Raman Chirakal

Cerebral Metabolism of 6–[18F]Fluoro‐l‐3,4‐Dihydroxyphenylalanine in the Primate

Abstract: The tracers 6‐[18F]fluoro‐1‐3,4‐dihydroxyphenyl‐alanine (6–[18F]fluoro‐l‐DOPA) and 1‐[14C]DOPA were injected simultaneously into rhesus monkeys, and the time course of their metabolites was measured in the striatum and in the occipital and frontal cortices. In the striatum, 6‐[18F]fluoro‐L‐DOPA was metabolized to 6–[18F]fluorodo‐pamine, 3,4‐dihydroxy‐6–[18F]fluorophenylaceticacid, and 6–[18F]fluorohomovanillic acid. The metabolite pattern was qualitatively similar to that of 1‐[14C]DOPA. 6–[18F]Fluorodopamine was synthesized faster than [14C]do‐pamine. In the frontal cortex, the major metabolite was also 6–[18F]fluorodopamine or [14C]dopamine. In the occipital cortex, the major metabolite was 3‐O‐methyl‐6–[18F]fluoro‐L‐DOPA. On the basis of these data, the images obtained with 6–[l8F]fluoro‐l‐DOPA and positron emission tomography in humans can now be interpreted in neurochemical terms.

6-L-18F-fluorodihydroxyphenylalanine PET in neuroendocrine tumors: basic aspects and emerging clinical applications.

In recent years, 6-l-18F-fluorodihydroxyphenylalanine (18F-DOPA) PET has emerged as a new diagnostic tool for the imaging of neuroendocrine tumors. This application is based on the unique property of neuroendocrine tumors to produce and secrete various substances, a process that requires the uptake of metabolic precursors, which leads to the uptake of 18F-DOPA. This nonsystematic review first describes basic aspects of 18F-DOPA imaging, including radiosynthesis, factors involved in tracer uptake, and various aspects of metabolism and imaging. Subsequently, this review provides an overview of current clinical applications in neuroendocrine tumors, including carcinoid tumors, pancreatic islet cell tumors, pheochromocytoma, paraganglioma, medullary thyroid cancer, hyperinsulinism, and various other clinical entities. The application of PET/CT in carcinoid tumors has unsurpassed sensitivity. In medullary thyroid cancer, pheochromocytoma, and hyperinsulinism, results are also excellent and contribute significantly to clinical management. In the remaining conditions, the initial experience with 18F-DOPA PET indicates that it seems to be less valuable, but further study is required.

Radiofluorination with 18F-labelled acetyl hypofluorite: [18F]L-6-fluorodopa

Abstract Acetyl hypofluorite labelled with 18F was produced in glacial acetic acid from [18F]F2 gas diluted with neon. L -3-Methoxy-4-hydroxyphenylalanine ethyl ester hydrochloride was reacted with the acetyl hypofluorite either in glacial acetic acid or in a mixture of glacial acetic and trifluoroacetic acids at room temperature for 20 min. After hydrolysis of the reaction products with 48% hydrobromic acid, L -[18F]6-fluorodopa (4%, EOB, radiochemical yield) was isolated by reverse phase high pressure liquid chromatography. Despite its low yield the method may be useful for the production of L -[18F]6-fluorodopa with which the dopamine rich regions of the brain can be demonstrated and with which dopamine metabolism can be measured by positron emission tomography.

The synthesis of [18F]Xenon difluoride from [18F]fluoride gas

Abstract A convenient procedure for the rapid synthesis of 18F labelled XeF2 was developed. Neon gas with 0.087 to 5% carrier fluorine was irradiated with 15 MeV deuterons to produce [18F]F2 with a yield of 17 mCi/μAh, EOB. It was, in turn, reacted with excess of xenon in a high pressure nickel vessel at 390°C for 40 min. The isolated reaction product was XeF2 exclusively. The production yield was 11 mCi/μAh at EOB and the specific activity was 450mCi/mmol. [18F]XeF2 has been shown to be a versatile intermediate for the syntheses of 18F-labelled radiopharmaceuticals, for example, [18F]2-fluoro-2-deoxy- D -glucose and L -[18F]6-fluorodopa.

Recovery rates of regional sympathetic reinnervation and myocardial blood flow after acute myocardial infarction

BACKGROUND The implication of an arrhythmogenic role for infarction-induced disruption of regional myocardial sympathetic nerve activity has led to a search for noninvasive methods to study regional sympathetic nerve activity in patients after infarction. METHODS AND RESULTS By using positron emission tomography, we measured the time course of myocardial hypoperfusion with [13N]-ammonia retention and sympathetic innervation with [18F]-6-fluorodopamine within the infarct zone in 10 patients at 2 weeks, 3 months, and 6 months after a first-onset Q-wave myocardial infarction. The time course for reestablishment of global cardiac autonomic function was also determined by measuring the power spectrum of heart rate variability with an autoregressive technique. The average infarct defect size as determined by the fractional uptake of [13N]-ammonia was 17.22% +/- 5.95% of the left ventricular myocardium. The fractional uptake of [18F]-fluorodopamine in the infarct zone was similar, at 15.83% +/- 4.45% (not significant). There was a significant increase (14% to 15%; P <.05) in myocardial blood flow and [18F]-fluorodopamine uptake to the infarct zone between 2 weeks and 3 months, with no further change between 3 months and 6 months. However, the average rate of loss (t1/ 2 hour) of [18F]- fluorodopamine continued to decrease between 2 weeks and 6 months. This paralleled a continuing fall in the low-frequency to high-frequency autospectral power ratio throughout the 6 months after infarction. CONCLUSIONS This study demonstrates a modest increase in myocardial blood flow and evidence for sympathetic reinnervation to the infarct zone between 2 weeks and 3 months after acute myocardial infarction. Despite a flow-dependent effect on the uptake of [18F]-fluorodopamine by 3 months, there is a suggestion that restoration of sympathetic activity within the infarct zone continues between 3 months and 6 months after acute myocardial infarction.

Radiochemical and NMR spectroscopic investigation of the solvent effect on the electrophilic elemental fluorination of L-DOPA: synthesis of []5-fluoro-L-DOPA

Abstract Differences in reactivity and selectivity of fluorine in the electrophilic fluorination of 3,4-dihydroxy phenyl-L-alanine (L-DOPA) in different solvents have been exploited to produce mCi quantities of [ 18 F ]5-fluoro-L-DOPA. Proton and 13 C NMR spectroscopy have been used to show that, while the orientation of electrophilic fluorination of L-DOPA in weak acids (trifluoroacetic acid, 10% trifluoroacetic acid in glacial acetic acid and formic acid) is influenced by the electron donating OH groups on the ring, the orientation of electrophilic fluorination of L-DOPA in strong acids (HF and HF/BF3) is mainly influenced by the side-chain.

PET/CT using ¹⁸F-FDOPA provides improved staging of carcinoid tumor patients in a Canadian setting.

AimIn Canada, staging of carcinoid tumors is largely based on computed tomography (CT) imaging sometimes complemented with somatostatin receptor scintigraphy (SRS). This study assessed the diagnostic accuracy of 6-[18F]fluoro-3,4-dihydroxyphenylalanine (18F-FDOPA) PET/CT in neuroendocrine tumors. MethodsWe prospectively included 27 patients with either suspected carcinoid (n=6, with all prior tests negative) or with an established diagnosis of intestinal carcinoid tumor (n=21) from two Canadian treatment centers. Findings of 18F-FDOPA PET/CT were compared with SRS, CT, and combined SRS/CT using a composite reference standard comprising all available imaging, biochemistry, surgery, and follow-up data. Sensitivity was calculated per patient, per body region, and per lesion. The contribution to patient management was estimated from the feedback of attending physicians. ResultsIn documented carcinoid patients, 18F-FDOPA PET/CT identified disease in 20 of 21 patients (patient-based sensitivity 95%). In 56 positive regions, 18F-FDOPA PET/CT detected 53, CT detected 34, SRS detected 34, and CT+SRS detected 39 regions, leading to region-based sensitivities of 95, 61, 62, and 71%, respectively. Lesion-based sensitivities were 96, 69, 50, and 72%, respectively. In the six patients with suspected disease only, one CT scan was positive, but 18F-FDOPA PET/CT was negative for all. 18F-FDOPA PET contributed to patient management in 12/21 patients (57%). Conclusion18F-FDOPA PET/CT proved to be an excellent modality for staging of carcinoid tumor patients, with superior performance compared with currently applied methods in Canada. In patients with suspected disease with negative prior imaging investigations, 18F-FDOPA was not helpful.

The effect of aromatic fluorine substitution in L-DOPA on the in vivo behaviour of [18F]2-, [18F]5- and [18F]6-fluoro-L-DOPA in the human brain

Abstract Remarkable differences in the human in vivo behaviour of each of the three [ 18 F ]-labelled ring fluorinated isomers of l -dihydroxyphenylalanine ( l -DOPA) are presented. Unlike [ 18 F ]2-fluoro- l -DOPA, which did not appear to cross the blood brain barrier, [ 18 F ]5-fluoro- l -DOPA appears to be taken up and cleared from the cerebellum and the striata. In contrast with the 2- and 5-fluoro isomers of l -DOPA, radioactivity derived after injection of [ 18 F ]6-fluoro- l -DOPA is specifically retained in the striata. The present study is the first direct comparison of the time course and distribution of radioactivity in the human brain after intravenous injections of [ 18 F ]2-, [ 18 F ]5- and [ 18 F ]6-fluoro- l -DOPA.

Selectivity of elemental fluorine towards l-tyrosine and l-α-methyltyrosine in acidic media and the syntheses of their []3-fluoro and []3,5-difluoro derivatives

Abstract Fluorinated derivatives of l -tyrosine and l -α-methyltyrosine ( l -α-MT) are known to be useful tracers for medical imaging with positron emission tomography. Direct fluorination of l -tyrosine and l -α-MT with [ 18 F ]F 2 in different acidic media show increases in the radio-chemical yield of the 3-fluoro isomers as the acidity of the reaction medium is increased. Lower radiochemical yields and increased production of the 3,5-difluoro isomers of the tyrosine derivatives resulted when solvent mixtures containing BF 3 added to anhydrous HF (aHF) were used. Lower yields in BF 3 /aHF have been studied by use of low-temperature (−70°C) 1 H and 13 C NMR spectroscopy of l -α-MT, which showed deactivation of the aromatic ring in BF 3 /aHF. Improved isocratic preparative and analytical HPLC methods for the separation of the fluorinated tyrosine derivatives were also developed. All compounds synthesized in this study were characterized by NMR spectroscopy and mass spectrometry.

Synthesis of [18F]XeF2, a novel agent for the preparation of 18F-radiopharmaceuticals

[18F]XeF2 was synthesised by isotopic exchange between XeF2 and anhydrous reactor-produced [18F]HF, [18F]SiF4, and [18F]AsF5 with a radiochemical yield of 30%; [18F]XeF2 may facilitate the direct radiofluorination of organic tracer molecules for positron emission tomography.