Marcel Guillaume

Effect of spinal cord stimulation on regional myocardial perfusion assessed by positron emission tomography

Spinal cord stimulation (SCS) can relieve symptoms in patients with severe angina pectoris refractory to conventional medical or surgical therapy. This symptomatic improvement may result from decreased myocardial ischemia. To test this hypothesis, positron emission tomography (PET) and potassium-38 as a flow tracer were used in 8 patients for the quantitative evaluation of regional myocardial perfusion at rest and after exercise, before and during SCS. Potassium uptake was evaluated as myocardial clearance (flow times net extraction) in ml/min/100 g. Tomographic segments were categorized as nonaffected and affected on the basis of the absence or presence of arterial stenosis on coronary angiography and on the basis of thallium scintigraphic data. In nonaffected segments, before SCS, regional myocardial clearance significantly increased from rest (28 +/- 4) to exercise (47 +/- 13 clearance units; p less than 0.004). A similar increase occurred after SCS. In affected segments, before SCS, regional myocardial clearance barely increased (p = 0.065) from rest (26 +/- 6) to exercise (33 less than or equal to 12). In comparison, after SCS, the resting regional myocardial clearance was slightly elevated (29 +/- 8) reflecting an increased double product, but did not increase (p = 0.192) with exercise (34 +/- 12). However, the magnitude and duration of ST-segment depression decreased during treatment with SCS. Anginal pain occurred in all patients during control exercise, but was attenuated in all but one with SCS. These results indicate that SCS improves exercise-induced angina and electrocardiographic signs of ischemia but this influence does not appear to be mediated by changes in regional myocardial perfusion.

Recommendations for fluorine-18 production

Abstract Data for the production of fluorine-18 (t 1/2 = 109.6 min; β + = 100%) are reviewed. The experience of some well-established European centres for positron emission tomography (PET), in the routine production of fluorine-18 for the purpose of labelling radiopharmaceuticals, is described. This experience is evaluated, along with published data, to give practical and technical recommendations to new PET group entering this key area.

Serotonin 5HT2 receptor imaging in the human brain using positron emission tomography and a new radioligand, [18F]Altanserin : results in young normal controls

Changes in serotonin-2 receptors have been demonstrated in brain autopsy material from patients with various neurodegenerative and affective disorders. It would be desirable to locate a ligand for the study of these receptors in vivo with positron emission tomography (PET). Altanserin is a 4-benzoylpiperidine derivative with a high affinity and selectivity for S2 receptors in vitro. Dynamic PET studies were carried out in nine normal volunteers with high-specific activity (376–1,680 mCi/μmol) [18F]altanserin. Arterial blood samples were obtained and the plasma time–activity curves were corrected for the presence of labeled metabolites. Thirty minutes after injection, selective retention of the radioligand was observed in cortical areas, while the cerebellum, caudate, and thalamus had low radioactivity levels. Specific binding reached a plateau between 30 and 65 min postinjection at 1.8% of the injected dose/L of brain and then decreased, indicating the reversibility of the binding. The total/nonspecific binding ratio reached 2.6 for times between 50 and 70 min postinjection. The graphical analysis proposed by Logan et al. allowed us to estimate the binding potential (Bmax/KD). Pretreatment with ketanserin was given to three volunteers and brain activity remained uniformly low. An additional study in one volunteer showed that [18F]altanserin can be displaced from the receptors by large doses of ketanserin. At the end of the study, unchanged altanserin was 57% of the total plasma activity. These results suggest that [18F]altanserin is selective for S2 receptors in vivo as it is in vitro. They indicate that [18F]altanserin is suitable for imaging and quantifying S2 receptors with PET in humans.

Ligands and tracers for PET studies of the 5-HT system--current status.

The status of the radiochemical development and biological evaluation of radioligands and tracers for PET studies of the serotonergic system is reviewed, indicating those agents with present value and those with future potential. Practical recommendations are given for the preparation of two useful radioligands for PET studies of central 5-HT2 receptors, namely [18F]setoperone and [18F]altanserin. Though, it has not proved possible to recommend tracers or radioligands for the study of other aspects of serotonergic system, prospects for future radiochemical development are indicated, especially for developing radioligands for the 5-HT re-uptake site, and for the 5-HT1 and 5-HT3 receptors.

Production of 6-[18F]fluoro-l-DOPA and its metabolism in vivo—a critical review

This report critically appraises methods for the synthesis of 6-[18F]fluoro-L-3,4-dihydroxyphenylalanine (6-FDOPA) that are based on labelling by non-regioselective electrophilic fluorination, regioselective fluorodemetalation or nucleophilic substitution. Recommendations for the standardization of labelling procedures, the optimization of radiochemical yield and the assurance of product quality and safety are given. Studies of the metabolism of 6-FDOPA in vivo are also reviewed to emphasize the importance of the biochemical component of the development of this tracer for positron emission tomography (PET).

A New Route for the Synthesis of [18f]Fluoroaromatic Substituted Amino Acids: No Carrier Added L-P-[18f]Fluorophenylalanine

L-p-[18F]fluorophenylalanine was designed as a potential marker for probing protein synthesis in the human brain by positron emission tomography. This radiotracer has been synthesized using nucleophilic displacement of the activated nitro group of p-nitrobenzaldehyde by NCA 18F- obtained from the 18O (p, n) reaction on enriched water. The L-form of the [18F]fluoroamino acid can be separated on an analytical scale chiral column. A typical production run of 22.2 GBq (600 mCi) of 18F obtained after a 10 microA.h bombardment of 18 MeV protons on 99.8% 18O-enriched water leads to a batch of 1.11 GBq (30 mCi) of NCA L-p-[18F]fluorophenylalanine after a total synthesis time of 120 min.

PET Radionuclide Production

Several short-lived positron-emitters are routinely used in PET studies while a few others are of potential interest. A brief review of the decay data and production methods for several of these positron-emitters is given. Special attention is paid to the production of the four major positron-emitters, namely carbon-11, nitrogen-13, oxygen-15 and fluorine-18, which are widely applied in several European PET centres.

Synthesis of fluorine-18 substituted aromatic aldehydes and benzyl bromides, new intermediates for n.c.a. [18F]fluorination☆

The synthesis of various [18F]fluoroaromatic aldehydes using activated nitro precursors and amino-polyether supported nucleophilic substitution with 18F− is reported. These radiolabelled fluorinated aldehydes (radiochemical yields: 50–75%) are powerful key intermediates leading after treatment with NaBH4 and SOBr2 (SOCL2) to further active intermediates for example substituted [18F]fluorobenzyl bromides (yields 30–50% EOB). These benzaldehydes and bromides are particularly useful for the preparation of new radiopharmaceuticals (e.g. fluorotroprapride, fluorodexetimide) either by reductive amination or by aromatic N-alkylation. The preparation of various amino acids in D, L (50:50) or enriched L form by asymmetric synthesis is also possible (e.g. L-6-[18F]fluorodopa, L-4-[18F]fluoro-m-tyrosine). It can be anticipated that the 18F-labelled fluoroaldehydes will find widespread application in radiopharmaceutical chemistry.

Nucleophilic enantioselective synthesis of 6-[18F]Fluoro-l-dopa via two chiral auxiliaries

Abstract Asymmetric nucleophilic synthesis of 6-[18F]fluoro- l -dopa was investigated in order to reach an enantiomeric excess of close to 100% of the l form of this amino acid. The radiochemical synthesis required [18F]fluoride as fluorinating agent and regioselective nucleophilic substitution of commercially available 6-nitroveratraldehyde. The [18F]fluorobenzaldehyde thus obtained was easily converted to the corresponding 2-[18F]fluoro-4,5-dimethoxybenzyl bromide. This alkylating agent was added to the lithium enolates of 1-(S)-(−)camphor imine of t-butyl glycinate (1) and (S)-(−)-1-Boc-2-t-butyl-3-methyl-4-imidazolidinone [(S)- Boc-BMI] (2) in order to compare the enantiomeric excess of the l form obtained in each case with these two chiral inductors. The l -isomer of fluorodopa was isolated after H1 hydrolysis and HPLC purification in 5–10% radiochemical yield (decay corrected). The overall synthesis time was of 110 min. Through this synthetic pathway, the l -isomer of fluorodopa was obtained in 83% e.e with 1 and 96% e.e with 2 respectively, as determined by chiral HPLC. A practical three step preparative scale synthesis of 6-[19F]fluoro- d,l -dopa is also presented.

The synthesis of no-carrier-added DL-4-[18F]fluorodeprenyl via the nucleophilic aromatic substitution reaction.

No-carrier-added DL-alpha-methyl-beta-4-[18F]fluorophenyl-N-methyl-N-propynylethylamin e (DL-4-[18F]fluorodeprenyl) was synthesized via the following 3-step procedure: (1) nucleophilic aromatic substitution by [18F]fluoride on 4-nitrobenzaldehyde to produce 4-[18F]fluorobenzaldehyde (yield 65%); (2) the reaction of 4-[18F]fluorobenzaldehyde with (1-chloro-1-(trimethylsilyl)ethyl)lithium followed by hydrolysis to give 4-[18F]fluorophenylacetone (yield 50%); and (3) reductive alkylation of 4-[18F]fluorophenylacetone with N-methyl-propynylamine in the presence of NaBH3CN (yield 35%) followed by HPLC purification to give a racemic mixture of 4-[18F]fluorodeprenyl. The overall yield was 11% (EOB corrected), the synthesis time was 90 min and the specific activity greater than 0.57 Ci/mumol (end of synthesis). This synthesis approach, the conversion of an aromatic aldehyde to a homologous methyl ketone, extends the flexibility of the nucleophilic aromatic substitution reaction by applying it to the synthesis of radiotracers which do not bear electron-withdrawing activating groups on the aromatic ring. The tissue distribution of DL-4-[18F]fluorodeprenyl in mice at 1, 10 and 60 min was also measured and showed that metabolic defluorination was not significant. Clearance of radioactivity from brain after injection of DL-4-[18F]fluorodeprenyl was more rapid than that previously observed for [11C]L-deprenyl.