyl borane with oxygen gas. The carrier-added synthesis and purification was accomplished in 4 min from the end of bombardment. The efficiency of radiolabel incorporation was 50%. The procedure described will produce [15O]butanol in an amount and quality sufficient for positron tomographic use. This compound is immediately useful for blood flow measurement based upon previous validation of butanol labeled with other radionuclides for that purpose.
Butanols↗
Synthesis of 18F-labeled 6- and 7-fluoropalmitic acids.
In order to investigate the uptake characteristics of palmitic (hexadecanoic) acid labeled with 18F at positions within the alkyl chain, [18F]6- and 7-fluoropalmitates were synthesized. A precursor synthesis of several steps was followed by no-carrier-added [18F] fluoride displacement of a methanesulfonate group and cleavage of the fatty acid benzyl ester. Preliminary myocardial uptake characteristics of the labeled compounds in rats were not markedly different from those of unsubstituted 11C labeled palmitic acid.
Animals↗