Two bifunctional desferrioxamine chelators for bioorthogonal labeling of biovectors with zirconium-89.

We report two bifunctional chelators, DFO-Cys and DFO-CBT, to label biovectors with zirconium-89 according to the 2-cyanobenzothiazole/1,2-aminothiol cycloaddition. Their features are high labeling yields, rapid and efficient bioconjugation, metabolically stable luciferin-based end products, and applicability to orthogonal two-step labeling of sensitive biomolecules.

SleepNet: automated sleep analysis via dense convolutional neural network using physiological time series.

OBJECTIVE: In this work, a dense recurrent convolutional neural network (DRCNN) was constructed to detect sleep disorders including arousal, apnea and hypopnea using polysomnography (PSG) measurement channels provided in the 2018 PhysioNet Challenge database. APPROACH: Our model structure is composed of multiple dense convolutional units (DCU) followed by a bidirectional long-short term memory (LSTM) layer followed by a softmax output layer. The sleep events, including sleep stages, arousal regions and multiple types of apnea and hypopnea, are manually annotated by experts, which enables us to train our proposed network using a multi-task learning mechanism. Three binary cross-entropy loss functions, corresponding to sleep/wake, target arousal and apnea-hypopnea/normal detection tasks, are summed up to generate our overall network loss function that is optimized using the Adam method. Our model performance was evaluated using two metrics: the area under the precision-recall curve (AUPRC) and the area under the receiver operating characteristic curve (AUROC). To measure our model generalization, 4-fold cross-validation was also performed. For training, our model was applied to full night recording data. MAIN RESULTS: Finally, the average AUPRC and AUROC values associated with the arousal detection task were 0.505 and 0.922, respectively, on our testing dataset. An ensemble of four models trained on different data folds improved the AUPRC and AUROC to 0.543 and 0.931, respectively. SIGNIFICANCE: Our proposed algorithm achieved the first place in the official stage of the 2018 PhysioNet Challenge for detecting sleep arousals with an AUPRC of 0.54 on the blind testing dataset.

Analysis of radioactive waste generated during the cyclotron production of 99mTc.

Past and prospective shortages of medical radioisotopes have driven recent developments in the direct production of 99mTc via the 100Mo(p,2n)99mTc reaction. The cyclotron-based production method has been shown to successfully produce 99mTc, however trace impurities present in the enriched molybdenum target can also lead to the unintended creation of other radioisotopes which constitute waste. The isotopic composition of the waste has to be investigated in order to determine how it can be handled, transported and safely stored. In this article, we report which waste radioisotopes are created alongside 99mTc during target irradiation. Results are based on the gamma spectroscopy of waste produced. Significant complexities in the emission spectra made automated identification of radioisotopes inaccurate; complexities were resolved using a manual radioisotope identification procedure. The impact of target composition, integrated beam current and duration of target irradiation on the waste produced was studied. Results indicate that an average of 0.059 ± 0.003 GBq of waste is generated per 1 GBq of 99mTc produced. Two-thirds of the total waste activity produced was attributed to 99Mo (T 1/2 = 66 h) alone, while a total of fifty radioisotopes were found in the waste. Long-lived isotopes (T 1/2 > 2 months) constituted only 1% of the total waste activity at end of beam (EOB). In conclusion, it was determined that the waste generated during cyclotron-based 99mTc production was acceptably low for routine clinical production.

Molybdenum target specifications for cyclotron production of 99mTc based on patient dose estimates.

In response to the recognized fragility of reactor-produced (99)Mo supply, direct production of (99m)Tc via (100)Mo(p,2n)(99m)Tc reaction using medical cyclotrons has been investigated. However, due to the existence of other Molybdenum (Mo) isotopes in the target, in parallel with (99m)Tc, other technetium (Tc) radioactive isotopes (impurities) will be produced. They will be incorporated into the labeled radiopharmaceuticals and result in increased patient dose. The isotopic composition of the target and beam energy are main factors that determine production of impurities, thus also dose increases. Therefore, they both must be considered when selecting targets for clinical (99m)Tc production. Although for any given Mo target, the patient dose can be predicted based on complicated calculations of production yields for each Tc radioisotope, it would be very difficult to reverse these calculations to specify target composition based on dosimetry considerations. In this article, a relationship between patient dosimetry and Mo target composition is studied. A simple and easy algorithm for dose estimation, based solely on the knowledge of target composition and beam energy, is described. Using this algorithm, the patient dose increase due to every Mo isotope that could be present in the target is estimated. Most importantly, a technique to determine Mo target composition thresholds that would meet any given dosimetry requirement is proposed.

Imaging study of using radiopharmaceuticals labeled with cyclotron-produced 99mTc.

Cyclotron-produced 99mTc (CPTc) has been recognized as an attractive and practical substitution of reactor/generator based 99mTc. However, the small amount of 92-98Mo in the irradiation of enriched 100Mo could lead to the production of other radioactive technetium isotopes (Tc-impurities) which cannot be chemically separated. Thus, these impurities could contribute to patient dose and affect image quality. The potential radiation dose caused by these Tc-impurities produced using different targets, irradiation conditions, and corresponding to different injection times have been investigated, leading us to create dose-based limits of these parameters for producing clinically acceptable CPTc. However, image quality has been not considered. The aim of the present work is to provide a comprehensive and quantitative analysis of image quality for CPTc. The impact of Tc-impurities in CPTc on image resolution, background noise, and contrast is investigated by performing both Monte-Carlo simulations and phantom experiments. Various targets, irradiation, and acquisition conditions are employed for investigating the image-based limits of CPTc production parameters. Additionally, the relationship between patient dose and image quality of CPTc samples is studied. Only those samples which meet both dose- and image-based limits should be accepted in future clinical studies.

Antimicrobial compounds from root, stem bark and seeds of Melia volkensii.

Three compounds, toosendanin (1), kulactone (2) and scopoletin (3), were isolated from either the root bark and/or the stem bark of Melia volkensii. Their structures were determined on the basis of spectroscopic data generated and by comparison with data from the literature. 1 and 2, isolated for the first time from M. volkensii, exhibited significant (p < 0.05) activity against Escherichia coli with minimum inhibitory concentration of 12.5 µg/mL, close to that of neomycin (6.25 µg/mL). The compounds also exhibited high activity against Aspergillus niger (MIC 6.25 µg/mL compared to 2.5 µg/mL for clotrimazole). Dichloromethane and methanol seed, hexane stem bark and methanol root bark extracts exhibited activities towards Escherichia coli, Staphylococcus aureus, Aspergillus niger and Plasmodium falciparum, respectively. Antimicrobial activity of the plant towards A. niger, P. falciparum and S. aureus is reported for the first time in the current work.

French-Canadian linguistic validation of the NIH Chronic Prostatitis Symptom Index.

INTRODUCTION: The NIH Chronic Prostatitis Symptom Index (CPSI) is recommended in the clinical evaluation of men with chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). However, its use is not possible in French speakers, as it has not been validated in this population. We performed a linguistic validation of the CPSI. METHODS: Linguistic translation followed the forward-backward-forward technique and relied on professional medical translators, bilingual health professionals, and patient input. Along with the SF-12, the translated version was administered to a convenience sample of men presenting for pre-vasectomy visits (controls) and to consecutive patients with established CP/CPPS (cases). Men with CP/CPPS were subsequently asked to complete a 14-day retest questionnaire. Psychometric testing addressed standard reliability and validity characteristics. RESULTS: Thirty-six cases and 38 controls with respective mean ages of 46.5 and 44.0 years participated and 33 (91.2%) cases completed the retest questionnaire. Pain (p<0.001), urinary (p<0.001) and quality-of-life (QOL) scale (p<0.001) score means differed between cases and controls. For the same scales, Cronbach's alphas for cases were respectively 0.70, 0.72 and 0.79 versus 0.80, 0.57, and 0.88 for controls. The retest product-moments were 0.83 for pain, 0.55 for urinary, and 0.83 for QOL scales. In cases, strong correlation was noted between QOL and pain scales (r=0.7), and between urinary and pain scales (r=0.6), versus moderate correlation between QOL and urinary scales (r=0.4). Negative correlation was recorded between CPSI scales and SF-12 scales, which ranged from -0.2 to -0.4. CONCLUSIONS: When applied to CPPS and control subjects, the French Canadian CPSI translation demonstrates excellent discriminant properties. Moreover, its reliability and validity characteristics confirm the qualities of the CPSI as a standard evaluative tool for men with CPPS.

Quantitative analysis of relationships between irradiation parameters and the reproducibility of cyclotron-produced (99m)Tc yields.

Cyclotron production of (99m)Tc through the (100)Mo(p,2n) (99m)Tc reaction channel is actively being investigated as an alternative to reactor-based (99)Mo generation by nuclear fission of (235)U. An exciting aspect of this approach is that it can be implemented using currently-existing cyclotron infrastructure to supplement, or potentially replace, conventional (99m)Tc production methods that are based on aging and increasingly unreliable nuclear reactors. Successful implementation will require consistent production of large quantities of high-radionuclidic-purity (99m)Tc. However, variations in proton beam currents and the thickness and isotopic composition of enriched (100)Mo targets, in addition to other irradiation parameters, may degrade reproducibility of both radionuclidic purity and absolute (99m)Tc yields. The purpose of this article is to present a method for quantifying relationships between random variations in production parameters, including (100)Mo target thicknesses and proton beam currents, and reproducibility of absolute (99m)Tc yields (defined as the end of bombardment (EOB) (99m)Tc activity). Using the concepts of linear error propagation and the theory of stochastic point processes, we derive a mathematical expression that quantifies the influence of variations in various irradiation parameters on yield reproducibility, quantified in terms of the coefficient of variation of the EOB (99m)Tc activity. The utility of the developed formalism is demonstrated with an example. We show that achieving less than 20% variability in (99m)Tc yields will require highly-reproducible target thicknesses and proton currents. These results are related to the service rate which is defined as the percentage of (99m)Tc production runs that meet the minimum daily requirement of one (or many) nuclear medicine departments. For example, we show that achieving service rates of 84.0%, 97.5% and 99.9% with 20% variations in target thicknesses requires producing on average 1.2, 1.5 and 1.9 times the minimum daily activity requirement. The irradiation parameters that would be required to achieve these service rates are described. We believe the developed formalism will aid in the development of quality-control criteria required to ensure consistent supply of large quantities of high-radionuclidic-purity cyclotron-produced (99m)Tc.

A fast and simple dose-calibrator-based quality control test for the radionuclidic purity of cyclotron-produced (99m)Tc.

Cyclotron production of 99mTc through the (100)Mo(p,2n)99mTc reaction channel is actively being investigated as an alternative to reactor-based (99)Mo generation by nuclear fission of (235)U. Like most radioisotope production methods, cyclotron production of 99mTc will result in creation of unwanted impurities, including Tc and non-Tc isotopes. It is important to measure the amounts of these impurities for release of cyclotron-produced 99mTc (CPTc) for clinical use. Detection of radioactive impurities will rely on measurements of their gamma (γ) emissions. Gamma spectroscopy is not suitable for this purpose because the overwhelming presence of 99mTc and the count-rate limitations of γ spectroscopy systems preclude fast and accurate measurement of small amounts of impurities. In this article we describe a simple and fast method for measuring γ emission rates from radioactive impurities in CPTc. The proposed method is similar to that used to identify (99)Mo breakthrough in generator-produced 99mTc: one dose calibrator (DC) reading of a CPTc source placed in a lead shield is followed by a second reading of the same source in air. Our experimental and theoretical analysis show that the ratio of DC readings in lead to those in air are linearly related to γ emission rates from impurities per MBq of 99mTc over a large range of clinically-relevant production conditions. We show that estimates of the γ emission rates from Tc impurities per MBq of 99mTc can be used to estimate increases in radiation dose (relative to pure 99mTc) to patients injected with CPTc-based radiopharmaceuticals. This enables establishing dosimetry-based clinical-release criteria that can be tested using commercially-available dose calibrators. We show that our approach is highly sensitive to the presence of 93gTc, 93mTc, 94gTc, 94mTc, 95mTc, 95gTc, and 96gTc, in addition to a number of non-Tc impurities.

Rapid washout of technetium-99m-MIBI from a large parathyroid adenoma.

We report a case of rapid 99mTc-methoxyisobutylisonitrile (MIBI) clearance from a parathyroid adenoma. A double-phase 99mTc-MIBI parathyroid scintigraphy was performed on a 62-yr-old female evaluated for primary hyperparathyroidism. A large parathyroid adenoma was visualized caudal to the left lobe of the thyroid gland with an unusually rapid washout of the tracer from tumor tissue. Histologic tissue examination confirmed the presence of a parathyroid adenoma and the absence of oxyphil cells. Care should be taken in interpretation of 99mTc-MIBI parathyroid scintigrams because some adenomas can present a rapid release of the radiotracer in a double-phase study. Technetium-99m-MIBI retention could be related to the number of mitochondria-rich cells in parathyroid adenomas or to hyperplasia.

Prognostic value of FDG PET imaging in malignant pleural mesothelioma.

UNLABELLED: Despite several attempts at treating malignant pleural mesothelioma with various modalities, mortality remains high, with median survival between 12 and 18 mo. This disease may have a highly variable clinical course, with occasional long-term survivors. The purpose of this study was to assess whether tumor metabolic activity, as assessed by fluorodeoxyglucose (FDG) PET imaging, correlates inversely with survival. METHODS: Twenty-eight patients with suspected mesothelioma underwent FDG PET scanning between September 1995 and May 1997. A diagnosis of mesothelioma was confirmed in 22. Fully corrected scans with attenuation correction of the entire chest were available in 17 patients with sufficient follow-up for survival analysis. Standardized uptake values (SUVs) were determined from the most active tumor site in each patient. RESULTS: Seven patients died during follow-up, at a median period of 5.3 mo after FDG PET scanning. Follow-up information was available on the remaining 10 patients for a median period of 15.6 mo after the PET study. The mean SUV of the deceased patients was 6.6+/-2.9, compared with 3.2+/-1.6 among the combined survivors. The deceased patients had tumor SUVs that were highly correlated with duration of survival after the PET study (r = 0.87, P < 0.05). The cumulative survival estimate by the Kaplan-Meier product limit method was 0.17 at 12 mo for the patients with tumor SUVs greater than the median value and 0.86 for those with lower SUVs. The survival distribution of the high SUV group showed significantly shorter survivals compared with the low SUV group (P < 0.01). CONCLUSION: Patients with highly active mesotheliomas on FDG PET imaging have a poor prognosis. High FDG uptake in these tumors indicates shorter patient survival.

Clinical evaluation of processing techniques for attenuation correction with 137Cs in whole-body PET imaging.

UNLABELLED: Transmission scanning can be successfully performed with a 137Cs single-photon emitting point source for three-dimensional PET imaging. However, the attenuation coefficients provided by this method are underestimated because of the energy difference between 662- and 511-keV photons, as well as scatter and emission contamination when the transmission data are acquired after injection. The purpose of this study was to evaluate, from a clinical perspective, the relative benefits of various processing schemes to resolve these issues. METHODS: Thirty-eight whole-body PET studies acquired with postinjection singles transmission scans were analyzed. The transmission images were processed and applied to the emission data for attenuation correction. Three processing techniques were compared: simple segmentation (SEG) of the transmission scan, emission contamination subtraction with scaling (ECS) of the resulting data to 511-keV attenuation coefficient values and a hybrid technique performing partial segmentation of some tissue densities on the ECS scan (THR). The corrected emission scans were blindly assessed for image noise, the presence of edge artifacts at the lung-soft-tissue interface and for overall diagnostic confidence using a semiquantitative scoring system. The count densities and the SDs in uniform structures were compared among the various techniques. The observations for each method were compared using a paired t test. RESULTS: The SEG technique produced images that were visually less noisy than the ECS method (P < 0.0001) and the THR technique, but at the expense of increased edge artifacts at the boundaries between the lungs and surrounding tissues. The THR technique failed to eliminate these artifacts compared with the ECS technique (P < 0.0001) but preserved the activity gradients in the hilar areas. The count densities (and thus, the standardized uptake values) were similar among the three techniques, but the SEG method tended to underestimate the activity in the lung fields and in chest tumors (slope = 0.79 and 0.94, respectively). CONCLUSION: For many clinical applications, SEG data remain an efficient method for processing 137Cs transmission scans. The ECS method produced noisier images than the other two techniques but did not introduce artifacts at the lung boundaries. The THR technique, more versatile in complex anatomic areas, allowed good preservation of density gradients in the lungs.

PET evaluation of therapeutic limb perfusion in Merkel's cell carcinoma.

An 87-yr-old woman diagnosed with recurrent Merkel's cell carcinoma was treated with therapeutic limb perfusion and underwent PET scanning with 18F-fluorodeoxyglucose (FDG). PET studies were obtained before and after treatment to determine the response to the intervention. A baseline whole-body study was obtained to assess the extent and degree of disease activity. This was followed by a repeat PET scan 2 mo. later after treatment with isolated limb chemotherapy with high-dose melphalan and tumor necrosis factor-alpha. The initial scan demonstrated multiple foci of high FDG uptake in the left calf, a left supraclavicular lesion and also detected concurrent keratinizing squamous cell metastasis in the right axilla. A repeat PET study showed complete metabolic resolution of the lesions in the left calf after treatment. FDG PET may be a useful technique for staging Merkel cell carcinoma and for assessing the tumor response after therapy of this rare tumor.

Self-administration in the pharmacological treatment of impotence.

Recent innovative research into the physiology and pharmacology of erection and the introduction of intracavernous injection of vasoactive agents have revolutionised our approach to the diagnosis and treatment of impotence. A thorough understanding of the rationale, indications, precautions and potential complications of intracavernous self-injection is essential for successful management. The commonly used drugs for injection are papaverine, either alone or in combination with phentolamine, and alprostadil (prostaglandin E1). The major adverse effects include priapism, prolonged erection, and fibrosis of the erectile tissue. With the proper technique and appropriate dosage, this is a safe, minimally invasive, and highly effective treatment.

Metabolic imaging of malignant pleural mesothelioma with fluorodeoxyglucose positron emission tomography.

BACKGROUND: The diagnosis of malignant mesothelioma is a challenging medical problem. CT often cannot differentiate between benign diffuse pleural thickening and malignant mesothelioma, while thoracentesis and CT-guided biopsies are insensitive. We have assessed the value of positron emission tomography (PET) with 2-fluoro-2-deoxy-D-glucose (FDG) in the evaluation of malignant mesothelioma. METHODS: Twenty-eight consecutive patients referred for the evaluation of suspected malignant mesothelioma were evaluated by FDG-PET imaging. Measured attenuation correction was performed in 26 of 28 cases for quantitation with the standardized uptake value (SUV) method. The results of PET imaging were compared with those of video-assisted thoracoscopy or surgical biopsies. RESULTS: Surgical biopsy specimens confirmed the presence of malignant disease in 24 patients and demonstrated benign processes in the remaining four. The uptake of FDG was significantly higher in malignant than in benign lesions (SUV=4.9+/-2.9 and SUV=1.4+/-0.6, respectively; p<0.0001). With a SUV cutoff of 2.0 to differentiate between malignant and benign disease, a sensitivity of 91% and a specificity of 100% could be achieved, although the activity in some epithelial mesotheliomas tended to be close to this threshold. FDG-PET images provided excellent delineation of the active tumor sites. Hypermetabolic lymph node involvement was noted on FDG-PET images in 12 patients, 9 of which appeared normal on CT scans. Histologic examination in six patients confirmed malignant nodal disease in five cases and indicated granulomatous lymphadenitis in one. CONCLUSION: In this highly selected population, FDG-PET imaging was a sensitive method to identify malignant mesothelioma and determine the extent of the disease process.

Calcitonin gene-related peptide: possibly neurotransmitter contributes to penile erection in monkeys.

The distribution of calcitonin gene-related peptide (CGRP) immunoreactivity in the cavernous tissue and the erectile response to intracavernous injection of CGRP was investigated in 7 monkeys. Intracavernous CGRP increased cavernous arterial flow and induced cavernous smooth muscle relaxation and venous outflow occlusion. Intracavernous injection of CGRP antibody did not significantly change the erectile response to cavernous nerve stimulation. Histologic staining for CGRP immunoreactivity showed nerve fiber-like staining within the cavernous arterial wall and the cavernous smooth muscles. These data suggest that CGRP may contribute to penile erection in monkeys.

Intracavernosal alprostadil is effective for the treatment of erectile dysfunction in diabetic men.

The efficacy and safety of intracavernosal alprostadil was evaluated for the treatment of erectile dysfunction in men with type I or type II diabetes mellitus. This was an open-label, flexible dose-escalating study involving 336 men (77% of whom were Asian/Oriental) enrolled by 15 centres in Australia, Canada and seven countries in Asia. The effective alprostadil dose, ie the dose producing penile rigidity adequate for intercourse and lasting up to 60 min, was established by titration at the clinic prior to entry into the 6 month self-treatment home phase. All men were fully trained in the self-injection technique before entry into the home phase. Efficacy and safety were assessed using patient and partner diaries and by interview at clinic visits during the titration phase and after 1, 3 and 6 months of treatment. An effective home dose was established by titration for 94% of the 336 men (median dose 20 microg, range 2.5-60 microg). Of 278 (83%) men who entered the home phase, 277 men (247 with type II diabetes and 30 with type I diabetes) had evaluable data for alprostadil dosage and clinical response. During the home phase, a satisfactory erectile response was achieved after 99% of injections, and the median alprostadil dose remained unchanged. The initial home dose and clinical response were similar in type I and type II diabetic men. Treatment was generally well tolerated with a low incidence of penile pain (24%) In conclusion, intracavernosal alprostadil was effective and well tolerated in type I and type II diabetic men with erectile dysfunction of mixed aetiology.

Erythrinaline alkaloids from the flowers and pods of Erythrina lysistemon and their DPPH radical scavenging properties.

Fourteen different erythrinaline alkaloids have been isolated from the flowers and pods of Erythrina lysistemon with four being reported for the first time in nature and five for the first time in this species and the rest having been re-isolated. The new compounds are (+)-11beta-hydroxyerysotramidine (1), (+)-11beta-methoxyerysotramidine (2), (+)-11beta-hydroxyerysotrine N-oxide (4) and (+)-11beta-hydroxyerysotrine (8). (+)-11alpha-Hydroxyerysotrine N-oxide (3), earlier misidentified as erythrartine N-oxide (beta-hydroxyerysotrine N-oxide 4), was also re-isolated along with four other alkaloids. Correct identification of compounds 4 and 8 was aided by the fact that the two sets of C-11 epimers 3, 4 and 8, 9 were both isolated in this study thus making it easier to identify and assign the individual epimers. (+)-Erythristemine (14) was found distributed in most of the plant parts investigated. Preliminary work on the crude chloroform/methanol (1:1) showed moderate toxicity to brine shrimp (LC50 23 ppm) and moderate (IC50 86 microg/ml) radical scavenging properties against stable 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical. The DPPH radical scavenging properties of the isolated compounds were assessed using TLC autographic and spectrophotometric assays whereupon only compounds 11 (1 microg; 90 microg/ml) and 12 (0.1 microg; 160 microg/ml) showed any notable activity. It appears the two compounds are slow reacting and do not reach steady state conditions within the standard half an hour time frame but only seemed to have reached steady state conditions after 4 h.

N-(n-Benzylpiperidin-4-yl)-2-[18F]fluorobenzamide: a potential ligand for PET imaging of breast cancer.

N-(N-Benzylpiperidin-4-yl)-2-[(18)F]fluorobenzamide (2), a potential ligand for PET imaging of sigma receptor, has been found to be a potential agent for detection of breast cancer. In vivo studies in severe combined immunodeficient (SCID) mice bearing MDA-MB231 tumors showed that the uptake of compound 2 in these tumors was high (3.8%/g); the ratios of tumor/muscle and tumor/blood were 6.2 and 7.0, respectively, at 1 h postinjection. Pretreatment of SCID mice with haldol increased the uptake of compound 2 in blood, muscle, and other well-perfused organs while decreasing its uptake in tumors. The ratios of tumor/muscle and tumor/blood decreased from 6.2 and 7.0 to 1.3 and 1.1, respectively, at 1 h postinjection. At 2 h postinjection, the ratios of tumor/muscle and tumor/blood decreased from 4.9 and 7.8 to 1.4 and 1.4, respectively. The tumor uptake of compound 2 in SCID mice bearing primary tumor explants from a human breast cancer patient was lower than that in MDA-MB231 tumors (1.66%/g versus 3.78%/g), and the ratios of tumor/muscle and tumor/blood were 3.5 and 3.7, respectively, at 1 h postinjection. These results suggest that compound 2 may be a potential ligand for PET imaging of breast cancer.

N-(N-benzylpiperidin-4-yl)-2-[18F]fluorobenzamide: a potential ligand for PET imaging of sigma receptors.

Four nitro- and fluorobenzamides (1-4) have been synthesized in good yields from nitro- and fluoro-substituted benzoyl chloride with 4-amino-1-benzylpiperidine. In vitro studies showed that these compounds have high affinities to sigma receptors. N-(N-Benzylpiperidin-4-yl)-2-fluorobenzamide (3), in particular, bound to sigma receptors with high affinity (Ki = 3.4 nM, guinea pig brain membranes) and high selectivity (sigma-2/sigma-1 = 120). It was, therefore, labeled with 18F and evaluated as a sigma receptor radioligand. N-(N-Benzylpiperidin-4-yl)-2-[18F]fluorobenzamide (3a) was synthesized in one step by nucleophile substitution of the 2-nitro precursor (1) with [18F]fluoride in DMSO at 140 degrees C for 20 min followed by purification with HPLC in 4-10% yield (decay corrected). The synthesis time was 90 min and the specific activity was 0.4-1.0 Ci/mumol. Tissue distribution in mice revealed that the uptakes of 3a in the brain, heart, liver, lungs, spleen, kidneys and small intestine were high, and the radioactivity in these organs remained constant from 60 to 120 min post-injection. The radioactivity in the bone did not significantly increase, suggesting in vivo defluorination may not be the major route of metabolism of 3a in mice. Blocking studies with haloperidol in rats indicated that the uptake of compound 3a in the rat brain was selective to haloperidol-sensitive sigma sites. These results suggest that compound 3a is a potent sigma receptor radioligand and may be a potential ligand for PET imaging of sigma receptors in humans.