In vitro assessment of the dermal penetration potential of sodium fluoroacetate using a formulated product.

This paper presents experimental data on the skin absorption of sodium fluoroacetate from a formulated product using an in vitro approach and human skin. Sodium fluoroacetate is a pesticide, typically applied in formulation (1080) for the control of unwanted vertebrate invasive species. It has been assigned a Skin Notation by the ACGIH, and other international workplace health regulatory bodies, due to its predicted ability to permeate intact and abraded human skin. However, there is a distinct lack of experimental data on the skin absorption of sodium fluoroacetate to support this assignment. This study found that sodium fluoroacetate, as a formulated product, permeated the human epidermis when in direct contact for greater than 10 hr. A steady-state flux (Jss) of 1.31 ± 0.043 µg/cm2/hr and a lag time of 6.1 hr was calculated from cumulative skin permeation data. This study provides important empirical evidence in support of the assignment of a Skin Notation.

Evaluation of Class IIa Histone Deacetylases Expression and In Vivo Epigenetic Imaging in a Transgenic Mouse Model of Alzheimer's Disease.

Epigenetic regulation by histone deacetylase (HDAC) is associated with synaptic plasticity and memory formation, and its aberrant expression has been linked to cognitive disorders, including Alzheimer's disease (AD). This study aimed to investigate the role of class IIa HDAC expression in AD and monitor it in vivo using a novel radiotracer, 6-(tri-fluoroacetamido)-1-hexanoicanilide ([18F]TFAHA). A human neural cell culture model with familial AD (FAD) mutations was established and used for in vitro assays. Positron emission tomography (PET) imaging with [18F]TFAHA was performed in a 3xTg AD mouse model for in vivo evaluation. The results showed a significant increase in HDAC4 expression in response to amyloid-ß (Aß) deposition in the cell model. Moreover, treatment with an HDAC4 selective inhibitor significantly upregulated the expression of neuronal memory-/synaptic plasticity-related genes. In [18F]TFAHA-PET imaging, whole brain or regional uptake was significantly higher in 3xTg AD mice compared with WT mice at 8 and 11 months of age. Our study demonstrated a correlation between class IIa HDACs and Aßs, the therapeutic benefit of a selective inhibitor, and the potential of using [18F]TFAHA as an epigenetic radiotracer for AD, which might facilitate the development of AD-related neuroimaging approaches and therapies.

Fexapotide triflutate: results of long-term safety and efficacy trials of a novel injectable therapy for symptomatic prostate enlargement.

PURPOSE: These studies were undertaken to determine if fexapotide triflutate 2.5 mg transrectal injectable (FT) has significant long-term (LT) safety and efficacy for the treatment of benign prostatic hyperplasia (BPH). METHODS: Two placebo controlled double-blind randomized parallel group trials with 995 BPH patients at 72 sites treated 3:2 FT:placebo, with open-label FT crossover (CO) re-injection in 2 trials n = 344 and long-term follow-up (LF) 2-6.75 years (mean 3.58 years, median 3.67 years; FT re-injection CO mean 4.27 years, median 4.42 years) were evaluated. 12 months post-treatment patients elected no further treatment, approved oral medications, FT, or interventional treatment. Primary endpoint variable was change in Symptom Score (IPSS) at 12 months and at LF. CO primary co-endpoints were 3-year incidence of (1) surgery for BPH in FT treated CO patients versus patients crossed over to oral BPH medications and (2) surgery or acute urinary retention in FT-treated CO placebo patients versus placebo patients crossed over to oral BPH medications. 28 CO secondary endpoints assessed surgical and symptomatic outcomes in FT reinjected patients versus conventional BPH medication CO and control subgroups at 2 and 3 years. RESULTS: FT injection had no significant safety differences from placebo. LF IPSS change from baseline was higher in FT treated patients compared to placebo (median FT group improvement - 5.2 versus placebo - 3.0, p < 0.0001). LF incidence of AUR (1.08% p = 0.0058) and prostate cancer (PCa) (1.1% p = 0.0116) were both reduced in FT treated patients. LF incidence of intervention for BPH was reduced in the FT group versus oral BPH medications (8.08% versus 27.85% at 3 years, p < 0.0001). LF incidence of intervention or AUR in placebo CO group with FT versus placebo CO group with oral medications was reduced (6.07% versus 33.3% at 3 years, p < 0.0001). 28/28 secondary efficacy endpoints were reached in LF CO re-injection studies. CONCLUSIONS: FT 2.5 mg is a safe and effective transrectal injectable for LT treatment of BPH. FT treated patients also had reduced need for BPH intervention, and reduced incidence of PCa and AUR.

Comparison of three ¹8F-labeled carboxylic acids with ¹8F-FDG of the differentiation tumor from inflammation in model mice.

BACKGROUND: The aim of this study was to compare the properties and feasibility of the glucose analog, 2-(18)F-fluoro-2-deoxy-D-glucose ((18)F-FDG), three short (18)F-labeled carboxylic acids, (18)F-fluoroacetate ((18)F-FAC), 2-(18)F-fluoropropionic acid ((18)F-FPA) and 4-((18)F)fluorobenzoic acid ((18)F-FBA), for differentiating tumors from inflammation. METHODS: Biodistributions of (18)F-FAC, (18)F-FPA and (18)F-FBA were determined on normal Kunming mice, and positron emission tomography (PET) imaging with these tracers were performed on the separate tumor-bearing mice model and inflammation mice model in comparison with (18)F-FDG. RESULTS: Biodistribution results showed that (18)F-FAC and (18)F-FPA had similar biodistribution profiles and the slow radioactivity clearance from most tissues excluding the in vivo defluorination of (18)F-FAC, and (18)F-FBA demonstrated a lower uptake and fast clearance in most tissues. PET imaging with (18)F-FDG, (18)F-FAC and (18)F-FPA revealed the high uptake in both tumor and inflammatory lesions. The ratios of tumor-to-inflammation were 1.63 ± 0.28 for (18)F-FDG, 1.20 ± 0.38 for (18)F-FAC, and 1.41 ± 0.33 for (18)F-FPA at 60 min postinjection, respectively. While clear tumor images with high contrast between tumor and inflammation lesion were observed in (18)F-FBA/PET with the highest ratio of tumor-to-inflammation (1.98 ± 0.15). CONCLUSIONS: Our data demonstrated (18)F-FBA is a promising PET probe to distinguish tumor from inflammation. But the further modification of (18)F-FBA structure is required to improve its pharmacokinetics.

Delayed sodium 18F-fluoride PET/CT imaging does not improve quantification of vascular calcification metabolism: results from the CAMONA study.

BACKGROUND: This study aimed to determine if delayed sodium (18)F-fluoride (Na(18)F) PET/CT imaging improves quantification of vascular calcification metabolism. Blood-pool activity can disturb the arterial Na(18)F signal. With time, blood-pool activity declines. Therefore, delayed imaging can potentially improve quantification of vascular calcification metabolism. METHODS AND RESULTS: Twenty healthy volunteers and 18 patients with chest pain were prospectively assessed by triple time-point PET/CT imaging at approximately 45, 90, and 180 minutes after Na(18)F administration. For each time point, global uptake of Na(18)F was determined in the coronary arteries and thoracic aorta by calculating the blood-pool-corrected maximum standardized uptake value (cSUV(MAX)). A target-to-background ratio (TBR) was calculated to determine the contrast resolution at 45, 90, and 180 minutes. Furthermore, we assessed whether the acquisition time-point affected the relation between cSUV(MAX) and the estimated 10-year risk for fatal cardiovascular disease (SCORE %). Coronary cSUV(MAX) (P = .533) and aortic cSUV(MAX) (P = .654) remained similar with time, whereas the coronary TBR (P < .0001) and aortic TBR (P < .0001) significantly increased with time. Even though the contrast resolution improved with time, positive correlations between SCORE % and coronary cSUV(MAX) (P < .020) and aortic cSUV(MAX) (P < .005) were observed at all investigated time points. CONCLUSIONS: Delayed Na(18)F PET/CT imaging does not improve quantification of vascular calcification metabolism. Although contrast resolution improves with time, arterial Na(18)F avidity is invariant to the time between Na(18)F administration and PET/CT acquisition. Therefore, the optimal PET/CT acquisition time-point to quantify vascular calcification metabolism is achieved as early as 45 minutes after Na(18)F administration.

Radiation dosimetry estimates of [18F]-fluoroacetate based on biodistribution data of rats.

We estimated the dosimetry of [(18)F]fluoroacetate (FAC) with the method established by MIRD based on biodistribution data of rats. We selected some important organs and computed their residence time, their absorbed doses and effective dose with the (%ID(Organ)) (human) data using OLINDA/EXM 1.1 program. We observed the highest absorbed doses in the heart wall (0.025mGy/MBq) and the lowest in skin (0.0079mGy/MBq). The total mean absorbed doses and the effective doses were 0.011mGy/MBq and 0.014mSv/MBq, respectively. A 370-MBq injection of FAC leads to an estimated effective dose of 5.2mSv. The potential radiation risk associated with FAC/PET imaging is well within the accepted limits.

Pharmacokinetics, metabolism, biodistribution, radiation dosimetry, and toxicology of (18)F-fluoroacetate ((18)F-FACE) in non-human primates.

INTRODUCTION: To facilitate the clinical translation of (18)F-fluoroacetate ((18)F-FACE), the pharmacokinetics, biodistribution, radiolabeled metabolites, radiation dosimetry, and pharmacological safety of diagnostic doses of (18)F-FACE were determined in non-human primates. METHODS: (18)F-FACE was synthesized using a custom-built automated synthesis module. Six rhesus monkeys (three of each sex) were injected intravenously with (18)F-FACE (165.4 ± 28.5 MBq), followed by dynamic positron emission tomography (PET) imaging of the thoracoabdominal area during 0-30 min post-injection and static whole-body PET imaging at 40, 100, and 170 min. Serial blood samples and a urine sample were obtained from each animal to determine the time course of (18)F-FACE and its radiolabeled metabolites. Electrocardiograms and hematology analyses were obtained to evaluate the acute and delayed toxicity of diagnostic dosages of (18)F-FACE. The time-integrated activity coefficients for individual source organs and the whole body after administration of (18)F-FACE were obtained using quantitative analyses of dynamic and static PET images and were extrapolated to humans. RESULTS: The blood clearance of (18)F-FACE exhibited bi-exponential kinetics with half-times of 4 and 250 min for the fast and slow phases, respectively. A rapid accumulation of (18)F-FACE-derived radioactivity was observed in the liver and kidneys, followed by clearance of the radioactivity into the intestine and the urinary bladder. Radio-HPLC analyses of blood and urine samples demonstrated that (18)F-fluoride was the only detectable radiolabeled metabolite at the level of less than 9% of total radioactivity in blood at 180 min after the (18)F-FACE injection. The uptake of free (18)F-fluoride in the bones was insignificant during the course of the imaging studies. No significant changes in ECG, CBC, liver enzymes, or renal function were observed. The estimated effective dose for an adult human is 3.90-7.81 mSv from the administration of 185-370 MBq of (18)F-FACE. CONCLUSIONS: The effective dose and individual organ radiation absorbed doses from administration of a diagnostic dosage of (18)F-FACE are acceptable. From a pharmacologic perspective, diagnostic dosages of (18)F-FACE are non-toxic in primates and, therefore, could be safely administered to human patients for PET imaging.

Vertebrate pesticide risk assessment by indigenous communities in New Zealand.

In New Zealand, the vertebrate pesticide sodium fluoroacetate (Compound 1080) is aerially applied in baits for control of the brush-tailed possum Trichosurus vulpecula (Kerr, 1792). Maori, the indigenous people of New Zealand, have raised concerns about 1080 impacts on culturally-important species. Here, we outline two steps taken to help Maori assess 1080 risk. First, field research was undertaken to determine if naturally-occurring plants utilized by a Maori community for food and medicine would take up 1080 from baits. Single baits were placed at the base of individual plants of two species, pikopiko (Asplenium bulbiferum) and karamuramu (Coprosma robusta). Plants were sampled at various times up to 56 days, and samples were analyzed for 1080 content. No 1080 was detected in any of the pikopiko samples, whereas 1080 was detected in karamuramu, at a maximum concentration of 5 ppb after seven days, and 2.5 ppb after 14 days. This concentration decreased to 0 at 28 days, indicating that 1080 was not persistent. The results of the present study suggest there is negligible risk of humans being poisoned by consuming plants that have taken up 1080 from baits. To allay community concerns that minute concentrations of 1080 might influence the medicinal properties of plants, it is suggested that a withholding period of 30 days after 1080 control operations could be adopted. Second, after further consultation we undertook a review of the scientific literature relating to 1080 impacts on additional non-target species of cultural importance to Maori. The information was presented on an interactive foodweb database that allowed the collection and presentation of a large volume of complex information about 1080 in a holistic and pictorial fashion. This database was presented to many Maori communities throughout New Zealand, and feedback was overwhelmingly positive. The database is likely to play a key role in informing these communities about 1080, and is seen as an important new tool to help these communities make their own risk assessments.

Sodium fluoroacetate (1080): assessment of occupational exposures and selection of a provisional biological exposure index.

AIM: Sodium fluoroacetate (1080) is used for control of vertebrate pests in New Zealand. Little is known about chronic effects in humans, but animal studies demonstrate potential for adverse fetal, male fertility, and cardiac effects. We aimed to employ analyses of 1080 to help assess the degree of exposure of bait formulators and distributors, and identify specific tasks where exposure reduction appeared most indicated. We also aimed to utilise the (limited) 1080 toxicity data to assess the significance of the analytical results. METHOD: Exposures during various activities were assessed by monitoring air levels and blood and urine concentrations. To help evaluate the results, a provisional "biological exposure index" (BEI) was later derived, by extrapolating from experimental data. RESULTS: Early monitoring indicated exposures were highest in relation to (cereal) bait manufacturing and aerial carrot baiting procedures. A provisional BEI of 15 microg/L for 1080 in urine was proposed. CONCLUSION: Further protective measures and ongoing workplace monitoring are required, particularly in the above situations. Compliance with the current BEI cannot guarantee complete safety. Any information regarding chronic adverse effects in humans, along with the associated urine levels, would assist risk assessment. Further investigation of the human kinetics of fluoroacetate would be helpful.

[(18)F]Fluoroacetate is not a functional analogue of [(11)C]acetate in normal physiology.

PURPOSE: [(11)C]Acetate (C-AC) is a general PET tracer of cellular carbon flux and useful for clinical imaging in heart disease as well as prostate cancer and other tumours. C-AC has a high (70%) whole-body extraction fraction, proportional to blood flow in many organs. Trapping is related to organ-specific enzymatic activation and formation of [(11)C]-acetyl-CoA, the fate of which has been well characterized. Due to the logistic challenges with C-AC, 2-[(18)F]fluoroacetate (F-AC) has been proposed as a marker for prostate cancer imaging. METHOD: We evaluated the potential of F-AC as a tracer for imaging blood flow and early enzymatic steps in the intermediary metabolism. C-AC and F-AC were injected serially in three cynomolgus monkeys and one domestic pig and scanned using PET/CT. A dynamic scan covering heart and liver was followed by repeated whole-body imaging. Kinetic patterns were compared for the myocardium, liver, blood and other organs. RESULTS: C-AC kinetics and organ distribution in both species were similar to those previously established in man. In contrast, F-AC showed prolonged blood retention, no detectable trapping in myocardium or salivary glands, rapid clearance from liver and extensive excretion to bile and urine. Massive defluorination was seen in the pig, resulting in intense skeletal activity. CONCLUSION: 2-[(18)F]Fluoroacetate cannot be regarded as a functional analogue of 1-[(11)C]acetate in normal physiology and appears to be of little use for studies of organ blood flow, intermediary metabolism or lipid synthesis.

Evaluation of 6-([(18)F]fluoroacetamido)-1-hexanoicanilide for PET imaging of histone deacetylase in the baboon brain.

INTRODUCTION: Histone deacetylases (HDACs) are enzymes involved in epigenetic modifications that shift the balance toward chromatin condensation and silencing of gene expression. Here, we evaluate the utility of 6-([(18)F]fluoroacetamido)-1-hexanoicanilide ([(18)F]FAHA) for positron emission tomography imaging of HDAC activity in the baboon brain. For this purpose, we assessed its in vivo biodistribution, sensitivity to HDAC inhibition, metabolic stability and the distribution of the putative metabolite [(18)F]fluoroacetate ([(18)F]FAC). METHODS: [(18)F]FAHA and its metabolite [(18)F]FAC were prepared, and their in vivo biodistribution and pharmacokinetics were determined in baboons. [(18)F]FAHA metabolism and its sensitivity to HDAC inhibition using suberanilohydroxamic acid (SAHA) were assessed in arterial plasma and by in vitro incubation studies. The chemical form of F-18 in rodent brain was assessed by ex vivo studies. Distribution volumes for [(18)F]FAHA in the brain were derived. RESULTS: [(18)F]FAHA was rapidly metabolized to [(18)F]FAC, and both labeled compounds entered the brain. [(18)F]FAHA exhibited regional differences in brain uptake and kinetics. In contrast, [(18)F]FAC showed little variation in regional brain uptake and kinetics. A kinetic analysis that takes into account the uptake of peripherally produced [(18)F]FAC indicated that SAHA inhibited binding of [(18)F]FAHA in the baboon brain dose-dependently. In vitro studies demonstrated SAHA-sensitive metabolism of [(18)F]FAHA to [(18)F]FAC within the cell and diffusion of [(18)F]FAC out of the cell. All radioactivity in brain homogenate from rodents was [(18)F]FAC at 7 min postinjection of [(18)F]FAHA. CONCLUSION: The rapid metabolism of [(18)F]FAHA to [(18)F]FAC in the periphery complicates the quantitative analysis of HDAC in the brain. However, dose-dependent blocking studies with SAHA and kinetic modeling indicated that a specific interaction of [(18)F]FAHA in the brain was observed. Validating the nature of this interaction as HDAC specific will require additional studies.

Biodistribution, pharmacokinetics and PET imaging of [(18)F]FMISO, [(18)F]FDG and [(18)F]FAc in a sarcoma- and inflammation-bearing mouse model.

UNLABELLED: 2-Deoxy-2-[(18)F]fluoro-d-glucose ([(18)F]FDG), [(18)F]fluoroacetate ([(18)F]FAc) and [(18)F]fluoromisonidazole ([(18)F]FMISO) were all considered to be positron emission tomography (PET) probes for tumor diagnosis, though based on different rationale of tissue uptake. This study compared the biodistribution, pharmacokinetics and imaging of these three tracers in a sarcoma- and inflammation-bearing mouse model. METHODS: C3H mice were inoculated with 2x10(5) KHT sarcoma cells in the right thigh on Day 0. Turpentine oil (0.1 ml) was injected in the left thigh on Day 11 to induce inflammatory lesion. Biodistribution, pharmacokinetics and microPET imaging of [(18)F]FMISO, [(18)F]FDG and [(18)F]FAc were performed on Day 14 after tumor inoculation. RESULTS: The inflammatory lesions were clearly visualized by [(18)F]FDG/microPET and autoradiography at 3 days after turpentine oil injection. The tumor-to-muscle and inflammatory lesion-to-muscle ratios derived from microPET imaging were 6.79 and 1.48 for [(18)F]FMISO, 8.12 and 4.69 for [(18)F]FDG and 3.72 and 3.19 for [(18)F]FAc at 4 h post injection, respectively. Among these, the tumor-to-inflammation ratio was the highest (4.57) for [(18)F]FMISO compared with that of [(18)F]FDG (1.73) and [(18)F]FAc (1.17), whereas [(18)F]FAc has the highest bioavailability (area under concentration of radiotracer vs. time curve, 116.2 hxpercentage of injected dose per gram of tissue). CONCLUSIONS: MicroPET images and biodistribution studies showed that the accumulation of [(18)F]FMISO in the tumor is significantly higher than that in inflammatory lesion at 4 h post injection. [(18)F]FDG and [(18)F]FAc delineated both tumor and inflammatory lesions. Our results demonstrated the potential of [(18)F]FMISO/PET in distinguishing tumor from inflammatory lesion.

Preparation and evaluation of ethyl [(18)F]fluoroacetate as a proradiotracer of [(18)F]fluoroacetate for the measurement of glial metabolism by PET.

INTRODUCTION: Changes in glial metabolism in brain ischemia, Alzheimer's disease, depression, schizophrenia, epilepsy and manganese neurotoxicity have been reported in recent studies. Therefore, it is very important to measure glial metabolism in vivo for the elucidation and diagnosis of these diseases. Radiolabeled acetate is a good candidate for this purpose, but acetate has little uptake in the brain due to its low lipophilicity. We have designed a new proradiotracer, ethyl [(18)F]fluoroacetate ([(18)F]EFA), which is [(18)F]fluoroacetate ([(18)F]FA) esterified with ethanol, to increase the lipophilicity of fluoroacetate (FA), allowing the measurement of glial metabolism. METHODS: The synthesis of [(18)F]EFA was achieved using ethyl O-mesyl-glycolate as precursor. The blood-brain barrier permeability of ethyl [1-(14)C]fluoroacetate ([(14)C]EFA) was estimated by a brain uptake index (BUI) method. Hydrolysis of [(14)C]EFA in the brain was calculated by the fraction of radioactivity in lipophilic and water fractions of homogenized brain. Using the plasma of five animal species, the stability of [(14)C]EFA was measured. Biodistribution studies of [(18)F]EFA in ddY mice were carried out and compared with [(18)F]FA. Positron emission tomography (PET) scanning using common marmosets was performed for 90 min postadministration. At 60 min postinjection of [(18)F]EFA, metabolite studies were performed. Organs were dissected from the marmosets, and extracted metabolites were analyzed with a thin-layer chromatography method. RESULTS: The synthesis of [(18)F]EFA was accomplished in a short time (29 min) and with a reproducible radiochemical yield of 28.6+/-3.6% (decay corrected) and a high radiochemical purity of more than 95%. In the brain permeability study, the BUI of [(14)C]EFA was 3.8 times higher than that of sodium [1-(14)C]fluoroacetate. [(14)C]EFA was hydrolyzed rapidly in rat brains. In stability studies using the plasma of five animal species, [(14)C]EFA was stable only in primate plasma. Biodistribution studies in mice showed that the uptake of [(18)F]EFA in selected organs was higher than that of [(18)F]FA. From nonprimate PET studies, [(18)F]EFA was initially taken into the brain after injection. Metabolites related to the tricarboxylic acid (TCA) cycle were detected in common marmoset brain. CONCLUSION: [(18)F]EFA rapidly enters the brain and is then converted into TCA cycle metabolites in the brains of common marmosets. [(18)F]EFA shows promise as a proradiotracer for the measurement of glial metabolism.

(18)F-labeled positron emission tomographic radiopharmaceuticals in oncology: an overview of radiochemistry and mechanisms of tumor localization.

Molecular imaging is the visualization, characterization, and measurement of biological processes at the molecular and cellular levels in a living system. At present, positron emission tomography/computed tomography (PET/CT) is one the most rapidly growing areas of medical imaging, with many applications in the clinical management of patients with cancer. Although [(18)F]fluorodeoxyglucose (FDG)-PET/CT imaging provides high specificity and sensitivity in several kinds of cancer and has many applications, it is important to recognize that FDG is not a "specific" radiotracer for imaging malignant disease. Highly "tumor-specific" and "tumor cell signal-specific" PET radiopharmaceuticals are essential to meet the growing demand of radioisotope-based molecular imaging technology. In the last 15 years, many alternative PET tracers have been proposed and evaluated in preclinical and clinical studies to characterize the tumor biology more appropriately. The potential clinical utility of several (18)F-labeled radiotracers (eg, fluoride, FDOPA, FLT, FMISO, FES, and FCH) is being reviewed by several investigators in this issue. An overview of design and development of (18)F-labeled PET radiopharmaceuticals, radiochemistry, and mechanism(s) of tumor cell uptake and localization of radiotracers are presented here. The approval of clinical indications for FDG-PET in the year 2000 by the Food and Drug Administration, based on a review of literature, was a major breakthrough to the rapid incorporation of PET into nuclear medicine practice, particularly in oncology. Approval of a radiopharmaceutical typically involves submission of a "New Drug Application" by a manufacturer or a company clearly documenting 2 major aspects of the drug: (1) manufacturing of PET drug using current good manufacturing practices and (2) the safety and effectiveness of a drug with specific indications. The potential routine clinical utility of (18)F-labeled PET radiopharmaceuticals depends also on regulatory compliance in addition to documentation of potential safety and efficacy by various investigators.

18F-fluoroacetate: a potential acetate analog for prostate tumor imaging--in vivo evaluation of 18F-fluoroacetate versus 11C-acetate.

UNLABELLED: PET with (11)C-acetate ((11)C-ACE) has a high sensitivity for detection of prostate cancer and several other cancers that are poorly detected with (18)F-FDG. However, the short half-life (20.4 min) of (11)C limits the general availability of (11)C-ACE. (18)F-Fluoroacetate ((18)F-FAC) is an analog of acetate with a longer radioactive half-life ((18)F = 110 min). This study was undertaken to assess the potential usefulness of (18)F-FAC as a prostate tumor imaging agent. METHODS: We developed an efficient radiosynthesis for (18)F-FAC, which has already been adapted to a commercial synthesizer. Biodistribution studies of (18)F-FAC were compared with (11)C-ACE in normal Sprague-Dawley male rats and CWR22 tumor-bearing nu/nu mice. We also performed a small-animal PET study of (18)F-FAC in CWR22 tumor-bearing nu/nu mice and a whole-body PET study in a baboon to examine defluorination. RESULTS: We obtained (18)F-FAC in a radiochemical yield of 55% +/- 5% (mean +/- SD) in approximately 35 min and with a radiochemical purity of >99%. Rat biodistribution showed extensive defluorination, which was not observed in the baboon PET, as indicated by the standardized uptake values (SUVs) (SUVs of iliac bones and femurs were 0.26 and 0.3 at 1 h and 0.22 and 0.4 at 2 h, respectively). CWR22 tumor-bearing nu/nu mice showed tumor uptake (mean +/- SD) of 0.78 +/- 0.06 %ID/g (injected dose per gram of tissue) for (11)C-ACE versus 4.01 +/- 0.32 %ID/g for (18)F-FAC. For most organs-except blood, muscle, and fat-the tumor-to-organ ratios at 30 min after injection were higher with (18)F-FAC, whereas the tumor-to-heart and tumor-to-prostate ratios were similar. CONCLUSION: All of these data indicate that (18)F-FAC may be a useful alternative to (11)C-ACE tracer for the detection of prostate tumors by PET.

Sodium fluoroacetate poisoning.

Sodium fluoroacetate was introduced as a rodenticide in the US in 1946. However, its considerable efficacy against target species is offset by comparable toxicity to other mammals and, to a lesser extent, birds and its use as a general rodenticide was therefore severely curtailed by 1990. Currently, sodium fluoroacetate is licensed in the US for use against coyotes, which prey on sheep and goats, and in Australia and New Zealand to kill unwanted introduced species. The extreme toxicity of fluoroacetate to mammals and insects stems from its similarity to acetate, which has a pivotal role in cellular metabolism. Fluoroacetate combines with coenzyme A (CoA-SH) to form fluoroacetyl CoA, which can substitute for acetyl CoA in the tricarboxylic acid cycle and reacts with citrate synthase to produce fluorocitrate, a metabolite of which then binds very tightly to aconitase, thereby halting the cycle. Many of the features of fluoroacetate poisoning are, therefore, largely direct and indirect consequences of impaired oxidative metabolism. Energy production is reduced and intermediates of the tricarboxylic acid cycle subsequent to citrate are depleted. Among these is oxoglutarate, a precursor of glutamate, which is not only an excitatory neurotransmitter in the CNS but is also required for efficient removal of ammonia via the urea cycle. Increased ammonia concentrations may contribute to the incidence of seizures. Glutamate is also required for glutamine synthesis and glutamine depletion has been observed in the brain of fluoroacetate-poisoned rodents. Reduced cellular oxidative metabolism contributes to a lactic acidosis. Inability to oxidise fatty acids via the tricarboxylic acid cycle leads to ketone body accumulation and worsening acidosis. Adenosine triphosphate (ATP) depletion results in inhibition of high energy-consuming reactions such as gluconeogenesis. Fluoroacetate poisoning is associated with citrate accumulation in several tissues, including the brain. Fluoride liberated from fluoroacetate, citrate and fluorocitrate are calcium chelators and there are both animal and clinical data to support hypocalcaemia as a mechanism of fluoroacetate toxicity. However, the available evidence suggests the fluoride component does not contribute. Acute poisoning with sodium fluoroacetate is uncommon. Ingestion is the major route by which poisoning occurs. Nausea, vomiting and abdominal pain are common within 1 hour of ingestion. Sweating, apprehension, confusion and agitation follow. Both supraventricular and ventricular arrhythmias have been reported and nonspecific ST- and T-wave changes are common, the QTc may be prolonged and hypotension may develop. Seizures are the main neurological feature. Coma may persist for several days. Although several possible antidotes have been investigated, they are of unproven value in humans. The immediate, and probably only, management of fluoroacetate poisoning is therefore supportive, including the correction of hypocalcaemia.

Characterization of the fluoroacetate detoxication enzymes of rat liver cytosol.

Two forms of fluoroacetate-specific defluorinase (FSD) were purified from rat hepatic cytosol. The first form, FSD1 (molecular weight 38 kDa), contained 81% of the total cytosolic fluoroacetate defluorination activity and did not bind to the glutathione-affinity, orange A or mono P columns used in the purification procedures. The second form, FSD2 (molecular weight 27 kDa), contained only 13% of the fluoroacetate defluorination activity, had a pI = 7.8, and exhibited a high glutathione S-transferase (GST)-like activity towards dichloroacetic acid. The FSD1 proteins were identified from peptide mass data and best matched with rat sorbitol dehydrogenase (SDH) (short form), although pure sheep liver SDH enzyme did not possess defluorination activity when subsequently investigated. The FSD2 protein was identified from peptide mass data and best matched with the amino acid sequence of mouse and human Zeta 1 of glutathione S-transferase (GSTZ1) and showed a high GSTZ1 specific activity. This study suggests that the major FSD component (FSD1) represents a new and unique dehalogenating or dehydrogenating enzyme present in rat liver cytosol. The minor FSD component (FSD2) is due to the GSTZ1 present in rat liver cytosol. However, it is not yet clear that FSD1 is indeed SDH and FSD2 is indeed GSTZ1, due to sequence homology being less than 60 and 45%, respectively.

Sodium monofluoroacetate (1080) risk assessment and risk communication.

Sodium monofluoroacetate (1080) is a vertebrate pesticide widely used for possum control in New Zealand. Fluoroacetate is also a toxic component of poisonous plants found in Australia, South Africa, South America, and India. Because of its importance and effectiveness in pest control and the highly toxic nature of this compound, its acute sub-lethal and target organ toxicity have been extensively studied. In relation to its use as a pesticide its environmental fate, persistence, non-target impacts and general toxicology have been and continue to be extensively studied. Toxic baits must be prepared and used with extreme care, otherwise humans, livestock, and non-target wildlife will be put at risk. The high risk of secondary poisoning of dogs is a cause for concern. 1080 acts by interfering with cellular energy production. Possums die from heart failure, usually within 6-18 h of eating baits. Long-term exposure to sub-lethal doses can have harmful effects and strict safety precautions are enforced to protect contractors and workers in the bait manufacturing industry. Considerable care is taken when using 1080 to ensure that the risks of using it are outweighed by the ecological benefits achieved from its use. When its use is controversial, risk communicators must take care not to trivialise the toxicity of the compound. The benefits of 1080 use in conservation, pest control, and disease control should be weighed up alongside the risks of using 1080 and other techniques for pest control.

A 90-day toxicological evaluation of Compound 1080 (sodium monofluoroacetate) in Sprague-Dawley rats.

Groups of Sprague-Dawley rats received sodium monofluoroacetate (Compound 1080) at 0.025, 0.075, and 0.25 mg/kg by oral gavage once daily for 90 days and were then euthanized. The control and 0.25 mg/kg/day groups included additional rats of each sex that were treated for 90 days, then maintained without treatment for a further 56-day recovery period. Microscopic changes were restricted to the testes and the heart, and were seen only in males dosed with 1080 at 0.25 mg/kg/day and included severe hypospermia in the epididymides, severe degeneration of the seminiferous tubules of the testes, and cardiomyopathy. Sperm evaluation indicated severe decreases in all three sperm parameters evaluated (concentration, % motile, and % abnormal) at 0.25 mg/kg/day. There were no microscopic changes or 1080-related effects on sperm parameters at 0.025 and 0.075 mg/kg/day. The no observable effects level (NOEL) for rats administered 1080 via oral gavage for 90 days was 0.075 mg/kg/day. The lowest observable effects level (LOEL) dose was 0.25 mg/kg/day. After dosing with the LOEL dose of 0.25 mg/kg/day, mean concentrations of 1080 in rat plasma were 0.26 micro g/ml at 1 h and 0.076 microg/ml at 12 h. Rat urine collected from the same animals contained 0.059 microg/ml.