Small animal positron emission tomography in food sciences

Summary. Positron emission tomography (PET) is a 3-dimensional imaging technique that has undergone tremendous developments during the last decade. Non-invasive tracing of molecular pathways in vivo is the key capability of PET. It has become an important tool in the diagnosis of human diseases as well as in biomedical and pharmaceutical research. In contrast to other imaging modalities, radiotracer concentrations can be determined quantitatively. By application of appropriate tracer kinetic models, the rate constants of numerous different biological processes can be determined. Rapid progress in PET radiochemistry has significantly increased the number of biologically important molecules labelled with PET nuclides to target a broader range of physiologic, metabolic, and molecular pathways. Progress in PET physics and technology strongly contributed to better scanners and image processing. In this context, dedicated high resolution scanners for dynamic PET studies in small laboratory animals are now available. These developments represent the driving force for the expansion of PET methodology into new areas of life sciences including food sciences. Small animal PET has a high potential to depict physiologic processes like absorption, distribution, metabolism, elimination and interactions of biologically significant substances, including nutrients, ‘nutriceuticals’, functional food ingredients, and foodborne toxicants. Based on present data, potential applications of small animal PET in food sciences are discussed.     

Principles of quantitative positron emission tomography

Summary. The central distinguishing feature of positron emission tomography (PET) is its ability to investigate quantitatively regional cellular and molecular transport processes in vivo with good spatial resolution. This review wants to provide a concise overview of the established principles underlying quantitative data evaluations of the acquired PET images. Especially, the compartment modelling framework is discussed on which virtually all quantification methods utilized in PET are based. The aim of the review is twofold: first, to provide the reader with an idea of the theoretical framework and mathematical tools and second, to enable an intuitive grasp of the possibilities and limitations of a quantitative approach to PET data evaluation. This should facilitate an understanding of how PET measurements translate into quantities such as regional blood flow, volume of distribution, and metabolic rates of specific substrates.     

Aspects of positron emission tomography radiochemistry as relevant for food chemistry

Summary. Positron emission tomography (PET) is a medical imaging technique using compounds labelled with short-lived positron emitting radioisotopes to obtain functional information of physiological, biochemical and pharmacological processes in vivo. The need to understand the potential link between the ingestion of individual dietary agents and the effect of health promotion or health risk requires the exact metabolic characterization of food ingredients in vivo. This exciting but rather new research field of PET would provide new insights and perspectives on food chemistry by assessing quantitative information on pharmocokinetics and pharmacodynamics of food ingredients and dietary agents. To fully exploit PET technology in food chemistry appropriately radiolabelled compounds as relevant for food sciences are needed. The most widely used short-lived positron emitters are ¹¹C (t_1/2 = 20.4 min) and ¹⁸F (t_1/2 = 109.8 min). Longer-lived radioisotopes are available by using ⁷⁶Br (t_1/2 = 16.2 h) and ¹²⁴I (t_1/2 = 4.12 d). The present review article tries to discuss some aspects for the radiolabelling of food ingredients and dietary agents either by means of isotopic labelling with ¹¹C or via prosthetic group labelling approaches using the positron emitting halogens ¹⁸F, ⁷⁶Br and ¹²⁴I.     

Application of positron emission tomography to neuroimaging in sports sciences

To investigate exercise-induced regional metabolic and perfusion changes in the human brain, various methods are available, such as positron emission tomography (PET), functional magnetic resonance imaging (fMRI), near-infrared spectroscopy (NIRS) and electroencephalography (EEG). In this paper, details of methods of metabolic measurement using PET, [¹⁸F]fluorodeoxyglucose ([¹⁸F]FDG) and [¹⁵O]radio-labelled water ([¹⁵O]H₂O) will be explained.Functional neuroimaging in the field of neuroscience was started in the 1970s using an autoradiography technique on experimental animals. The first human functional neuroimaging exercise study was conducted in 1987 using a rough measurement system known as ¹³³Xe inhalation. Although the data was useful, more detailed and exact functional neuroimaging, especially with respect to spatial resolution, was achieved by positron emission tomography. Early studies measured the cerebral blood flow changes during exercise. Recently, PET was made more applicable to exercise physiology and psychology by the use of the tracer [¹⁸F]FDG. This technique allowed subjects to be scanned after an exercise task is completed but still obtain data from the exercise itself, which is similar to autoradiography studies.In this report, methodological information is provided with respect to the recommended protocol design, the selection of the scanning mode, how to evaluate the cerebral glucose metabolism and how to interpret the regional brain activity using voxel-by-voxel analysis and regions of interest techniques (ROI).Considering the important role of exercise in health promotion, further efforts in this line of research should be encouraged in order to better understand health behavior. Although the number of research papers is still limited, recent work has indicated that the [¹⁸F]FDG-PET technique is a useful tool to understand brain activity during exercise.     

Metabolite analysis in positron emission tomography studies: examples from food sciences

Summary. Substances of various chemical structures can be labelled with appropriate positron emitting isotopes and applied as tracer compounds in PET examinations. Using dynamic data acquisition protocols, time-activity curves of radioactivity uptake in organs can be derived and the measurements of tissue tracer concentrations can be translated into quantitative values of tissue function. However, analysis of metabolites of these tracers regarding their nature and distribution in the living organism is an essential need for the quantitative analysis of PET measurements. In addition, metabolite analysis contributes to the interpretation of the images obtained as well as to the identification of pathological changes in metabolic pathways. This paper reports on representative examples of radiolabelled compounds which might be of importance in food science (e.g., amino acids, polyphenols, and model compounds for advanced glycation end products (AGEs)). Typical procedures of analysis (radio-HPLC, radio-TLC) including pre-analytical sample preparation are described. Specific challenges of the method, e.g., trace amounts of radiolabelled compounds and the influence of the often very short half-lives of positron-emitting nuclides used are highlighted. Representative results of analyses of plasma, urine, and tissue samples are presented and discussed in terms of the metabolic fate of the tracers.     

(18)F-labelling of A-ring substituted 16alpha-fluoro-estradiols as potential radiopharmaceuticals for PET imaging

The 2-methoxy derivative of estradiol is currently in Phase II clinical trial as an anticancer agent while the 4-methyl derivative has been shown to interact with cytoplasmic and nuclear estrogen receptors in rat pituitary gland and hypothalamus. We hypothesize that the 16alpha-(18)F-analogs of these estrogens could be suitable radiotracers to evaluate action mechanisms of the parent compounds. In this study we report the synthesis of the 16alpha-(18)F and 16alpha-(19)F-analogs of the A-ring substituted estradiols in high yield via stereoselective opening of the intermediate 16beta,17beta-O-cyclic sulfones with [(18)F]F(-) or F(-) followed by deprotection.     

Catabolism of native and oxidized low density lipoproteins: in vivo insights from small animal positron emission tomography studies

Summary. The human organism is exposed to numerous processes that generate reactive oxygen species (ROS). ROS may directly or indirectly cause oxidative modification and damage of proteins. Protein oxidation is regarded as a crucial event in the pathogenesis of various diseases ranging from rheumatoid arthritis to Alzheimer’s disease and atherosclerosis. As a representative example, oxidation of low density lipoprotein (LDL) is regarded as a crucial event in atherogenesis. Data concerning the role of circulating oxidized LDL (oxLDL) in the development and outcome of diseases are scarce. One reason for this is the shortage of methods for direct assessment of the metabolic fate of circulating oxLDL in vivo. We present an improved methodology based on the radiolabelling of apoB-100 of native LDL (nLDL) and oxLDL, respectively, with the positron emitter fluorine-18 (¹⁸F) by conjugation with N-succinimidyl-4-[¹⁸F]fluorobenzoate ([¹⁸F]SFB). Radiolabelling of both nLDL and oxLDL using [¹⁸F]SFB causes neither additional oxidative structural modifications of LDL lipids and proteins nor alteration of their biological activity and functionality, respectively, in vitro. The method was further evaluated with respect to the radiopharmacological properties of both [¹⁸F]fluorobenzoylated nLDL and oxLDL by biodistribution studies in male Wistar rats. The metabolic fate of [¹⁸F]fluorobenzoylated nLDL and oxLDL in rats in vivo was further delineated by dynamic positron emission tomography (PET) using a dedicated small animal tomograph (spatial resolution of 2 mm). From this study we conclude that the use of [¹⁸F]FB-labelled LDL particles is an attractive alternative to, e.g., LDL iodination methods, and is of value to characterize and to discriminate the kinetics and the metabolic fate of nLDL and oxLDL in small animals in vivo.     

<Superscript>18</Superscript>F-labeled tyrosine derivatives: Synthesis and experimental studies on accumulation in tumors and abscesses

Tyrosine derivatives labeled with a short-lived fluorine-18 isotope (T _1/2 110 min), namely 2-[¹⁸F]fluoro-L-tyrosine (FTYR) and O-(2′-[¹⁸F]fluoroethyl)-L-tyrosine (FET), promising radiopharmaceuticals (RPs) for positron emission tomography (PET), were obtained by asymmetric syntheses. Accumulation of FTYR and FET in the rat tumor “Glioma 35 rats tumor” and in abscesses induced in Wistar rats muscles was studied and compared with that of a well-known glycolysis radiotracer 2-[¹⁸F]fluoro-2-deoxy-D-glucose (FDG). It was shown that the relative accumulation indices of amino acid RPs were considerably lower than those of FDG. At the same time, tumor/muscle ratios were high enough (2.9 for FET and 3.9 for FTYR 120 min after injection) for reliable tumor visualization. The data obtained indicated a possibility in principle to use FTYR and FET for differentiated PET diagnostics of brain tumors and inflammation lesions. Of the tyrosine derivatives studied, FET seems to be the most promising agent due to a simple and easily automated method of preparation based on direct nucleophilic substitution of the leaving tosyloxy group of an enantiomerically pure Ni-(S)-BPS-(S)-Tyr(CH₂CH₂OTs) precursor by an activated [¹⁸F]fluoride.     

Synthesis of 18F-labeled streptozotocin derivatives and an in-vivo kinetics study using positron emission tomography

Glucose transporter 2 (GLUT2) is involved in glucose uptake by hepatocytes, pancreatic beta cells, and absorptive cells in the intestine and proximal tubules in the kidney. Pancreatic GLUT2 also plays an important role in the mechanism of glucose-stimulated insulin secretion. In this study, novel Fluorine-18-labeled streptozotocin (STZ) derivatives were synthesized to serve as glycoside analogs for in-vivo GLUT2 imaging. Fluorine was introduced to hexyl groups at the 3′-positions of the compounds, and we aimed to synthesize compounds that were more stable than STZ. The nitroso derivatives exhibited relatively good stability during purification and purity analysis after radiosynthesis. We then evaluated the compounds in PET imaging and ex-vivo biodistribution studies. We observed high levels of radioactivity in the liver and kidney, which indicated accumulation in these organs within 5 min of administration. In contrast, the denitroso derivatives accumulated only in the kidney and bladder shortly after administration. Compounds with nitroso groups are thus expected to accumulate in GLUT2-expressing organs, and the presence of a nitroso group is essential for in-vivo GLUT2 imaging.     

Synthesis and evaluation of 6-[1-(2-[(18)F]fluoro-3-pyridyl)-5-methyl-1H-1,2,3-triazol-4-yl]quinoline for positron emission tomography imaging of the metabotropic glutamate receptor type 1 in brain

The purpose of this study was to synthesize 6-[1-(2-[¹⁸F]fluoro-3-pyridyl)-5-methyl-1H-1,2,3-triazol-4-yl]quinoline ([¹⁸F]FPTQ, [¹⁸F]7a) and to evaluate its potential as a positron emission tomography ligand for imaging metabotropic glutamate receptor type 1 (mGluR1) in the rat brain. Compound [¹⁸F]7a was synthesized by [¹⁸F]fluorination of 6-[1-(2-bromo-3-pyridyl)-5-methyl-1H-1,2,3-triazol-4-yl]quinoline (7b) with potassium [¹⁸F]fluoride. At the end of synthesis, 1280-1830 MBq (n = 8) of [¹⁸F]7a was obtained with >98% radiochemical purity and 118-237 GBq/??mol specific activity using 3300-4000 MBq of [¹⁸F]F⁻. In vitro autoradiography showed that [¹⁸F]7a had high specific binding with mGluR1 in the rat brain. Biodistribution study using a dissection method and small-animal PET showed that [¹⁸F]7a had high uptake in the rat brain. The uptake of radioactivity in the cerebellum was reduced by unlabeled 7a and mGluR1-selective ligand JNJ-16259685 (2), indicating that [¹⁸F]7a had in vivo specific binding with mGluR1. Because of a low amount of radiolabeled metabolite present in the brain, [¹⁸F]7a may have a limiting potential for the in vivo imaging of mGluR1 by PET.     

Synthesis and evaluation of 18F-labeled tertiary benzenesulfonamides for imaging carbonic anhydrase IX expression in tumours with positron emission tomography

Three tertiary benzenesulfonamide inhibitors 4a–c were radiolabeled with ¹⁸F and evaluated for imaging carbonic anhydrase IX (CA IX) expression with positron emission tomography. All three inhibitors exhibit <10 nM affinity for CA IX with no measurable affinity for CA II. Despite good affinity/selectivity to CA IX and excellent stability in plasma, uptake of [¹⁸F]4a–c in CA IX-expressing HT-29 tumours was low without significant contrast. [¹⁸F]4a,b were excreted rapidly, while [¹⁸F]4c exhibited significant in vivo defluorination leading to high bone uptake. Due to minimal uptake in HT-29 tumours compared to normal organs/tissues, ¹⁸F-labeled benzenesulfonamides [¹⁸F]4a–c are not suitable as CA IX imaging agents.     

Synthesis of fluorinated analogues of sphingosine-1-phosphate antagonists as potential radiotracers for molecular imaging using positron emission tomography

Sphingosine-1-phosphate (S1P) receptors play major roles in cardiovascular, immunological and neurological diseases. The recent approval of the sphingolipid drug Fingolimod (Gilenya®), a sphingosine-1-phosphate agonist for relapsing multiple sclerosis, in 2010 exemplifies the potential for targeting sphingolipids for the treatment of human disorders. Moreover, non-invasive in vivo imaging of S1P receptors that are not available till now would contribute to the understanding of their role in specific pathologies and is therefore of preclinical interest. Based on fluorinated analogues of the S1P₁ receptor antagonist W146 showing practically equal in vitro potency as the lead structure, the first S1P receptor antagonist [¹⁸F]-radiotracer has been synthesized and tested for in vivo imaging of the S1P₁ receptor using positron emission tomography (PET). Though the tracer is serum stable, initial in vivo images show fast metabolism and subsequent accumulation of free [¹⁸F]fluoride in the bones.     

Synthesis and in vitro evaluation of [18F]fluoroethyl triazole labelled [Tyr3]octreotate analogues using click chemistry

A novel class of alkyne linked [Tyr³]octreotate analogues have been labelled by a copper catalysed azide-alkyne cycloaddition reaction (CuAAC) to form a 1,4-substituted triazole using the reagent [¹⁸F]2-fluoroethyl azide. An unexpected variability in reactivity during the CuAAC reaction was observed for each alkyne analogue which has been investigated. Two lead alkyne linked [Tyr³]octreotate analogues, G-TOCA (3a) and βAG-TOCA (5a) have been identified to be highly reactive in the click reaction showing complete conversion to the [¹⁸F]2-fluoroethyl triazole linked [Tyr³]octreotate analogues FET-G-TOCA (3b) and FET-βAG-TOCA (5b) under mild conditions and with short synthesis times (5 min at 20 °C). As well as ease of synthesis, in vitro binding to the pancreatic tumour AR42J cells showed that both FET-G-TOCA and FET-βAG-TOCA have high affinity for the somatostatin receptor with IC₅₀ of 4.0 ± 1.4, and 1.6 ± 0.2 nM, respectively.     

Kinetic modeling of [18F]VAT,a novel radioligand for positron emission tomography imaging vesicular acetylcholine transporter in non‐human primate brain

Molecular imaging of vesicular acetylcholine transporter (VACh T) in the brain provides an important cholinergic biomarker for the pathophysiology and treatment of dementias including Alzheimer's disease. In this study, kinetics modeling methods were applied and compared for quantifying regional brain uptake of the VACh T‐specific positron emission tomography radiotracer, ((?)‐(1‐(‐8‐(2‐fluoroethoxy)‐3‐hydroxy‐1,2,3,4‐tetrahydronaphthalen‐2‐yl)piperidin‐4‐yl)(4‐fluorophenyl)‐methanone) ([¹⁸F]VAT ) in macaques. Total volume distribution (V _T ) estimates were compared for one‐tissue compartment model (1TCM ), two‐tissue compartment model (2TCM ), Logan graphic analysis (LoganAIF ) and multiple linear analysis (MA 1) with arterial blood input function using data from three macaques. Using the cerebellum‐hemispheres as the reference region with data from seven macaques, three additional models were compared: reference tissue model (RTM ), simplified RTM (SRTM ), and Logan graphic analysis (LoganREF ). Model selection criterion indicated that a) 2TCM and SRTM were the most appropriate kinetics models for [¹⁸F]VAT ; and b) SRTM was strongly correlated with 2TCM (Pearson's coefficients r  > 0.93, p  < 0.05). Test–retest studies demonstrated that [¹⁸F]VAT has good reproducibility and reliability (TRV < 10%, ICC > 0.72). These studies demonstrate [¹⁸F]VAT is a promising VACh T positron emission tomography tracer for quantitative assessment of VACh T levels in the brain of living subjects.

     

Fluorine-18 labeled galactosyl-neoglycoalbumin for imaging the hepatic asialoglycoprotein receptor

Asialoglycoprotein receptors (ASGP-R) are well known to exist on the mammalian liver, situate on the surface of hepatocyte membrane. Quantitative imaging of asialoglycoprotein receptors could estimate the function of the liver. ^99mTc labeled galactosyl-neoglycoalbumin (NGA) and diethylenetriaminepentaacetic acid galactosyl human serum albumin (GSA) have been developed for SPECT imaging and clinical used in Japan. In this study, we labeled the NGA with ¹⁸F to get a novel PET tracer [¹⁸F]FNGA and evaluated its hepatic-targeting efficacy and pharmacokinetics. Methods: NGA was labeled with ¹⁸F by conjugation with N-succinimidyl-4-¹⁸F-fluorobenzoate ([¹⁸F]SFB) under a slightly basic condition. The in vivo metabolic stability of [¹⁸F]FNGA was determined. Ex vivo biodistribution of [¹⁸F]FNGA and blocking experiment was investigated in normal mice. MicroPET images were acquired in rat with and without block at 5 min and 15 min after injection of the radiotracer (3.7 MBq/rat), respectively. Results: Starting with ¹⁸F⁻ Kryptofix 2.2.2./K₂CO₃ solution, the total reaction time for [¹⁸F]FNGA is about 150 min. Typical decay-corrected radiochemical yield is about 8–10%. After rapid purified with HiTrap desalting column, the radiochemical purity of [¹⁸F]FNGA was more than 99% determined by radio-HPLC. [¹⁸F]FNGA was metabolized to produce [¹⁸F]FB-Lys in urine at 30 min. Ex vivo biodistribution in mice showed that the liver accumulated 79.18 ± 7.17% and 13.85 ± 3.10% of the injected dose per gram at 5 and 30 min after injection, respectively. In addition, the hepatic uptake of [¹⁸F]FNGA was blocked by pre-injecting free NGA as blocking agent (18.55 ± 2.63%ID/g at 5 min pi), indicating the specific binding to ASGP receptor. MicroPET study obtained quality images of rat at 5 and 15 min post-injection. Conclusion: The novel ASGP receptor tracer [¹⁸F]FNGA was synthesized with high radiochemical yield. The promising biological properties of [¹⁸F]FNGA afford potential applications for assessment of hepatocyte function in the future. It may provide quantitative information and better resolution which particularly help to the liver surgery.     

Synthesis and evaluation of 18F-labeled CJ-042794 for imaging prostanoid EP4 receptor expression in cancer with positron emission tomography

The potent and selective prostanoid EP4 receptor antagonist CJ-042794 was radiolabeled with ¹⁸F, and evaluated for imaging EP4 receptor expression in cancer with positron emission tomography (PET). The fluorination precursor, arylboronic acid pinacol ester 4, was prepared in 4 steps with 42% overall yield. ¹⁸F-CJ-042794 was synthesized via a copper-mediated ¹⁸F-fluorination reaction followed by base hydrolysis, and was obtained in 1.5 ± 1.1% (n = 2) decay-corrected radiochemical yield. PET/CT imaging and biodistribution studies in mice showed that ¹⁸F-CJ-042794 was excreted through both renal and hepatobiliary pathways with significant retention in blood. The EP4-receptor-expressing LNCaP prostate cancer xenografts were clearly visualized in PET images with 1.12 ± 0.08%ID/g (n = 5) uptake value and moderate tumour-to-muscle contrast ratio (2.73 ± 0.22) at 1 h post-injection. However, the tumour uptake was nonspecific as it could not be blocked by co-injection of cold standard, precluding the application of ¹⁸F-CJ-042794 for PET imaging of EP4 receptor expression in cancer.     

The use of positron emission tomography for studies of long-distance transport in plants: uptake and transport of 18F

Abstract. Positron emission tomography (PET) has been utilized to obtain dynamic images of long distance nutrient translocation in plants. Positron emitting ¹⁸F, produced by a Van de Graaff accelerator using the reaction ¹⁸O(p,n)¹⁸F, was fed in solution to excised stems of Glycine max positioned vertically in a large-aperture PET detector system. Images of tracer activity were recorded with a time resolution of 0.5 min and a spatial resolution of 4 mm. Maximum tracer activities at stem sites were obtained within 3 min of the pulse feed. A model is presented enabling evaluation of regional values for tracer flow, tracer binding, flow speed and flow volume. Analysis of data for one stem position yielded a flow volume of 2.1mm³ min⁻¹ and a flow speed of 36cm min⁻¹. Comparison with the distribution of ¹⁴C-inulin, which was simultaneously fed to the cut stems, indicates the ¹⁸F is suitable for use as an apoplastic tracer; 92% of the tracer activity accumulated in the leaves. The fraction of ¹⁸F that remained bound was most concentrated at stem nodal regions, an observation consistent with the existence of transfer cells at these sites. Advantages and limitations of PET applied to plant physiological investigations are discussed.     

Synthesis of [¹¹C]PBR06 and [¹⁸F]PBR06 as agents for positron emission tomographic (PET) imaging of the translocator protein (TSPO)

The translocator protein 18 kDa (TSPO) is an attractive target for molecular imaging of neuroinflammation and tumor progression. [¹⁸F]PBR06, a fluorine-18 labeled form of PBR06, is a promising PET TSPO radioligand originally developed at NIMH. [¹¹C]PBR06, a carbon-11 labeled form of PBR06, was designed and synthesized for the first time. The standard PBR06 was synthesized from 2,5-dimethoxybenzaldehyde in three steps with 71% overall chemical yield. The radiolabeling precursor desmethyl-PBR06 was synthesized from 2-hydroxy-5-methoxybenzaldehyde in five steps with 12% overall chemical yield. The target tracer [¹¹C]PBR06 was prepared by O-[¹¹C]methylation of desmethyl-PBR06 with [¹¹C]CH₃OTf in CH₃CN at 80 °C under basic condition and isolated by HPLC combined with SPE purification with 40–60% decay corrected radiochemical yield and 222–740 GBq/μmol specific activity at EOB. On the similar grounds, [¹⁸F]PBR06 was also designed and synthesized. The previously described Br-PBR06 precursor was synthesized from 2,5-dimethoxybenzaldehyde in two steps with 78% overall chemical yield. A new radiolabeling precursor tosyloxy-PBR06, previously undescribed tosylate congener of PBR06, was designed and synthesized from ethyl 2-hydroxyacetate, 4-methylbenzene-1-sulfonyl chloride, and N-(2,5-dimethoxybenzyl)-2-phenoxyaniline in four steps with 50% overall chemical yield. [¹⁸F]PBR06 was prepared by the nucleophilic substitution of either new tosyloxy-PBR06 precursor or known Br-PBR06 precursor in DMSO at 140 °C with K[¹⁸F]F/Kryptofix 2.2.2 for 15 min and HPLC combined with SPE purification in 20–60% decay corrected radiochemical yield, >99% radiochemical purity, 87–95% chemical purity, and 37–222 GBq/μmol specific activity at EOB. Radiosynthesis of [¹⁸F]PBR06 using new tosylated precursor gave similar radiochemical purity, and higher specific activity, radiochemical yield and chemical purity in comparison with radiosynthesis using bromine precursor.     

Age-related decline of dopamine synthesis in the living human brain measured by positron emission tomography with L-[beta-11C]DOPA

Loss of dopamine synthesis in the striatum with normal human aging has been observed in the postmortem brain. To investigate whether there is age-associated change in dopamine synthesis in the extrastriatal brain regions similar to that in the striatum, positron emission tomography studies with (11)C-labelled l-DOPA were performed on 21 normal healthy male subjects (age range 20-67 years). Decline in the tissue fraction of gray matter per region of interest was also investigated. The overall uptake rate constant for each region of interest was quantified by the Patlak plot method using the occipital cortex as reference region. Regions of interest were set on the dorsolateral prefrontal cortex, lateral temporal cortex, medial temporal cortex, occipital cortex, parietal cortex, anterior cingulate, thalamus, midbrain, caudate nucleus, and putamen. Test-retest analysis indicated good reproducibility of the overall uptake rate constant. Significant age-related declines of dopamine synthesis were observed in the striatum and extrastriatal regions except midbrain. The decline in the overall uptake rate constant was more prominent than in the tissue fraction of gray matter. These results indicate that the previously demonstrated age-related decline in striatal dopamine synthesis extends to several extrastriatal regions in normal human brain.     

Triaryl (Z)-olefins suitable for radiolabeling with iodine-124 or fluorine-18 radionuclides for positron emission tomography imaging of estrogen positive breast tumors

A group of (Z)-1,2-diphenyl-1-[4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl]but-1-enes were synthesized using methodologies that will allow incorporation of a [¹²⁴I]iodine substituent at the para-position of either the C-1 phenyl ring or the C-2 phenyl ring, or a [¹⁸F]OCH₂CH₂F substituent at the para-position of the C-2 phenyl ring. These [¹²⁴I] and [¹⁸F] radiotracers are designed as potential radiopharmaceuticals to image estrogen positive breast tumors using positron emission tomography (PET).