Bringing revolution through quadcopter technology in the field of supplying medicine in the Himalayan regions of Uttarakhand: Case example of Pithoragarh.

BACKGROUND: Quadcopters are used in various forms in the civil arena, from crop insurance to agricultural drones, as loudspeakers for announcing government guidelines, resilience tools in infrastructure monitoring, real-time vehicle detection, etc. However, the usage of quadcopters and hexacopters in supplying medical aid to inhospitable and far-flung terrains is being studied and researched in less detail throughout the globe. AIM: This paper focuses on the basics of quadcopter technology in supplying medicines and its advantages to the affected patients who get life-saving medicines from earlier inaccessible roads. The efficacy of quadcopters in terms of time, economy, and manpower in supplying essential and inescapable medical supplies is exponentially high, especially in the Pithoragarh Region of Uttarakhand State, where the villages are not connected to the roads. METHODS: The road structure of the hilly terrain of Uttarakhand, India, was studied in detail to know the state of people who do not get access to life-saving drugs due to the non-availability of roads near them. RESULTS: The result informs us that the quad/hexacopter if used in abundance can provide a glimmer of hope to people in remote places. CONCLUSION: The quadcopter can provide hope to the residents of the Pithoragarh district of Uttarakhand, India, located in far-flung places devoid of basic medical facilities.

Simlukafusp alfa (FAP-IL2v) immunocytokine is a versatile combination partner for cancer immunotherapy.

Simlukafusp alfa (FAP-IL2v, RO6874281/RG7461) is an immunocytokine comprising an antibody against fibroblast activation protein α (FAP) and an IL-2 variant with a retained affinity for IL-2Rßγ > IL-2 Rßγ and abolished binding to IL-2 Rα. Here, we investigated the immunostimulatory properties of FAP-IL2v and its combination with programmed cell death protein 1 (PD-1) checkpoint inhibition, CD40 agonism, T cell bispecific and antibody-dependent cellular cytotoxicity (ADCC)-mediating antibodies. The binding and immunostimulatory properties of FAP-IL2v were investigated in vitro and compared with FAP-IL2wt. Tumor targeting was investigated in tumor-bearing mice and in a rhesus monkey. The ability of FAP-IL2v to potentiate the efficacy of different immunotherapies was investigated in different xenograft and syngeneic murine tumor models. FAP-IL2v bound IL-2 Rßγ and FAP with high affinity in vitro, inducing dose-dependent proliferation of natural killer (NK) cells and CD4+/CD8+ T cells while being significantly less potent than FAP-IL2wt in activating immunosuppressive regulatory T cells (Tregs). T cells activated by FAP-IL2v were less sensitive to Fas-mediated apoptosis than those activated by FAP-IL2wt. Imaging studies demonstrated improved tumor targeting of FAP-IL2v compared to FAP-IL2wt. Furthermore, FAP-IL2v significantly enhanced the in vitro and in vivo activity of therapeutic antibodies that mediate antibody-dependent or T cell-dependent cellular cytotoxicity (TDCC) and of programmed death-ligand 1 (PD-L1) checkpoint inhibition. The triple combination of FAP-IL2v with an anti-PD-L1 antibody and an agonistic CD40 antibody was most efficacious. These data indicate that FAP-IL2v is a potent immunocytokine that potentiates the efficacy of different T- and NK-cell-based cancer immunotherapies.

Visual interpretation, not SUV ratios, is the ideal method to interpret 18F-DOPA PET scans to aid in the cure of patients with focal congenital hyperinsulinism.

INTRODUCTION: Congenital hyperinsulinism is characterized by abnormal regulation of insulin secretion from the pancreas causing profound hypoketotic hypoglycemia and is the leading cause of persistent hypoglycemia in infants and children. The main objective of this study is to highlight the different mechanisms to interpret the 18F-DOPA PET scans and how this can influence outcomes. MATERIALS AND METHODS: After 18F-Fluoro-L-DOPA was injected intravenously into 50 subjects' arm at a dose of 2.96-5.92 MBq/kg, three to four single-bed position PET scans were acquired at 20, 30, 40 and 50-minute post injection. The radiologist interpreted the scans for focal and diffuse hyperinsulinism using a visual interpretation method, as well as determining the Standard Uptake Value ratios with varying cut-offs. RESULTS: Visual interpretation had the combination of the best sensitivity and positive prediction values. CONCLUSIONS: In patients with focal disease, SUV ratios are not as accurate in identifying the focal lesion as visual inspection, and cases of focal disease may be missed by those relying on SUV ratios, thereby denying the patients a chance of cure. We recommend treating patients with diazoxide-resistant hyperinsulinism in centers with dedicated multidisciplinary team comprising of at least a pediatric endocrinologist with a special interest in hyperinsulinism, a radiologist experienced in interpretation of 18F-Fluoro-L-DOPA PET/CT scans, a histopathologist with experience in frozen section analysis of the pancreas and a pancreatic surgeon experienced in partial pancreatectomies in patients with hyperinsulinism.

Rapid Brain Nicotine Uptake from Electronic Cigarettes.

This study sought to determine brain nicotine kinetics from use of the increasingly popular electronic cigarette (E-cig). Methods: In 17 E-cig users (9 men and 8 women), brain uptake of nicotine after inhalation from E-cigs was directly assessed using 11C-nicotine PET. The brain nicotine kinetics were compared with those from smoking combustible cigarettes (C-cigs). Results: A single puff of E-cig vapor caused the nicotine concentration in the brain to rise quickly (mean time to reach 50% of maximum brain nicotine concentration, 27 s), with a peak amplitude 25% higher in women than men, resembling previous observations with C-cigs. Nonetheless, the accumulation from E-cigs (24%) was less than that from C-cigs (32%) in both men and women. Conclusion: E-cigs can deliver nicotine to the brain with a rapidity similar to that of C-cigs. Therefore, to the extent that rapid brain uptake promotes smoking reward, E-cigs might maintain a degree of nicotine dependence and also serve as a noncombustible substitute for cigarettes.

Whole Body PET Imaging with a Norepinephrine Transporter Probe 4-[18F]Fluorobenzylguanidine: Biodistribution and Radiation Dosimetry.

PURPOSE: 4-[18F]Fluorobenzylguanidine ([18F]PFBG) is a positron emission tomography (PET) probe for non-invasive targeting of the norepinephrine transporter. The aim of this study was to assess uptake and distribution characteristics of this PET probe. PROCEDURES: Three cynomolgus monkeys were injected with 269 ± 51 MBq (7.3 ± 1.4 mCi) of [18F]PFBG and 21 whole body PET scans were acquired over 165 min. s around organs to generate time-activity curves. The absorbed doses to individual organs and the effective dose to the whole body were estimated. RESULTS: Favorable distribution of [18F]PFBG was noted with a fast wash-in and wash-out of radioactivity from several tissues. [18F]PFBG rapidly distributed in the heart, liver, kidneys, and adrenal glands. The uptake presented as %ID in the brain, lung, and spleen was 1.06 ± 0.45, 6.28 ± 0.33, and 1.39 ± 0.35 at 1 min and decreased to 0.29 ± 0.02, 1.78 ± 0.31, and 0.66 ± 0.22 by 112 min. In general, a two- to fourfold reduction was noted from peak radioactivity levels. Rapid uptake and significant retention of radioactivity was noted in the heart and the septal wall was distinctly visible by 20 min. Fast wash-in and washout kinetics for [18F]PFBG resulted in shorter residence times. The residence time for the liver, lungs, kidneys, and spleen were 28.01 ± 7.73 min, 2.97 ± 0.56 min, 6.04 ± 3.41 min, and 1.09 ± 0.33 min, respectively. The mean effective dose for the 70-kg male was 0.04 ± 0.00 mSv/MBq. The organs receiving the highest radiation dose in the 70-kg male model were the testes (0.11 ± 0.02 mGy/MBq), adrenals (0.08 ± 0.01 mGy/MBq), and urinary bladder wall (0.08 ± 0.01 mGy/MBq). CONCLUSIONS: [18F]PFBG shows a favorable biodistribution pattern. Rapid and persistent uptake was noted in innervated organs. Renal clearance was the major path for elimination of [18F]PFBG. The estimated radiation burden from [18F]PFBG was significantly lower than that from [124I]MIBG.

Pancreatic uptake and radiation dosimetry of 6-[18F]fluoro-L-DOPA from PET imaging studies in infants with congenital hyperinsulinism.

METHODS: After injecting 25.6 ± 8.8 MBq (0.7 ± 0.2 mCi) of 18F-Fluoro-L-DOPA intravenously, three static PET scans were acquired at 20, 30, and 40 min post injection in 3-D mode on 10 patients (6 male, 4 female) with congenital hyperinsulinism. Regions of interest (ROIs) were drawn over several organs visible in the reconstructed PET/CT images and time activity curves (TACs) were generated. Residence times were calculated using the TAC data. The radiation absorbed dose for the whole body was calculated by entering the residence times in the OLINDA/EXM 1.0 software. RESULTS: The mean residence times for the 18F-Fluoro-L-DOPA in the liver, lungs, kidneys, muscles, and pancreas were 11.54 ± 2.84, 1.25 ± 0.38, 4.65 ± 0.97, 17.13 ± 2.62, and 0.89 ± 0.34 min, respectively. The mean effective dose equivalent for 18F-Fluoro-L-DOPA was 0.40 ± 0.04 mSv/MBq. The CT scan used for attenuation correction delivered an additional radiation dose of 5.7 mSv. The organs receiving the highest radiation absorbed dose from 18F-Fluoro-L-DOPA were the urinary bladder wall (2.76 ± 0.95 mGy/MBq), pancreas (0.87 ± 0.30 mGy/MBq), liver (0.34 ± 0.07 mGy/MBq), and kidneys (0.61 ± 0.11 mGy/MBq). The renal system was the primary route for the radioactivity clearance and excretion. CONCLUSIONS: The estimated radiation dose burden from 18F-Fluoro-L-DOPA is relatively modest to newborns.

Selective targeting of melanoma using N-(2-diethylaminoethyl) 4-[18F]fluoroethoxy benzamide (4-[18F]FEBZA): a novel PET imaging probe.

BACKGROUND: The purpose of this study was to develop a positron emission tomography (PET) imaging probe that is easy to synthesize and selectively targets melanoma in vivo. Herein, we report the synthesis and preclinical evaluation of N-(2-diethylaminoethyl) 4-[18F]Fluoroethoxy benzamide (4-[18F]FEBZA). A one-step synthesis was developed to prepare 4-[18F]FEBZA in high radiochemical yields and specific activity. The binding affinity, the in vitro binding, and internalization studies were performed using B16F1 melanoma cell line. The biodistribution studies were performed in C57BL/6 normal mice, C57BL/6 mice bearing B16F1 melanoma tumor xenografts, and nu/nu athymic mice bearing HT-29 human adenocarcinoma tumor and C-32 amelanotic melanoma tumor xenografts. MicroPET studies were performed in mice bearing B16F1 and HT-29 tumor xenografts. RESULTS: 4-[18F]FEBZA was prepared in 53 ± 14% radiochemical yields and a specific activity of 8.7 ± 1.1 Ci/µmol. The overall synthesis time for 4-[18F]FEBZA was 54 ± 7 min. The in vitro binding to B16F1 cells was 60.03 ± 0.48% after 1 h incubation at 37 °C. The in vivo biodistribution studies show a rapid and high uptake of F-18 in B16F1 tumor with 8.66 ± 1.02%IA/g in this tumor at 1 h. In contrast, the uptake at 1 h in HT-29 colorectal adenocarcinoma and C-32 amelanotic melanoma tumors was significantly lower with 3.68 ± 0.47%IA/g and 3.91 ± 0.23%IA/g in HT-29 and C-32 tumors, respectively. On microPET images, the melanoma tumor was clearly visible by 10 min post-injection and the intensity in the tumor continued to increase with time. In contrast, the HT-29 tumor was not visible on the microPET scans. CONCLUSIONS: A rapid and facile synthesis of 4-[18F]FEBZA is developed. This method offers a reliable production of 4-[18F]FEBZA in high radiochemical yields and specific activity. A high binding affinity to melanoma cells and high uptake in tumor was noted. The microPET scan clearly delineates the melanoma tumor by 10 min post-injection. The results from these preclinical studies support the potential of 4-[18F]FEBZA as an effective probe to image melanoma.

A programmable smoke delivery device for PET imaging with cigarettes containing 11C-nicotine.

INTRODUCTION: PET imaging with 11C-nicotine-loaded cigarettes is a valuable tool to directly assess fast nicotine kinetics and its neuropharmacological role in tobacco dependence. To eliminate variations among puffs inhaled by subjects, this work aimed to develop a programmable smoke delivery device (SDD) to produce highly reproducible and adjustable puffs of cigarette smoke for PET experiments. NEW METHOD: The SDD was built around a programmable syringe pump as a smoking machine to draw a puff of smoke from a 11C-nicotine-loaded cigarette and make it available for a subject to take the smoke into the mouth and then inhale it during PET data acquisition. Brain nicotine time activity curves and total body absorbed 11C-nicotine doses (TAD) were measured in smokers who inhaled a single puff of smoke via the SDD from a 11C-nicotine-loaded cigarette. RESULTS: Nearly identical brain nicotine kinetics were observed between participants who inhaled a puff of smoke through the SDD and those who inhaled directly from a cigarette. COMPARISON WITH EXISTING METHODS: This new device minimizes puff variations that exist with earlier smoke delivery apparatuses which could introduce confounding factors. CONCLUSIONS: The SDD is effective in delivering 11C-nicotine from the study cigarettes. Despite a 2-s increase in aging of smoke delivered through the SDD versus smoke taken directly from a cigarette, the difference in brain nicotine kinetics after 11C-nicotine delivery with and without use of the SDD is negligible. This refined device may be useful for future research on the deposition and pharmacokinetics of nicotine inhaled with tobacco smoke.

4-11C-Methoxy N-(2-Diethylaminoethyl) Benzamide: A Novel Probe to Selectively Target Melanoma.

We report the synthesis and preclinical evaluation of a 11C-labeled probe to target melanoma using PET. Methods: The target compound 4-11C-methoxy N-(2-diethylaminoethyl) benzamide (4-11C-MBZA) was prepared via the 11C-methylation of 4-hydroxy N-(2-diethylaminoethyl) benzamide (4-HBZA). The in vitro binding was performed using B16F1 (melanoma cells), MCF-10A (breast epithelial cells), and MDA-MB 231 (breast cancer cells). The internalization studies were conducted using B16F1 cells. In vivo biodistribution and small-animal PET imaging were performed in mice bearing B16F1 melanoma tumor xenografts. Results: The target compound 4-11C-MBZA was prepared in 46% ± 7% radiochemical yields by reacting 11C-methyltriflate with 4-HBZA followed by high-performance liquid chromatography purification. The specific activity of this compound was 853 ± 29.6 GBq/µmol (23 ± 0.8 Ci/µmol). The binding of 4-11C-MBZA to B16F1, MCF-10A, and MDA-MB-231 cells was 6.41% ± 1.28%, 1.51% ± 0.17%, and 0.30% ± 0.17%, respectively. Internalization studies using B16F1 melanoma cells show 60.7% of the cell-bound activity was internalized. Results from biodistribution studies show a rapid and high uptake of radioactivity in the tumor, with uptake levels reaching 5.85 ± 0.79 and 8.13 ± 1.46 percentage injected dose per gram at 10 and 60 min, respectively. Low uptake in normal tissues in conjunction with high tumor uptake resulted in high tumor-to-tissue ratios. On small-animal PET images, the tumor was clearly delineated soon after 4-11C-MBZA injection and tumor uptake reached 4.2 percentage injected dose per gram by 20 min. These preclinical evaluations show a high propensity of 4-11C-MBZA toward melanoma tumor. Conclusion: We successfully developed 4-11C-MBZA as a PET imaging probe, displaying properties advantageous over those for its 18F analogs. These preclinical evaluation results demonstrate the clinical potential of this probe to selectively target melanoma.

Biodistribution and Radiation Dosimetry of 11C-Nicotine from Whole-Body PET Imaging in Humans.

This study assessed the in vivo distribution of 11C-nicotine and the absorbed radiation dose from whole-body 11C-nicotine PET imaging of 11 healthy (5 male and 6 female) subjects. Methods: After an initial CT attenuation scan, 11C-nicotine was administered via intravenous injection. A dynamic PET scan was acquired for 90 s with the brain in the field of view, followed by a series of 13 whole-body PET scans acquired over a 90-min period. Regions of interest were drawn over organs visible in the reconstructed PET images. Time-activity curves were generated, and the residence times were calculated. The absorbed radiation dose for the whole body was calculated by entering the residence time in OLINDA/EXM 1.0 software to model the equivalent organ dose and the effective dose for a 70-kg man. Results: The mean residence times for 11C-nicotine in the liver, red marrow, brain, and lungs were 0.048 ± 0.010, 0.031 ± 0.005, 0.021 ± 0.004, and 0.020 ± 0.005 h, respectively. The mean effective dose for 11C-nicotine was 5.44 ± 0.67 µSv/MBq. The organs receiving the highest absorbed dose from the 11C-nicotine injection were the urinary bladder wall (14.68 ± 8.70 µSv/MBq), kidneys (9.56 ± 2.46 µSv/MBq), liver (8.94 ± 1.67 µSv/MBq), and spleen (9.49 ± 3.89 µSv/MBq). The renal and hepatobiliary systems were the major clearance and excretion routes for radioactivity. Conclusion: The estimated radiation dose from 11C-nicotine administration is relatively modest and would allow for multiple PET examinations on the same subject.

Sex-specific effects of cigarette mentholation on brain nicotine accumulation and smoking behavior.

Menthol cigarettes are likely associated with greater risks of smoking dependence than non-menthol cigarettes. We sought to test the hypothesis that menthol increases the rate of brain nicotine accumulation (BNA) during smoking and thereby enhances its addictive effects. In a counter-balanced cross-over design, 10 menthol and 9 non-menthol smokers (10 females and 9 males; mean age 44.3) underwent two study phases. In each phase, the participant smoked exclusively either menthol or non-menthol research cigarettes for approximately 1 week prior to a positron emission tomography (PET) scan session, during which the subject's head was scanned following inhalation of a single puff of smoke from a cigarette containing (11)C-nicotine. No differences in initial slope, Cmax, area under curve (AUC), and T1/2 of BNA were found between menthol and non-menthol cigarettes across all subjects; however, menthol relative to non-menthol cigarettes were associated with steeper initial slopes in men (p=0.008). Unexpectedly, women had faster BNA as indicated by greater values of the initial slope, Cmax, AUC, and shorter T1/2 than men (all ps<0.04). The rates of BNA were significantly correlated with ratings of smoking motivations of getting a 'rush', getting relaxing effects and marginally with alleviation of craving. These results do not provide strong support for the putative role of menthol in enhancing BNA, although further studies should explore the apparent effect of menthol on BNA in men. Fast BNA during smoking and preference of sensory properties of menthol cigarettes may independently or jointly contribute to smoking dependence among women.

Further characterization of quinpirole-elicited yawning as a model of dopamine D3 receptor activation in male and female monkeys.

The dopamine (DA) D3 receptor (D3R) has been associated with impulsivity, pathologic gambling, and drug addiction, making it a potential target for pharmacotherapy development. Positron emission tomography studies using the D3R-preferring radioligand [(11)C]PHNO ([(11)C](+)-propyl-hexahydro-naphtho-oxazin) have shown higher binding potentials in drug abusers compared with control subjects. Preclinical studies have examined D3R receptor activation using the DA agonist quinpirole and the unconditioned behavior of yawning. However, the relationship between quinpirole-elicited yawning and D3R receptor availability has not been determined. In Experiment 1, eight drug-naive male rhesus monkeys were scanned with [(11)C]PHNO, and the ability of quinpirole (0.01-0.3 mg/kg i.m.) to elicit yawning was examined. Significant positive (globus pallidus) and negative (caudate nucleus, putamen, ventral pallidum, and hippocampus) relationships between D3R receptor availability and quinpirole-induced yawns were noted. Experiment 2 replicated earlier findings that a history of cocaine self-administration (n = 11) did not affect quinpirole-induced yawning and extended this to examine monkeys (n = 3) with a history of methamphetamine (MA) self-administration and found that monkeys with experience self-administering MA showed greater potency and significantly higher quinpirole-elicited yawning compared with controls. Finally, quinpirole-elicited yawning was studied in drug-naive female monkeys (n = 6) and compared with drug-naive male monkeys (n = 8). Sex differences were noted, with quinpirole being more potent and eliciting significantly more yawns in males compared with females. Taken together these findings support the use of quinpirole-elicited yawning as a behavioral tool for examining D3R activation in monkeys and that both drug history and sex may influence individual sensitivity to the behavioral effects of D3R compounds.

Effects of repeated treatment with the dopamine D2/D3 receptor partial agonist aripiprazole on striatal D2/D3 receptor availability in monkeys.

RATIONALE: Chronic treatment with dopamine (DA) receptor agonists and antagonists can differentially affect measures of DA D2/D3 receptor number and function, but the effects of chronic treatment with a partial D2/D3 receptor agonist are not clear. OBJECTIVE: We used a within-subjects design in male cynomolgus monkeys to determine the effects of repeated (17-day) treatment with the D2/D3 receptor partial agonist aripiprazole (ARI; 0.03 mg/kg and 0.1 mg/kg i.m.) on food-reinforced behavior (n = 5) and on D2/D3 receptor availability as measured with positron emission tomography (PET; n = 9). METHODS: Five monkeys responded under a fixed-ratio 50 schedule of food reinforcement and D2/D3 receptor availability was measured before and 4 days after ARI treatment using PET and the D2/D3 receptor-selective radioligand [18F]fluoroclebopride (FCP). Four additional monkeys were studied using [11C]raclopride and treated sequentially with each dose of ARI for 17 days. RESULTS: ARI decreased food-maintained responding with minimal evidence of tolerance. Repeated ARI administration increased FCP and raclopride distribution volume ratios (DVRs) in the caudate nucleus and putamen in most monkeys, but decreases were observed in monkeys with the highest baseline DVRs. CONCLUSIONS: The results indicate that repeated treatment with a low-efficacy DA receptor partial agonist produces effects on brain D2/D3 receptor availability that are qualitatively different from those of both high-efficacy receptor agonists and antagonists, and suggest that the observed individual differences in response to ARI treatment may reflect its partial agonist activity.

Effects of nicotinic acetylcholine receptor agonists on cognition in rhesus monkeys with a chronic cocaine self-administration history.

Cocaine use is associated with impaired cognitive function, which may negatively impact treatment outcomes. One pharmacological strategy to improve cognition involves nicotinic acetylcholine receptor (nAChR) stimulation. However, the effects of chronic cocaine exposure on nAChR distribution and function have not been characterized. Thus, one goal of this study was to examine nAChR availability in rhesus monkeys with an extensive cocaine self-administration history (n = 4; ~6 years, mean intake, 1463 mg/kg) compared to age-matched cocaine-naive control monkeys (n = 5). Using [¹¹C]-nicotine and positron emission tomography (PET) imaging, cocaine-experienced monkeys showed significantly higher receptor availability in the hippocampus compared to cocaine-naive monkeys. A second goal was to examine the effects of nAChR agonists on multiple domains of cognitive performance in these same monkeys. For these studies, working memory was assessed using a delayed match-to-sample (DMS) task, associative learning and behavioral flexibility using stimulus discrimination and reversal learning tasks. When administered acutely, the nonselective high-efficacy agonist nicotine, the low-efficacy α4ß2* subtype-selective agonist varenicline and the high-efficacy α7 subtype-selective agonist, PNU-282987 significantly improved DMS performance in both cocaine-naive and cocaine-experienced monkeys. Individual doses of nicotine and varenicline that engendered maximum cognitive enhancing effects on working memory did not affect discrimination or reversal learning, while PNU-282987 disrupted reversal learning in the cocaine-naive monkeys. These findings indicate that a cocaine self-administration history influenced nAChR distribution and the effects of nAChR agonists on cognitive performance, including a reduced sensitivity to the disrupting effects on reversal learning. The cognitive enhancing effects of nAChR agonists may be beneficial in combination with behavioral treatments for cocaine addiction. This article is part of a Special Issue entitled 'Cognitive Enhancers'.

Social dominance in female monkeys: dopamine receptor function and cocaine reinforcement.

BACKGROUND: Brain imaging and behavioral studies suggest an inverse relationship between dopamine (DA) D2/D3 receptors and vulnerability to cocaine abuse, although most research has used males. For example, male monkeys that become dominant in a social group have significant elevations in D2/D3 receptor availability and are less vulnerable to cocaine reinforcement. METHODS: DA D2/D3 receptor availability was assessed in female cynomolgus monkeys (n = 16) with positron emission tomography (PET) while they were individually housed, 3 months after stable social hierarchies had formed, and again when individually housed. In addition, PET was used to examine changes in dopamine transporter (DAT) availability after social hierarchy formation. After imaging studies were complete, monkeys received implantation with indwelling intravenous catheters and self-administered cocaine (.001-.1 mg/kg/injection) under a fixed-ratio 30 schedule of reinforcement. Acquisition of cocaine reinforcement occurred when response rates were significantly higher than when saline was self-administered. RESULTS: Neither DAT nor D2/D3 receptor availability in the caudate nucleus and putamen was predictive of social rank, but both significantly changed after formation of social hierarchies. DA D2/D3 receptor availability significantly increased in females that became dominant, whereas DAT availability decreased in subordinate females. Dominant female monkeys acquired cocaine reinforcement at significantly lower doses than subordinate monkeys. CONCLUSIONS: The relationship between D2/D3 receptor availability and vulnerability to cocaine reinforcement seems, on the basis of these findings, opposite in females and males. These data indicate that the social environment profoundly affects the DA system but does so in ways that have different functional consequences for females than for males.

Recent trends in antibody-based oncologic imaging.

Antibodies, with their unmatched ability for selective binding to any target, are considered as potentially the most specific probes for imaging. Their clinical utility, however, has been limited chiefly due to their slow clearance from the circulation, longer retention in non-targeted tissues and the extensive optimization required for each antibody-tracer. The development of newer contrast agents, combined with improved conjugation strategies and novel engineered forms of antibodies (diabodies, minibodies, single chain variable fragments, and nanobodies), have triggered a new wave of antibody-based imaging approaches. Apart from their conventional use with nuclear imaging probes, antibodies and their modified forms are increasingly being employed with non-radioisotopic contrast agents (MRI and ultrasound) as well as newer imaging modalities, such as quantum dots, near infra red (NIR) probes, nanoshells and surface enhanced Raman spectroscopy (SERS). The review article discusses new developments in the usage of antibodies and their modified forms in conjunction with probes of various imaging modalities such as nuclear imaging, optical imaging, ultrasound, MRI, SERS and nanoshells in preclinical and clinical studies on the diagnosis, prognosis and therapeutic responses of cancer.

Kinetics of brain nicotine accumulation in dependent and nondependent smokers assessed with PET and cigarettes containing 11C-nicotine.

Tobacco smoking is a chronic, relapsing disorder that constitutes one of the primary preventable causes of death in developed countries. Two of the popular hypotheses to explain the development and maintenance of strong nicotine dependence in cigarette smokers posit (i) a rapid brain nicotine accumulation during cigarette smoking and/or (ii) puff-associated spikes in brain nicotine concentration. To address these hypotheses, we investigated the dynamics of nicotine accumulation in the smoker's brain during actual cigarette smoking using PET with 3-s temporal resolution and (11)C-nicotine loaded into cigarettes. The results of the study, performed in 13 dependent smokers (DS) and 10 nondependent smokers (NDS), suggest that puff-associated spikes in the brain nicotine concentration do not occur during habitual cigarette smoking. Despite the presence of a puff-associated oscillation in the rate of nicotine accumulation, brain nicotine concentration gradually increases during cigarette smoking. The results further suggest that DS have a slower process of brain nicotine accumulation than NDS because they have slower nicotine washout from the lungs and that DS have a tendency to compensate for their slower rate of brain nicotine accumulation compared with NDS by inhaling a larger volume of smoke. For these reasons, smokers' dependence on cigarette smoking, or the resistance of NDS to becoming dependent, cannot be explained solely by a faster brain nicotine accumulation.

Design, synthesis, and preliminary in vitro and in vivo evaluation of N-(2-diethylaminoethyl)-4-[18F]fluorobenzamide ([18F]-DAFBA): a novel potential PET probe to image melanoma tumors.

In order to develop a PET radiopharmaceutical to image malignant melanoma, we synthesized N-(2-diethylaminoethyl)-4-[(18)F]fluorobenzamide ([(18)F]-DAFBA). In vitro studies show a high uptake of [(18)F]-DAFBA by the B16F1 melanoma cells. No significant binding was seen for DAFBA to the sigma-1 and sigma-2 receptors in vitro. The in vivo biodistribution studies performed in normal ICR mice showed a low uptake in the normal tissues followed by further elimination of radioactivity from these tissues with time. The biodistribution studies performed in C57 mice bearing the melanoma tumor xenograft showed a rapid uptake of radioactivity in the tumor that reached a plateau within 30 min postinjection. The F-18 uptake in the tumor was 7.00 +/- 2.76, 6.57 +/- 1.66, and 5.80 +/- 0.98%ID/g at 60, 120, and 180 min, respectively. A steady uptake of radioactivity in the tumor and low uptake in normal tissues resulted in high tumor to normal tissue ratios. For example, at 180 min postinjection, the tumor to tissue ratios were 14.90 +/- 6.47, 21.90 +/- 4.68, 32.91 +/- 6.11, 39.73 +/- 11.78, and 6.33 +/- 1.9, for the spleen, lungs, muscle, blood, and liver, respectively. The radioactivity rapidly cleared from the blood pool, and it decreased from 0.68 +/- 0.21%ID/g at 60 min to 0.13 +/- 0.03%ID/g at 180 min. The F-18 uptake in the bones at 60, 120, and 180 min was 0.91 +/- 0.27, 0.57 +/- 0.32, and 0.17 +/- 0.05%ID/g, respectively. This low uptake in the bones reflects its in vivo resistance toward defluorination. A low residual activity in normal tissues and a high tumor uptake signifies the superior imaging potential of this compound. Because of these positive traits, [(18)F]-DAFBA could help delineate the tumor and its metastases when used for imaging applications. Further in vivo studies are underway to assess the potential of [(18)F]-DAFBA as a promising PET imaging probe.

Effect of menstrual cycle phase on dopamine D2 receptor availability in female cynomolgus monkeys.

Sex differences have been reported in a variety of affective and neurodegenerative disorders that involve dysfunctional dopamine (DA) neurotransmission. In addition, there is evidence for differences in sensitivity to the abuse-related effects of psychostimulants across the menstrual cycle which may result from effects of ovarian hormones on DA function. The goal of the present study was to extend previous work examining menstrual cycle-related changes in DA D2 receptor availability in humans to drug-naive female cynomolgus monkeys (n=7) using the selective D2-like receptor ligand [(18)F]fluoroclebopride (FCP) and a high-resolution microPET P4 scanner. Menstrual cycle phase was characterized by daily vaginal swabs and measurements of serum progesterone levels. PET studies were conducted once during the luteal phase and once during the follicular phase. Regions of interest in the caudate nucleus, putamen, and cerebellum were defined on coregistered MRIs. Distribution volumes were calculated for FCP in each structure and the distribution volume ratio (DVR) for both brain regions relative to the cerebellum was used as a measure of D2 receptor availability. FCP DVRs were significantly higher in the luteal phase compared to the follicular phase in both the caudate nucleus (11.7% difference, p=0.02) and putamen (11.6% difference, p=0.03). These findings extend earlier work in humans and suggest that changes in DA receptor availability may be involved in the variation in symptoms of various neuropsychiatric disorders across the menstrual cycle, including differences in sensitivity to the abuse-related effects of stimulants.

A remote controlled system for the preparation of 7 alpha-[18F]fluoro-17 alpha-methyl 5 alpha-dihydrotestosterone ([18F]FMDHT) using microwave.

For non-invasive imaging of the prostate cancer, we synthesized 7 alpha-fluoro-17 alpha-methyl 5 alpha-dihydrotestosterone ([(18)F]FMDHT) for androgen receptor mediated PET imaging. Preliminary in vitro and in vivo evaluations of this compound show promise. We designed and implemented a remote controlled system for reliable, efficient, and safe handling of radioactivity during the radiochemical synthesis of [(18)F]FMDHT. The key features of this report are the microwave assisted radiochemical synthesis, increased radiochemical yields, improved radiochemical purity, reduced overall synthesis time, and remote controlled automation of the entire synthesis. The overall synthesis using microwave reaction took 60-70 min and provided the desired product in 20-30% radiochemical yields with >99% radiochemical purity.