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PubMed1980

Choline uptake by the neuroblastoma x glioma hybrid, NG108-15.

The neuroblastoma x glioma hybrid clone NG108-15 is able to release acetylcholine upon depolarization and form cholinergic neuromuscular synapses in culture. Normal functioning of cholinergic synapses is thought to be dependent on the ability of a neuron to take up extracellular choline, since neurons are unable to synthesize choline de novo. For these two reasons it became important to characterize the choline uptake system of NG108-15 cells. The uptake system appears to bear little if any resemblance to the Na+-dependent high-affinity choline uptake system normally associated with cholinergic neurons. Although the cells appear to possess both high- and low-affinity choline uptake systems, neither system is dependent on Na+ and uptake actually is increased about 60% by the substitution of sucrose for NaCl. Acetylcholine synthesis also is not dependent on Na+, since sucrose, substituted for NaCl, also stimulates acetylcholine synthesis. Changes in the concentrations of the other ions in the uptake medium have little effect on uptake, with the exception that elevated Ca2+ or Mg2+ reverses the stimulation of choline uptake produced by substitution of sucrose for NaCl. Choline uptake is inhibited by hemicholinium-3, but only at high concentrations of the drug (IC50 = 30-80 microM). The metabolic poisons cyanide and iodoacetate inhibit uptake by only 30-40%. Growth of the cells in N6,O2' dibutyryladenosine-3',5'-cyclic monophosphate, which promotes functional and morphological differentiation of the cells, decreased slightly the total amount of choline taken up but had no additional effect on the uptake system. Thus, it appears that NG108-15 cells are capable of forming functional cholinergic synapses with muscle cells even though the neuroblastoma does not possess the high-affinity choline uptake system normally associated with cholinergic neurons.

Animals↗
PubMed1981

Deanol affects choline metabolism in peripheral tissues of mice.

Administration of 2-dimethylaminoethanol (deanol) to mice induced an increase in both the concentration and the rate of turnover of free choline in blood. Treatment with deanol also caused an increase in the concentration of choline in kidneys, and markedly inhibited the rates of oxidation and phosphorylation of intravenously administered [3H-methyl]choline. In the liver, deanol inhibited the rate of phosphorylation of [3H-methyl]choline, but did not inhibit its rate of oxidation or cause an increase in the level of free choline. These findings suggest that deanol increases the choline concentration in blood by inhibition of its metabolism in tissues. Deanol may ultimately produce its central cholinergic effects by inhibition of choline metabolism in peripheral tissues, causing free choline choline to accumulate in blood, enter the brain, and stimulate cholinergic receptors.

Animals↗
PubMed1982

Choline-containing bacteriophage receptors in Streptococcus pneumoniae.

Choline-containing teichoic acid seems to be essential for the adsorption of bacteriophage Dp-1 to pneumococci. This conclusion is based on the following observations: In contrast to pneumococci grown in choline-containing medium, cells grown in medium containing ethanolamine or other submethylated aminoalcohols instead of choline were found to be resistant to infection by Dp-1. Live choline-grown bacteria and heat- or UV-inactivated cells and purified cell walls prepared from these cells were capable of adsorbing phage Dp-1; ethanolamine-grown pneumococci or cell wall preparations were unable to do so. Adsorption of Dp-1 to choline-containing cell walls was competitively inhibited by phosphorylcholine and by several choline-containing soluble cell surface components, such as the Forssman antigen and the teichoic acid-glycan complexes formed by autolytic cell wall degradation. Cell walls prepared from pneumococci grown in ethanolamine or phosphorylethanolamine were inactive. Electron microscopic studies with pneumococci that had segments of choline-containing cell wall material amid ethanolamine-containing regions indicated that the Dp-1 phage particles adsorbed exclusively to the choline-containing surface areas. We suggest that the choline residues of the pneumococcal teichoic acid are essential components of the Dp-1 phage receptors in this bacterium.

Adsorption↗
PubMed1994

Osmoregulation in Bacillus subtilis: synthesis of the osmoprotectant glycine betaine from exogenously provided choline.

Exogenously provided glycine betaine functions as an efficient osmoprotectant for Bacillus subtilis in high-osmolarity environments. This gram-positive soil organism is not able to increase the intracellular level of glycine betaine through de novo synthesis in defined medium (A. M. Whatmore, J. A. Chudek, and R. H. Reed, J. Gen. Microbiol. 136:2527-2535, 1990). We found, however, that B. subtilis can synthesize glycine betaine when its biosynthetic precursor, choline, is present in the growth medium. Uptake studies with radiolabelled [methyl-14C]choline demonstrated that choline transport is osmotically controlled and is mediated by a high-affinity uptake system. Choline transport of cells grown in low- and high-osmolarity media showed Michaelis-Menten kinetics with Km values of 3 and 5 microM and maximum rates of transport (Vmax) of 10 and 36 nmol min-1 mg of protein-1, respectively. The choline transporter exhibited considerable substrate specificity, and the results of competition experiments suggest that the fully methylated quaternary ammonium group is a key feature for substrate recognition. Thin-layer chromatography revealed that the radioactivity from exogenously provided [methyl-14C]choline accumulated intracellularly as [methyl-14C]glycine betaine, demonstrating that B. subtilis possesses enzymes for the oxidative conversion of choline into glycine betaine. Exogenously provided choline significantly increased the growth rate of B. subtilis in high-osmolarity media and permitted its proliferation under conditions that are otherwise strongly inhibitory for its growth. Choline and glycine betaine were not used as sole sources of carbon or nitrogen, consistent with their functional role in the process of adaptation of B. subtilis to high-osmolarity stress.

Bacillus subtilis↗
PubMed1992

Transport of choline by plasma membrane vesicles from lung-derived epithelial cells.

A549 cells, a lung epithelium-derived cell line, were used as a model system to study choline transport by granular pneumocytes. Intact cells accumulated free choline against a concentration gradient by a low-affinity transport system with kinetic characteristics similar to that previously described for granular pneumocytes (Am. J. Respir. Cell Mol. Biol. 1: 455, 1989). Membrane vesicles prepared from these cells showed a 10-fold enrichment in plasma membrane marker enzymes with a vesicular H2O space of 5.7 +/- 0.05 (SE) microliters/mg protein. Vesicles showed a time- and concentration-dependent uptake of free [3H]choline in Na(+)-free medium. With 5 microM choline, choline uptake reached an apparent steady-state concentration gradient (inside/outside) of 50. 3H that was membrane associated ("bound" choline) represented approximately 5% of total uptake. In the presence of an initial gradient of NaCl, choline uptake showed an overshoot with a plateau value similar to Na(+)-free conditions; a similar effect was observed for plasma membrane vesicles from rat lung type 2 epithelial cells. The steady-state uptake of choline was inhibited at low pH (6.5) and by the presence of valinomycin or carbonyl cyanide p-tri-fluoromethoxyphenylhydrazone and was abolished when both were present. These results show that plasma membrane vesicles from A549 cells accumulate choline by binding to the membranes and by Na(+)-dependent and -independent transport mechanisms, the latter apparently reflecting a transmembrane proton gradient.

Animals↗
PubMed2002

Regulation of neuronal function by choline and 4OH-GTS-21 through alpha 7 nicotinic receptors.

A unique feature of alpha7 nicotinic acetylcholine receptor physiology is that, under normal physiological conditions, alpha7 receptors are constantly perfused with their natural selective agonist, choline. Studying neurons of hypothalamic tuberomammillary (TM) nucleus, we show that choline and the selective alpha7 receptor agonist 4OH-GTS-21 can regulate neuronal functions directly, via activation of the native alpha7 receptors, and indirectly, via desensitizing those receptors or transferring them into a state "primed" for desensitization. The direct action produces depolarization and thereby increases the TM neuron spontaneous firing (SF) rate. The regulation of the spontaneous firing rate is robust in a nonphysiological range of choline concentrations >200 microM. However, modest effects persist at concentrations of choline that are likely to be attained perineuronally under some conditions (20-100 microM). At high physiological concentration levels, the indirect choline action reduces or even eliminates the responsiveness of alpha7 receptors and their availability to other strong cholinergic inputs. Similarly to choline, 4OH-GTS-21 increases the TM neuron spontaneous firing rate via activation of alpha7 receptors, and this regulation is robust in the range of clinically relevant concentrations of 4OH-GTS-21. We conclude that factors that regulate choline accumulation in the brain and in experimental slices such as choline uptake, hydrolysis of ACh, membrane phosphatidylcholine catabolism, and solution perfusion rate influence alpha7 nAChR neuronal and synaptic functions, especially under pathological conditions such as stroke, seizures, Alzheimer's disease, and head trauma, when the choline concentration in the CSF is expected to rise.

Aconitine↗
PubMed2001

Maternal choline availability alters the localization of p15Ink4B and p27Kip1 cyclin-dependent kinase inhibitors in the developing fetal rat brain hippocampus.

Previously we have shown that changes in maternal dietary choline are associated with permanent behavioral changes in offspring. Importantly, in adult male rats, feeding a choline-deficient diet increases the localization of cyclin-dependent kinase inhibitors (CDKIs) in the liver, whereas young adult CDKI knockout mice (p15Ink4B or p27Kip1) exhibit behavioral abnormalities. Thus, maternal dietary choline-CDKI interactions could underlie the changes we observe in fetal hippocampal development and cognitive function in offspring. Here, timed-pregnant rats on embryonic day E12 were fed the AIN-76 diet with varying levels of dietary choline for 6 days, and, on E18, fetal brain sections were collected, and the localization of CDKI proteins was studied using immunohistochemistry and an unbiased image analysis method. In choline-supplemented animals compared to controls, the number of cells with nuclear immunoreactivity for p15Ink4b CDKI protein was decreased 2- to 3-fold in neuroepithelial ventricular zones and adjacent subventricular zones corresponding to the fimbria, primordial dentate gyrus and Ammon's horn regions in the fetal hippocampus. In contrast, maternal dietary choline deficiency significantly decreased nuclear p15Ink4b immunoreactivity in the neuroepithelial layer of the dentate gyrus. Unlike p15Ink4b, the CDKI protein p27Kip1 was observed almost exclusively in the cytoplasm, though the protein was distributed throughout the proliferating and postmitotic zones in the E18 fetal hippocampus. Maternal dietary choline supplementation decreased the cytoplasmic staining intensity for p27Kip1 throughout the fetal hippocampus compared to control animals. Choline deficiency increased the staining intensity of p27Kip1 throughout the hippocampus in association with increased expression of MAP-1 and vimentin proteins. These results link maternal dietary choline availability to CDKI protein immunoreactivity and commitment to differentiation during fetal hippocampal development.

Animal Nutritional Physiological Phenomena↗
PubMed2005

11C-choline positron emission tomography in prostate cancer: primary staging and recurrent site staging.

OBJECTIVES: To evaluate the usefulness of 11C-choline positron emission tomography (PET) for primary staging and re-staging of prostate cancer. PATIENTS AND METHODS: 11C-choline PET, a total of 22 scans, was performed on 13 patients with histologically proven prostate cancer in primary staging (n = 6) and recurrent site staging; following radical prostatectomy (n = 5) and following radiation therapy (n = 3). In 1 patient, 11C-choline PET was performed in both primary staging and re-staging. Also, 3 patients histologically proven to have no malignant prostate were included. RESULTS: Because urinary 11C-choline activity was low, it did not interfere with the visualization of pelvic structures. 11C-choline PET visualized normal prostate with a mean SUV of 2.99 (range 2.27-3.68) and primary prostate cancer as a hot spot in 5/6 scans with a mean SUV of 4.21 (range 2.99-6.2). In re-staging, 11C-choline PET was true positive in 9/16 scans and true negative in 2/16 scans. 5/16 scans in 2 patients were false negative with negative conventional imaging. CONCLUSIONS: In primary staging, 11C-choline PET may not be of use because of no reliable differential 11C-choline uptake of BPH and prostate cancer. On the other hand, 11C-choline PET may be of value in recurrent site staging and monitoring for the prostate cancer.

Aged↗
PubMed1989

Focal ischemia enhances choline output and decreases acetylcholine output from rat cerebral cortex.

Choline concentration is rate limiting in the synthesis of acetylcholine. There is a negative arteriovenous difference for choline concentration across the brain, indicating the steady output of choline from this organ. Cerebral ischemia may increase extracellular choline concentration by interfering with its removal by the circulation and by enhancing its net production from phospholipids. We tested this hypothesis in six rats subjected to middle cerebral artery occlusion. We determined choline and acetylcholine output from the ischemic cerebral cortex by analyzing their concentrations in the fluid contained in cortical cups by gas chromatography-mass spectrometry. Mean +/- SEM choline output over 40 minutes before ischemia (baseline value) was 31.1 +/- 1.6 pmol/min/cm2. During ischemia, mean +/- SEM choline output rose to 100.8 +/- 13, 97.3 +/- 12.7, 100 +/- 22.4, and 93.1 +/- 16.9 pmol/min/cm2 in four consecutive 10-minute periods, respectively. Mean +/- SEM acetylcholine output was 15.6 +/- 1.1 before and 5.9 +/- 1.2, 8.3 +/- 2.6, 8.6 +/- 2.1, and 13.7 +/- 4.6 pmol/min/cm2 in the four 10-minute collection periods during ischemia. All four choline values and the first acetylcholine value during ischemia were significantly different from their respective baseline values. We conclude that ischemia induces an increase in extracellular choline concentration with possible implications for acetylcholine metabolism. The attending transient decline in acetylcholine output may be due to impaired release due to local hypoxia or to decreased acetylcholine synthesis.

Acetylcholine↗
PubMed1992

Inhibitors of choline transport in alveolar type II epithelial cells.

Isolated alveolar type II epithelial cells (granular pneumocytes) from rat lung accumulate free choline against a concentration gradient by an energy-dependent saturable transport process with apparent Km approximately 18 microM. In order to evaluate the structural requirements for choline transport by these cells, the inhibition of the initial rate of cellular uptake of [3H]choline (5 microM) by its analogue was measured. There was no significant inhibition of substrate uptake by analogues lacking an amino group while the presence of a quaternary nitrogen was most effective. N,N'-dimethylethanolamine (apparent Ki, 7 microM) and n-decylcholine (apparent Ki, 0.5 microM) were potent competitive inhibitors of choline transport. Substitution of the hydroxyl group in choline greatly diminished the inhibitory effect; fluorocholine, thiocholine, betaine, and betaine aldehyde showed little or no inhibition. This requirement for a hydroxyl group raises the possibility of hydrogen bonding of choline with the transport protein. The choline transport system in granular pneumocytes appears to differ from that in synaptosomes by the lower affinity of the carrier for substrate and for hemicholinium-3 and from that in erythrocytes by the role of the hydroxyl in the substrate molecule. The availability of inhibitory analogues for choline transport will facilitate isolation and study of the granular pneumocyte choline transport protein.

Amines↗
PubMed1998

Choline depletion, frq mutations, and temperature compensation of the circadian rhythm in Neurospora crassa.

In the fungus Neurospora crassa, the chol-1 mutation blocks the synthesis of the lipid phosphatidylcholine and also lengthens the period of the circadian rhythm of conidiation under conditions of choline depletion. The frq mutations, which have no known metabolic defect, affect both the period of the rhythm and temperature compensation. In this article, the chol-1 mutant strain has been further characterized with respect to its temperature compensation and its interactions with frq. Choline depletion of chol-1 abolishes good temperature compensation: Low temperatures lengthen the period under choline-depleted conditions, and low choline lengthens the period at any one temperature. Double-mutant strains carrying both chol-1 and one of a series of frq alleles demonstrate interactions between chol-1 and frq: On high choline, the periods of the double mutants are identical to the corresponding chol+ strains, whereas on low choline all double mutants display very long periods (greater than 50 h). Short-period frq mutations shorten the long period on low choline, whereas long-period frq mutations frq mutations have no effect. A null frq mutation in the chol-1 background is arrhythmic on high choline but is robustly rhythmic on low choline and has no effect on the long period. The interactions between frq and chol-1 are similar to the interactions between frq and cel, another lipid-deficient mutant. These results provide support for the hypothesis that membrane lipids may be involved in temperature compensation of the circadian rhythm. The possibility is discussed that the frq gene may not be required for circadian rhythmicity under some conditions and therefore may not be a central component of the circadian oscillator but rather a component of an input pathway.

Choline↗
PubMed2004

Hormone regulation of choline uptake and incorporation in mouse mammary gland explants.

Choline is a nutrient in milk that is essential for the nourishment and growth of newborns. In rat milk, choline is present in concentrations that are more than an order of magnitude higher than in maternal serum. Using cultured mammary tissues taken from 12-14-day pregnant mice, the effects of the three primary lactogenic hormones--prolactin (PRL), insulin (I), and cortisol (H)--on choline uptake and incorporation into lipids were determined. By itself or in the presence of H and/or PRL, I was the only hormone that increased the accumulation of choline in aqueous tissue fractions. In contrast, PRL, when present with I plus H, was the only hormone that stimulated the incorporation of choline into the lipid fraction of tissues. Choline uptake was found to be sodium and time dependent; maximum distribution ratios >18 were achieved after a 6-hr uptake time. In kinetic studies the apparent Km for choline uptake was calculated to be approximately 2.7 mM, whereas the Vmax was 7.4 mM intracellular water per 30 mins. These results suggest the existence of a sodium-dependent active transporter for choline in the mouse mammary gland that is specifically stimulated by I. PRL, in contrast, only stimulates the incorporation of choline into lipids.

Animals↗
PubMed1980

Normal plasma choline responses to ingested lecithin.

We examined plasma choline changes after ingestion of diets composed of common foodstuffs, with choline contents bracketing the average daily intake in the American diet, and ingestion of diets supplemented with exogenous purified lecithin. A diet with low choline content did not increase plasma choline concentrations; a diet with high choline content doubled plasma choline levels. A lecithin-supplemented (25 gm; 80% phosphatidylcholine) low-choline diet increased plasma choline levels 400%. These findings indicate that normal diets cause only small elevations in plasma choline; purified lecithin supplements are likely to have greater effects in treating neurologic diseases.

Adolescent↗
PubMed1993

Transport mechanism of choline in rat renal brush-border membrane.

The transport mechanism of choline was examined using rat renal brush-border membrane vesicles in comparison with tetraethylammonium transport. The stimulatory effect of an outward H+ gradient on choline uptake was weak compared with that on tetraethylammonium uptake. [14C]Tetraethylammonium uptake was cis-inhibited and trans-stimulated by choline, but the effects were less pronounced than those produced by unlabeled tetraethylammonium. [3H]Choline uptake was trans-stimulated by unlabeled choline, but not by tetraethylammonium. An interior-negative membrane potential induced marked stimulation of choline uptake against its concentration gradient (overshoot phenomenon), and the uptake was saturable with an apparent Km of 0.77 mM. Various compounds such as hemicholinium-3 inhibited the choline uptake by renal brush-border membrane vesicles, but a sulfhydryl reagent did not. These findings suggest that choline can be actively transported by a carrier-mediated system driven by cell interior-negative membrane potential in renal brush-border membrane, and this system may play an important role in the tubular reabsorption of choline.

4-Chloromercuribenzenesulfonate↗
PubMed1994

Contents of lecithin and choline in crude drugs.

The determination of lecithin and choline in crude drugs was established by a combination of high performance liquid chromatography (HPLC) with electrochemical detector (ECD) and enzyme reaction. Lecithin in crude drugs extracted with a mixture of chloroform-methanol (2:1) at room temperature was hydrolyzed by phospholipase D. The hydrolyzate was injected to HPLC, and choline was separated from impurities by reverse phase column. The choline was converted to betaine and hydrogen peroxide by passing through column packed with immobilized choline oxidase. This hydrogen peroxide was detected by ECD. The peak area of hydrogen peroxide derived from lecithin was proportional to the concentration of lecithin from 0.10 to 1.52 microgram/ml. Choline in crude drugs was extracted with ethanol under reflux and determined under the same HPLC conditions as lecithin. The peak area of hydrogen peroxide derived from choline was proportional to the concentration of choline from 0.01 to 0.45 microgram/ml. The contents of lecithin and choline in 31 kinds of crude drugs were determined by these established methods. The results showed that Cervi Parvum Cornu, Kokurozin, Foenigraeci Semen and Psoraleae Semen contained more lecithin than other crude drugs, while Angelicae Radix, Foenigraeci Semen, Psoraleae Semen, and especially Hippocampus were found to contain more choline than other crude drugs.

Choline↗
PubMed2003

Uptake rates of 18F-fluorodeoxyglucose and 11C-choline in lung cancer and pulmonary tuberculosis: a positron emission tomography study.

STUDY OBJECTIVE: The purpose of this study was to examine the uptake rates of (18)F-fluorodeoxyglucose (FDG) and (11)C-choline in patients with lung cancer, pulmonary tuberculosis, and atypical mycobacterial infection of the lung by positron emission tomography (PET) scanning with relation to their tumor size. DESIGN: Ninety-seven patients with untreated lung cancer, 14 patients with untreated pulmonary tuberculosis, and 5 patients with untreated atypical mycobacterial infection were examined. The diagnosis of lung cancer was confirmed pathologically after biopsy and surgery. The diagnosis of tuberculosis and atypical mycobacterial infection was confirmed by bacterial culture. The uptake rates of FDG and (11)C-choline were presented quantitatively as the standardized uptake value (SUV). SETTING: International Medical Center of Japan. RESULTS: In lung cancer patients, the SUV of FDG increased with increasing tumor size, whereas the SUV of (11)C-choline was almost constant at around 3.5 for every tumor size. In tuberculosis patients, the SUV of FDG increased with increasing tumor size, whereas the SUV of (11)C-choline was almost constant at around 2 for every tumor size. In atypical mycobacterial infection patients, the SUV of FDG and the SUV of (11)C-choline were equally low at around < or = 2. CONCLUSION: The differences in the SUVs of FDG and (11)C-choline in patients with lung cancer, tuberculosis, and atypical mycobacterial infection for the same tumor size (tumor size, > 1.5 cm) were distinct. In lung cancer patients, the SUVs of both FDG and (11)C-choline were high. In tuberculosis patients, the SUV of FDG was high, but the SUV of (11)C-choline was low. In atypical mycobacterial infection patients, the SUVs of both FDG and (11)C-choline were low. It may be possible to apply this principle to make a presumptive diagnosis of a solitary pulmonary nodule if it is too small to make a definitive diagnosis pathologically and bacteriologically.

Aged↗
PubMed1999

CDP-choline: neuroprotection in transient forebrain ischemia of gerbils.

CDP-choline is a rate-limiting intermediate in the biosynthesis of phosphatidylcholine (PtdCho), an important component of the neural cell membrane. The ability of CDP-choline to alter phospholipid metabolism is an important function in the treatment of ischemic injury. Exogenous treatment with CDP-choline stimulates PtdCho synthesis and prevents release of free fatty acids (FFA), especially arachidonic acid (AA), after ischemia/reperfusion. Phase III clinical trials of CDP-choline in the treatment of stroke are currently underway. Here we report the neuroprotection by CDP-choline in transient forebrain ischemia of gerbils. CDP-choline significantly attenuated the blood-brain barrier (BBB) dysfunction after ischemia with 6-hr reperfusion, and considerably reduced the increase of AA in FFA and leukotriene C(4) (LTC(4)) synthesis at 1 day. Edema was significantly elevated after 1 and 2 days, but attained maximum at 3-day reperfusion. CDP-choline substantially attenuated edema at 3 days. Ischemia resulted in 80 +/- 8% CA(1) hippocampal neuronal death after 6-day reperfusion, and CDP-choline provided 65 +/- 6% neuroprotection. CDP-choline may act by increasing PtdCho synthesis via two pathways: (1) conversion of 1, 2-diacylglycerol to PtdCho, and (2) biosynthesis of S-adenosyl-L-methionine, thus stabilizing the membrane and reducing AA release and metabolism to leukotriene C(4). This would result in decreased toxicity due to AA, leukotrienes, oxygen radicals, lipid peroxidation, and altered glutamate uptake, thus limiting BBB dysfunction, edema and providing neuroprotection.

Animals↗
PubMed2001

Synthesis and evaluation of (18)F-labeled choline analogs as oncologic PET tracers.

UNLABELLED: Elevated levels of choline (trimethyl-2-hydroxyethylammonium) and choline kinase (CK) activity in neoplasms have motivated the development of positron-labeled choline analogs for noninvasive detection of cancer using PET. The aim of this study was to further evaluate [(18)F]fluorocholine (fluoromethyl-dimethyl-2-hydroxyethylammonium [FCH]) as an oncologic probe in comparison with several other closely related molecules. METHODS: FCH, [(18)F]fluoromethyl-methylethyl-2-hydroxyethylammonium (FMEC), [(18)F]fluoroethyl-dimethyl-2-hydroxyethylammonium (FEC), and [(18)F]fluoropropyl-dimethyl-2-hydroxyethylammonium (FPC) were synthesized through [(18)F]fluoroalkylation reactions. In vitro phosphorylation rates of the (18)F-labeled choline analogs and [methyl-(14)C]choline (CH) were studied using yeast CK. Several choline radiotracers were also evaluated in cultured PC-3 human prostate cancer cells. Data on chemical stability, radiation dosimetry, and toxicity of FCH were obtained. PET studies with FCH were performed on a patient with prostate cancer and a patient with a brain tumor. RESULTS: FCH and FMEC revealed in vitro phosphorylation by CK that was similar to that of choline, whereas rates of phosphorylation of FEC and FPC were 30% (P < 0.01) and 60% (P < 0.01) lower, respectively. Accumulations of FCH, CH, and FPC in cultured PC-3 cancer cells were comparable, whereas uptake of FEC was approximately one fifth that of FCH. Dosimetry estimates using FCH biodistribution data in mice indicated that the kidneys are radiation-dose-critical organs for FCH. PET images of a patient with recurrent prostate cancer showed uptake of FCH in the prostatic bed and in metastases to lymph nodes. FCH PET showed uptake in malignancies in a patient with metastatic breast cancer. PET revealed FCH uptake in biopsy-proven recurrent brain tumor with little confounding uptake by normal brain tissues. CONCLUSION: The fluoromethyl choline analog FCH may serve as a probe of choline uptake and phosphorylation in cancer cells, whereas fluoroethyl (FEC) and fluoropropyl (FPC) analogs appear to have relatively poorer biologic compatibility. Preliminary PET studies on patients with prostate cancer and with breast cancer and brain tumor support further studies to evaluate the usefulness of FCH as an oncologic probe.

Adult↗