Pilot PET Study to Assess the Functional Interplay Between ABCB1 and ABCG2 at the Human Blood-Brain Barrier.

ABCB1 and ABCG2 work together at the blood-brain barrier (BBB) to limit brain distribution of dual ABCB1/ABCG2 substrates. In this pilot study we used positron emission tomography (PET) to assess brain distribution of two model ABCB1/ABCG2 substrates ([(11) C]elacridar and [(11) C]tariquidar) in healthy subjects without (c.421CC) or with (c.421CA) the ABCG2 single-nucleotide polymorphism (SNP) c.421C>A. Subjects underwent PET scans under conditions when ABCB1 and ABCG2 were functional and during ABCB1 inhibition with high-dose tariquidar. In contrast to the ABCB1-selective substrate (R)-[(11) C]verapamil, [(11) C]elacridar and [(11) C]tariquidar showed only moderate increases in brain distribution during ABCB1 inhibition. This provides evidence for a functional interplay between ABCB1 and ABCG2 at the human BBB and suggests that both ABCB1 and ABCG2 need to be inhibited to achieve substantial increases in brain distribution of dual ABCB1/ABCG2 substrates. During ABCB1 inhibition c.421CA subjects had significantly higher increases in [(11) C]tariquidar brain distribution than c.421CC subjects, pointing to impaired cerebral ABCG2 function.

Using positron emission tomography to study transporter-mediated drug-drug interactions in tissues.

Drug disposition is highly regulated by membrane transporters. Some transporter-mediated drug-drug interactions (DDIs) may not manifest themselves in changes in systemic exposure but rather in changes in tissue exposure of drugs. To better assess the impact of transporter-mediated DDIs in tissues, positron emission tomography (PET)-a noninvasive imaging method--plays an increasingly important role. In this article, we provide examples of how PET can be used to assess transporter-mediated DDIs in different organs.

18F, 11C and 68Ga in small animal PET imaging. Evaluation of partial volume correction methods.

AIM: The partial volume effect (PVE) significantly affects quantitative accuracy in PET. In this study we used a micro-hollow sphere phantom filled with 18F, 11C or 68Ga to evaluate different partial volume correction methods (PVC). Additionally, phantom data were applied on rat brain scans to evaluate PVC methods on in vivo datasets. METHODS: The four spheres (7.81, 6.17, 5.02, 3.90 mm inner diameter) and the background region were filled to give sphere-to-background (sph/bg) activity ratios of 20 : 1, 10 : 1, 5 : 1 and 2 : 1. Two different acquisition and reconstruction protocols and three radionuclides were evaluated using a small animal PET scanner. From the obtained images the recovery coefficients (RC) and contrast recovery coefficients (CRC) for the different sph/bg ratios were calculated. Three methods for PVC were evaluated: a RC based, a CRC based and a volume of interest (VOI) based method. The most suitable PVC methods were applied to in vivo rat brain data. RESULTS: RCs were shown to be dependent on the radionuclide used, with the highest values for 18F, followed by 11C and 68Ga. The calculated mean CRCs were generally lower than the corresponding mean RCs. Application of the different PVC methods to rat brain data led to a strong increase in time-activity curves for the smallest brain region (entorhinal cortex), whereas the lowest increase was obtained for the largest brain region (cerebellum). CONCLUSION: This study was able to show the importance and impact of PVE and the limitations of several PVC methods when performing quantitative measurements in small structures.

Pharmacokinetics of single ascending doses of the P-glycoprotein inhibitor tariquidar in healthy subjects.

We assessed the pharmacokinetics (PK), tolerability and safety of tariquidar (TQD), a P-glycoprotein (Pgp) inhibitor, after intravenous administration of single ascending doses. Employed doses were up to 4-fold higher than in previous clinical trials in cancer patients and are capable of inhibiting Pgp at the blood-brain barrier. Fifteen male healthy volunteers were randomized to receive single intravenous doses of TQD at 4, 6 or 8 mg/kg body weight and underwent blood sampling for over 24 h. TQD concentrations were determined in plasma samples with high-performance liquid chromatography mass spectrometry. No dose-limiting toxicities of TQD were observed. The area under the plasma concentration-time curve from start until 24 h after the end of infusion was positively correlated with an administered TQD dose (r = 0.8981, p < 0.0001). Moreover, we found a positive correlation for volume of distribution at steady state (r = 0.7129, p = 0.0004) with TQD dose. Dose dependency of volume of distribution at steady state points to non-linear PK of TQD, which was in all likelihood caused by transporter saturation at high TQD doses. Acceptable safety and tolerability as well as dose-linear increases in plasma exposure support the future use of TQD at doses up to 8 mg/kg to inhibit Pgp at the human blood-brain barrier.

The third-generation P-glycoprotein inhibitor tariquidar may overcome bacterial multidrug resistance by increasing intracellular drug concentration.

OBJECTIVES: The use of efflux pump inhibitors may be a powerful strategy to overcome transporter-mediated bacterial multidrug resistance. In the present study, we set out to investigate the potency of tariquidar, a third-generation P-glycoprotein inhibitor in clinical development, for overcoming bacterial resistance towards ciprofloxacin. METHODS: Staphylococcus aureus 29213 (SA29213) and S. aureus 1199B (SA1199B), which overexpresses the multidrug transporter NorA, as well as Pseudomonas aeruginosa 27853 and Stenotrophomonas maltophilia BAA-85, which expresses SmeDEF, were exposed to ciprofloxacin in the presence and absence of tariquidar or, for comparative reasons, elacridar. Activity of both P-glycoprotein inhibitors was evaluated by determination of MICs and time-kill curves, and by quantification of uptake of ciprofloxacin into bacterial cells. RESULTS: Activity of tariquidar and elacridar was comparable for S. aureus strains, and both dose-dependently increased susceptibility towards ciprofloxacin. Highest effects were observed for SA1199B, where the addition of tariquidar resulted in a 10-fold reduction of the ciprofloxacin MIC, while no effect was observed for P. aeruginosa. For S. maltophilia, elacridar but not tariquidar improved susceptibility. Uptake of [14C]ciprofloxacin and modification of susceptibility showed significant correlations (r=0.89, P<0.0001). Tariquidar had no intrinsic activity against any strain tested. CONCLUSIONS: We conclude that tariquidar has potent inhibitory effect against certain bacterial efflux pumps in vitro. Their high activity at clinically achievable concentrations might yield this class of drugs promising for future applications in infectious diseases.

Amyloid PET and MRI in Alzheimer's disease and mild cognitive impairment.

The neurodegenerative disorder Alzheimer's disease (AD) is the most common form of dementia. It is characterized by progressive impairment of cognitive functions and behavior. To distinguish clinically AD from other forms of dementia is an ongoing challenge. In addition, although mild cognitive impairment (MCI) is recognized as a risk factor for dementia, it remains a challenge to predict on an individual level who will convert to become demented. Amyloid beta (Abeta) is one of the crucial pathological findings in AD. Recently, amyloid tracers for PET imaging have been developed successfully which may offer the unique possibility for measuring fibrillar Abeta load in the living brain. Therefore, in the near future positron emission tomography (PET) may become an important tool for in vivo amyloid imaging contributing to early (differential) diagnosis as well as evaluation of treatment response in AD. Moreover, Abeta may play a role in prediction the conversion of MCI to AD. In this paper we review the recent development of the molecular imaging technique PET and its different radiopharmaceuticals on the trail for imaging amyloid in AD and the conversion of MCI to AD.

FDG uptake is a surrogate marker for defining the optimal biological dose of the mTOR inhibitor everolimus in vivo.

This study aimed to test whether [(18)F]fluoro-D-glucose (FDG) uptake of tumours measured by positron emission tomography (PET) can be used as surrogate marker to define the optimal biological dose (OBD) of mTOR inhibitors in vivo. Everolimus at 0.05, 0.5, 5 and 15 mg kg(-1) per day was administered to gastric cancer xenograft-bearing mice for 23 days and FDG uptake of tumours was measured using PET from day 1 to day 8. To provide standard comparators for FDG uptake, tumour volume, S6 protein phosphorylation, Ki-67 staining and everolimus blood levels were evaluated. Everolimus blood levels increased in a dose-dependent manner but antitumour activity of everolimus reached a plateau at doses >or=5 mg kg(-1) per day (tumour volume treated vs control (T/C): 51% for 5 mg kg(-1) per day and 57% for 15 mg kg(-1) per day). Correspondingly, doses >or=5 mg kg(-1) per day led to a significant reduction in FDG uptake of tumours. Dose escalation above 5 mg kg(-1) per day did not reduce FDG uptake any further (FDG uptake T/C: 49% for 5 mg kg(-1) per day and 52% for 15 mg kg(-1) per day). Differences in S6 protein phosphorylation and Ki-67 index reflected tumour volume and changes in FDG uptake but did not reach statistical significance. In conclusion, FDG uptake might serve as a surrogate marker for dose finding studies for mTOR inhibitors in (pre)clinical trials.

Pre-eclampsia and gestational diabetes mellitus: does a correlation exist early in pregnancy?

OBJECTIVE: We investigated whether blood pressure profile early in pregnancy was associated with the development of pre-eclampsia in patients with gestational diabetes mellitus (GDM). METHODS: A retrospective longitudinal database study of 1664 GDM subjects was performed. Systolic and diastolic blood pressure measurements were taken bi-weekly during the first and second trimesters. GDM patients who developed pre-eclampsia were compared to GDM patients who did not. Subjects were further stratified by maternal age, parity, race, prepregnancy body mass index (BMI) and weight gain during pregnancy. Logistic regression was performed to identify the net effect of each factor on the development of pre-eclampsia. RESULTS: Overall, 167/1664 (10%) GDM patients developed pre-eclampsia. GDM patients who developed pre-eclampsia were more obese, gained more weight during pregnancy and had more severe GDM in comparison to GDM patients who did not. Although all mean blood pressure measurements were within the normal range, significantly higher systolic and diastolic values were recorded in the GDM patients who developed pre-eclampsia throughout the first and the second trimesters of pregnancy. Logistic regression revealed that higher parity (p = 0.04), maternal age (p = 0.03) and pre-pregnancy BMI (p = 0.03) were all contributing factors to pre-eclampsia. In contrast, weight gain during pregnancy and race were not related. CONCLUSION: In GDM patients, higher blood pressure readings early in pregnancy, even prior to GDM diagnosis, were associated with the subsequent development of pre-eclampsia.

Recurrence of gestational diabetes: pregnancy outcome and birth weight diversity.

OBJECTIVE: We sought to evaluate birth weight diversity and pregnancy outcome in women with two consecutive pregnancies complicated with gestational diabetes mellitus (GDM). METHODS: A retrospective longitudinal study of 389 patients with two consecutive GDM pregnancies was assessed for pregnancy outcome and fetal weight diversity. Since there is a tendency towards repetition or moderate increase in fetal weight in subsequent non-diabetic pregnancies, consecutive GDM pregnancies were stratified into three categories. They consisted of: an increase in birth weight of more than 250 g between GDM pregnancies for the same gestational age at delivery, and considered significant; an increase in birth weight of more than 100 g but less than 250 g; and a decrease in birth weight in the second GDM pregnancy compared to the index pregnancy. Any change in birth weight of up to 100 g between the two pregnancies was considered comparable. RESULTS: The mean interval between the two diabetic pregnancies was 3 years. The change in weight above the biologically expected weight was evaluated. In 181/389 (46%), an elevation in birth weight between pregnancies was recorded and from this group only 125/181 (69%) had significant increases in birth weight (> 250 g) with a mean of 531 +/- 49 g. Furthermore, 130/389 (33.4%) had decreased fetal weight between the two pregnancies (mean 373 +/- 31 g). In 78/389 (20.1%), birth weight changes were considered similar (< 100 g). Fasting plasma glucose (FBG) and pre-pregnancy body mass index (BMI) were significantly elevated in the second pregnancy (FBG 97 +/- 15 vs. 102 +/- 4.7 mg/dl; BMI 25.9 +/- 4.7 vs. 27 +/- 6.7 kg/m2, respectively; p = 0.02). No difference was found in the mean maternal weight gain during pregnancy, gestational age at delivery, mean blood glucose, macrosomia or large-for-gestational-age rates. No difference in neonatal outcome (neonatal intensive care unit admission, the need for respiratory support, stillbirth rate or shoulder dystocia) was found between the two pregnancies. CONCLUSION: In GDM patients, owing to the role of glycemic control and environmental factors, an expected increase in birth weight between pregnancies cannot be predicted.

When diet fails: insulin and oral hypoglycemic agents as alternatives for the management of gestational diabetes mellitus.

The principal approach for attaining glycemic control in gestational diabetes mellitus is diet, with the addition of insulin or oral hypoglycemic agents when needed. The purpose of this review is to provide an overview for the understanding of management guidelines that have been validated by appropriately conducted research trials. The similarity between gestational diabetes mellitus and type 2 diabetes is highlighted. Criteria for insulin initiation as well as the role of a hypoglycemic agent as a potential alternative to insulin are discussed.

Intrapartum fetal head position I: comparison between transvaginal digital examination and transabdominal ultrasound assessment during the active stage of labor.

OBJECTIVE: To test the null hypothesis that no correlation exists between transvaginal digital and the gold standard technique of transabdominal suprapubic ultrasound assessments of fetal head position during labor. A secondary objective was to compare the performance of attending physicians vs. senior residents in depicting fetal head position by transvaginal digital examination in comparison with ultrasound, respectively. METHODS: Consecutive patients in active labor at term with normal singleton cephalic-presenting fetuses were included. All participants had ruptured membranes, cervical dilation > or = 4 cm and fetal head at ischial spine station -2 or lower. Transvaginal sterile digital examinations were performed by either senior residents or attending physicians and followed immediately by transverse suprapubic transabdominal ultrasound assessments. Examiners were blinded to each other's findings. Power-analyses dictated number of subjects required. Statistical analyses included Chi-square, Cohen's Kappa test and logistic regression analysis. P < 0.05 was considered statistically significant. RESULTS: One hundred and two patients were studied (n = 102). In only 24% of patients (n = 24), transvaginal digital examinations were consistent with ultrasound assessments (P = 0.002, 95% confidence interval, 16-33). Logistic regression revealed that cervical effacement (P = 0.03) and ischial spine station (P = 0.01) significantly affected the accuracy of transvaginal digital examination. Parity, gestational age, combined spinal epidural anesthesia, cervical dilation, birth weight and examiner experience did not significantly affect accuracy of the examination. The accuracy of the transvaginal digital exams was increased to 47% (n = 48) (95% confidence interval, 37-57) when fetal head position at transvaginal digital examination was recorded as correct if reported within +/- 45 degrees of the ultrasound assessment. The rate of agreement between the two assessment methods for attending physicians vs. residents was 58% vs. 33%, respectively (P = 0.02) with the +/- 45 degrees analysis. CONCLUSIONS: Using ultrasound assessment as the gold standard, our data demonstrate an overall high rate of error (76%) in transvaginal digital determination of fetal head position during active labor, consistent with the null hypothesis. Attending physicians exhibited an almost two-fold higher success rate in depicting correct fetal head position by physical examination vs. residents in the +/- 45 degrees analysis. Intrapartum ultrasound increases the accuracy of fetal head position assessment during active labor and may serve as an educational tool for physicians in training.

Intrapartum fetal head position II: comparison between transvaginal digital examination and transabdominal ultrasound assessment during the second stage of labor.

OBJECTIVE: To test the null hypothesis that no correlation exists between transvaginal digital examination compared with the gold standard technique of transabdominal suprapubic ultrasound assessment of fetal head position during the second stage of labor. A secondary objective was to compare the performance of attending physicians vs. senior residents in depicting fetal head position by transvaginal digital examination in comparison with ultrasound assessment. METHODS: Consecutive patients in the second-stage of labor at term with normal singleton cephalic-presenting fetuses and ruptured membranes were included. Transvaginal digital examinations were performed by either attending physicians or senior residents and were followed immediately by transverse suprapubic transabdominal sonographic assessments performed by a single sonographer. Examiners were blinded to each other's findings. Power analysis dictated sample size. Exact binomial confidence intervals around observed rates were compared with chi 2 and Cohen's kappa-tests. Logistic regression was applied. P < 0.05 was considered significant throughout. RESULTS: One hundred and twelve patients were studied. The absolute error of transvaginal digital examinations was recorded in 65% of patients (95% confidence interval, 56-74%). Parity, pelvic station, combined spinal epidural anesthesia, length of first or second stages of labor, use of oxytocin augmentation, gestational age, mode of delivery, birth weight, and examiner experience did not significantly affect examination accuracy. Stratification, when the transvaginal digital examination was recorded as correct if occurring within +/- 45 degrees of the ultrasound assessment, reduced the error of the transvaginal digital examinations to 39% (95% confidence interval, 30-49%). Independent variables again did not affect examination accuracy in this assessment modality. Rates of agreement between the two methods for attending physicians compared with residents were not significantly different. The overall degrees of agreement were 40% (95% confidence interval, 26-55%) and 68% (95% confidence interval, 53-80%) (kappa = 0.25 and 0.30) for the absolute agreement and +/- 45 degrees assessment modalities, respectively, for attending physicians, and 31% (95% confidence interval, 20-44%) and 55% (95% confidence interval, 42-68%) (kappa = 0.14 and 0.12) for senior residents. CONCLUSION: Using ultrasound assessment as the gold standard, our data demonstrate a high rate of error (65%) in transvaginal digital determination of fetal head position during the second stage of labor. The performance of senior residents in transvaginal digital examinations did not differ significantly from that of attending physicians. Intrapartum ultrasound increases the accuracy of fetal head position assessment during the second stage of labor.

Oral hypoglycemic agents in pregnancy: their time has come.

Oral agents are the mainstay of pharmacological treatment for non-pregnant women with type 2 diabetes. It has been proposed that, owing to the similarity between gestational and type 2 diabetes, some of these drugs could be used effectively and safely as alternatives to insulin therapy. This efficacious alternative provides the physician with more choices that, in turn, translate into more complex decision-making for the management of gestational diabetes. This article illustrates the pharmacological characteristics of oral hypoglycemic agents and placental transfer, provides evidence for the lack of association between congenital anomalies and the drugs, and reviews current studies and the clinical outcomes when these drugs are used.

The controversy surrounding fetal lung maturity in diabetes in pregnancy: a re-evaluation.

It is beyond the scope of this article to discuss the biochemical markers of fetal lung maturity and their pathophysiological characteristics. This information can be found in several textbooks and review articles. Instead, this article addresses controversial issues that confront the obstetrician in daily clinical practice related to the role of diabetes (glucose) as the teratogen for lung morbidity, and the association between lung maturity testing results and actual lung morbidity.

Mid-trimester endovaginal sonography in women at high risk for spontaneous preterm birth.

CONTEXT: Although shortened cervical length has been consistently associated with spontaneous preterm birth, it is not known when in gestation this risk factor becomes apparent. OBJECTIVE: To determine whether sonographic cervical findings between 16 weeks' and 18 weeks 6 days' gestation predict spontaneous preterm birth and whether serial evaluations up to 23 weeks 6 days' gestation improve prediction in high-risk women. DESIGN, SETTING, AND PARTICIPANTS: Blinded observational study performed between March 1997 and November 1999 at 9 university-affiliated medical centers in the United States in 183 women with singleton gestations who previously had experienced a spontaneous birth before 32 weeks' gestation. OBSERVATION: Certified sonologists performed 590 endovaginal sonographic examinations at 2-week intervals. Cervical length was measured from the external os to the functional internal os along a closed endocervical canal. Funneling and dynamic cervical shortening were also recorded. MAIN OUTCOME MEASURE: Spontaneous preterm birth before 35 weeks' gestation, analyzed by selected cutoff values of cervical length. RESULTS: Forty-eight women (26%) experienced spontaneous preterm birth before 35 weeks' gestation. A cervical length of less than 25 mm at the initial sonographic examination was associated with a relative risk (RR) for spontaneous preterm birth of 3.3 (95% confidence interval [CI], 2.1-5.0; sensitivity = 19%; specificity = 98%; positive predictive value = 75%). After controlling for cervical length, neither funneling (P =.24) nor dynamic shortening (P =.054) were significant independent predictors of spontaneous preterm birth. However, using the shortest ever observed cervical length on serial evaluations, after any dynamic shortening, the RR of a cervical length of less than 25 mm for spontaneous preterm birth increased to 4.5 (95% CI, 2.7-7.6; sensitivity = 69%; specificity = 80%; positive predictive value = 55%). Compared with a single cervical measurement at 16 weeks' to 18 weeks 6 days' gestation, serial measurements at up to 23 weeks 6 days significantly improved the prediction of spontaneous preterm birth in a receiver operating characteristic curve analysis (P =.03). CONCLUSIONS: Cervical length assessed by endovaginal sonography between 16 weeks' and 18 weeks 6 days' gestation, augmented by serial evaluations, predicts spontaneous preterm birth before 35 weeks' gestation in high-risk women.

Failure of metronidazole to prevent preterm delivery among pregnant women with asymptomatic Trichomonas vaginalis infection.

BACKGROUND: Infection with Trichomonas vaginalis during pregnancy has been associated with preterm delivery. It is uncertain whether treatment of asymptomatic trichomoniasis in pregnant women reduces the occurrence of preterm delivery. METHODS: We screened pregnant women for trichomoniasis by culture of vaginal secretions. We randomly assigned 617 women with asymptomatic trichomoniasis who were 16 to 23 weeks pregnant to receive two 2-g doses of metronidazole (320 women) or placebo (297 women) 48 hours apart. We treated women again with the same two-dose regimen at 24 to 29 weeks of gestation. The primary outcome was delivery before 37 weeks of gestation. RESULTS: Between randomization and follow-up, trichomoniasis resolved in 249 of 269 women for whom follow-up cultures were available in the metronidazole group (92.6 percent) and 92 of 260 women with follow-up cultures in the placebo group (35.4 percent). Data on the time and characteristics of delivery were available for 315 women in the metronidazole group and 289 women in the placebo group. Delivery occurred before 37 weeks of gestation in 60 women in the metronidazole group (19.0 percent) and 31 women in the placebo group (10.7 percent) (relative risk, 1.8; 95 percent confidence interval, 1.2 to 2.7; P=0.004). The difference was attributable primarily to an increase in preterm delivery resulting from spontaneous preterm labor (10.2 percent vs. 3.5 percent; relative risk, 3.0; 95 percent confidence interval, 1.5 to 5.9). CONCLUSIONS: Treatment of pregnant women with asymptomatic trichomoniasis does not prevent preterm delivery. Routine screening and treatment of asymptomatic pregnant women for this condition cannot be recommended.

Brain radioligands--state of the art and new trends.

Non-invasive radioligand imaging methods for brain receptor studies use either short-lived positron-emitting radionuclides such as 11C and 18F for positron emission tomography (PET) or single photon-emitting radionuclides such as 123I for single photon emission computed tomography (SPECT). PET and SPECT use radioligands which are injected intravenously into experimental animals, human volunteers or patients. The main applications of radioligands in brain research concern human neuropsychopharmacology and the discovery and development of novel drugs to be used in thetherapy of neurological and psychiatric disorders. A basic problem in PET and SPECT brain receptor studies is the lack of useful radioligands with appropriate binding characteristics. Prerequisite criteria need to be satisfied for a radioligand to reveal target binding sites in vivo. This section will discuss these important criteria and also review recent examples in neuroreceptor radioligand development such as selective radioligands for brain monoamine transporters.

Synthesis of high-specific-radioactivity 4- and 6-[18F]fluorometaraminol-PET tracers for the adrenergic nervous system of the heart.

Fluorine-18- (t(1/2) 109.8 min) and carbon-11 (t(1/2) 20.4 min)-labeled norepinephrine analogues have been found previously to be useful positron-emission-tomography (PET) radioligands to map adrenergic nerve terminals of the heart. Metaraminol ((1R,2S)-2-amino-1-(3-hydroxyphenyl)-1-propanol) is a metabolically stable structural analogue of norepinephrine and possesses high affinity towards the norepinephrine transporter and the vesicular monoamine transporter. This paper presents the radiosynthesis of new positron-emission-tomography halogeno analogues of metaraminol labeled with high specific radioactivity. Firstly, fluorine-18-labeled 4-fluorometaraminol (4-[18F]FMR or (1R,2S)-2-amino-1-(4-[18F]fluoro-3-hydroxyphenyl)-1-propanol) and its three other stereoisomers were prepared based on the following key steps: (a) condensation of the corresponding no-carrier-added labeled fluorobenzaldehyde with nitroethane, and (b) HPLC (C18 and chiral) resolution of the diastereomeric product mixture into the four individual enantiomers. Secondly, the corresponding 6-fluoro analogues, fluorine-18-labeled 6-fluorometaraminol (6-[18F]FMR or (1R,2S)-2-amino-1-(2-[18F]fluoro-5-hydroxyphenyl)-1-propanol) and its three other enantiomers, were prepared in an analogous way. Typically, 0.48-0.55 GBq of 4-[18F]FMR and 0.14-0.15 GBq of 6-[18F]FMR could be obtained after 120-160 min total synthesis time, with a specific radioactivity of 56-106 GBq/micromol. Furthermore, the synthesis of racemic 4-fluorometaraminol and 6-fluorometaraminol as reference compounds was performed. as well as independent chiral syntheses of the optically active (1R,2S) enantiomers. For the chiral syntheses, the key step was an electrophilic fluorination with acetyl hypofluorite of (1R,2S)-configurated organometallic derivatives of metaraminol. Tissue distribution studies in rats suggested that both 4-[18F]FMR and 6-[18F]FMR display similar affinity towards the presynaptic adrenergic nerve terminal in the heart. From a practical point of view, 4-[18F]FMR appeared to be the more attractive candidate for future PET investigations, due to higher radiochemical yields.