Value of monocyte distribution width for predicting severe cholecystitis: a retrospective cohort study.

OBJECTIVES: Acute cholecystitis is a gallbladder inflammation, and the Tokyo Guidelines 2018 (TG18) can be used to predict its presence and severity with high sensitivity and specificity. However, TG18 grading require the collection of excessive parameters. Monocyte distribution width (MDW) is a parameter used to detect sepsis early. Therefore, we investigated the correlation between MDW and cholecystitis severity. METHODS: We conducted a retrospective study of patients with cholecystitis admitted to our hospital from November 1, 2020, to August 31, 2021. The primary outcome was severe cholecystitis analyzed as a composite of intensive care unit (ICU) admission and mortality. The secondary outcomes were length of hospital stay, ICU stay, and TG18 grade. RESULTS: A total of 331 patients with cholecystitis were enrolled in this study. The average MDWs for TG18 grades 1, 2, and 3 were 20.21 ± 3.99, 20.34 ± 3.68, and 25.77 ± 6.61, respectively. For patients with severe cholecystitis, the average MDW was 25.42 ± 6.83. Using the Youden J statistic, we set a cutoff MDW of 21.6. Multivariate logistic regression revealed that patients with an MDW≥21.6 had a higher risk of severe cholecystitis (odds ratio=4.94; 95 % CI, 1.71-14.21; p=0.003). The Cox model revealed that patients with an MDW≥21.6 were more likely to have a prolonged hospital stay. CONCLUSIONS: MDW is a reliable indicator of severe cholecystitis and prolonged length of stay. Additional MDW testing and a complete blood count may provide simple information for predicting severe cholecystitis early.

Percutaneous radiofrequency trigeminal rhizotomy benefits in patients with refractory trigeminal neuralgia.

ABSTRACT: A significant number of patients suffers from refractory trigeminal neuralgia (TN) after receiving microvascular decompression (MVD) or other neuro-destructive procedure such as gamma knife radiosurgery (GKRS). This study aims to demonstrate a remediable, reproducible approach to treating refractory pain effectively by percutaneous radiofrequency trigeminal rhizotomy (RF-TR).A total of 392 patients with TN were treated by RF-TR during the past 10 years. Among these patients, 48 cases who had received either MVD, GKRS alone, or a combination of both were assigned to group A. Those who had not received any form of treatment (125 patients) or failed to respond medically (130 patients) were assigned as the control group (group B). All the RF-TR were performed by a single surgeon with the aid of intraoperative computed tomography (iCT)-based neuronavigation with magnetic resonance (MR) image fusion. The outcome measure was the numerical rating scale (NRS) expressed subjectively by patients. The paired Student t test and the analysis of covariance (ANCOVA) were used for statistical analysis.In group A, 21 of 24 patients (88%) had significant improvement (NRS change ≥5) in facial pain after RF-TR. The average NRS score was 9.75 ±â€Š0.53 before the procedure and 1.92 ±â€Š3.35 post-treatment (significant NRS decrease [P = .000]). On the other hand, in group B, 226 of 255 patients (89%) also had dramatic amelioration of facial pain after RF-TR. The average NRS score was 9.46 ±â€Š0.69 before the procedure and 1.62 ±â€Š2.85 post-treatment (7.84 ±â€Š2.82 in NRS decrease [P = .008]). By using a univariate ANCOVA, no statistical significance was found in NRS score improvement between the two groups.Repeated MVD and GKRS for refractory TN may be less desirable due to a greater risk of mortality (up to 0.8%) and morbidity (4% of serious complications). Conversely, RF-TR administration with the novel navigation technique by using iCT and MR image fusion is free from any remarkable and irreversible morbidities. In this study, RF-TR not only provided an alternative and effective strategy if TN recurred but also resulted in the same NRS score improvement regardless of the status of prior treatment.

The impact of needle location on clinical outcome of radiofrequency rhizotomy for trigeminal neuralgia.

BACKGROUND: Radiofrequency thermocoagulation trigeminal rhizotomy (RT-TR) through the foramen ovale is a minimally invasive treatment for trigeminal neuralgia. Navigation of magnetic resonance imaging (MRI) and CT fusion imaging is a well-established method for cannulation of the Gasserian ganglion. In this study, we use the inline measurements from fusion image to analyze the anatomical parameters between the actual and simulation trajectories and compare the short- and intermediate-term outcomes according to determinable factors. METHODS: The study included thirty-six idiopathic neuralgia patients who had undergone RT-TR with MRI and CT fusion image as a primary modality or repeated procedures. RESULTS: Among thirty-six treated patients, the inline length of the trigeminal cistern was longer for the simulated trajectory (8.4 ± 2.4 versus 6.5 ± 2.8 mm; p < 0.05), and the predominant structure at risk extrapolated from the inline trajectory was the brainstem, which signified a more medially directed route, in contrast with the equal weighting of temporal lobe and brainstem for the actual trajectory. The preoperative visual analogue scale (VAS) was 9.3 ± 1.0, which decreased to 2.5 ± 2.6 and 2.9 ± 3.1 at first (mean, 3 months) and second (mean, 14 months) postoperative follow-up, respectively. The postoperative VAS scores at the two follow-ups were not statistically significant without a covariate analysis. After adjustment for covariate risk factors, the second follow-up sustained therapeutic benefit was evident in patients with no prior history of related treatment, an ablation temperature greater than 70 °C, and needle location within or adjacent to the trigeminal cistern. CONCLUSIONS: This preliminary study demonstrated that the needle location between cistern and ganglion also plays a significant role in better intermediate-term results.

Percutaneous Radiofrequency Rhizotomy Is Equally Effective for Trigeminal Neuralgia Patients with or Without Neurovascular Compression.

BACKGROUND: Neurovascular compression (NVC) in patients with trigeminal neuralgia (TN) can be a factor of treatment outcome, especially in microvascular decompression and stereotactic radiosurgery. No such effect has been reported in percutaneous radiofrequency rhizotomy (RF). This study aims to investigate whether NVC affects the efficacy of RF in patients with TN. METHODS: We retrospectively reviewed patients with TN who received RF in our institution. Pretreatment magnetic resonance imaging was performed in every patient, and the presence of NVC was reviewed independently by two physicians. The patients were followed up at least for a year after the treatment. Pain severity was assessed with a numeric rating scale (NRS). RESULTS: Sixty-two patients were included in the study. All of the patients had single-sided lesions, and 35 patients had NVC. There were no significant differences between these two groups of patients in terms of gender distribution, age, and pretreatment pain severity. Comparable pain severity improvement was found at 1-year follow-up between these two groups (NRS 7.93 ± 0.492 without compression vs 7.57 ± 0.451 with compression, P = 0.600). No significant difference in posttreatment pain severity at 1 year was found between these two patient groups (NRS 1.37 ± 0.466 without compression vs 1.66 ± 0.458 with compression, P = 0.667). CONCLUSIONS: For patients with TN treated by RF, the presence or absence of NVC is not likely to affect the 1-year pain control rate.

Using [¹8F]FBAU for imaging brain tumor progression in an F98/tk-luc glioma-bearing rat model.

1-(2-Deoxy-2-[18F]fluoro-ß-D-arabinofuranosyl)-5-bromouracil ([18F]FBAU), a substitute for thymine, has been reported as an effective reporter probe by which to trace cellular metabolism with its positron emission. In the present study, a rat xenograft model bearing F98 glioma transfected with dual reporter genes, herpes simplex virus type 1 thymidine kinase (HSV1-tk) and firefly luciferase (luc) was used for monitoring tumor progression by multimodalities of molecular imaging using [18F]FBAU and D-luciferase as probes. Rat F98 glioma cells were transfected with the pC1-tk-IRES-luc vectors. The selected stable clone was renamed as the F98/tk-luc cell line. Fischer 344 male rats bearing orthotropic F98/tk-luc gliomas in the left brain were used. On day 13 post tumor inoculation, biodistribution, positron emission tomography (PET), magnetic resonance imaging (MRI) and ex vivo autoradiography were performed. The surviving fraction of F98/tk-luc cells treated with 15 µM ganciclovir (GCV) was 15.9%, and the uptake of [131I]FIAU in these cells was significantly enhanced when compared with F98 cells. The correlation coefficient of tumor volume vs. the bioluminescence in the F98/tk-luc glioma-bearing rats was 0.90. The biodistribution showed that the accumulation ratios of [18F]FBAU for glioma-to-normal brain were 9.16, 14.24, 5.7 and 13.7 at 30, 60, 90 and 120 min post i.v. injection, respectively. Consistent tumor enhancement of [18F]FBAU/PET imaging was also noted from 30-90 min post injection. Ex vivo autoradiography also confirmed significant [18F]FBAU uptake in tumors. In conclusion, [18F]FBAU may be used as a PET probe for monitoring glioma progression in animal models and may have potential for clinical use as well.

Curcumin synergistically enhances the radiosensitivity of human oral squamous cell carcinoma via suppression of radiation-induced NF-κB activity.

The anticancer effect of curcumin has been widely reported. However, whether curcumin can enhance the radiosensitivity of human oral squamous cell carcinoma (OSCC) remains to be elucidated. The aim of the present study was to evaluate the efficacy of curcumin combined with radiation against OSCC. SAS cells were transfected with the luciferase gene (luc) and named SAS/luc. NF-κB/DNA binding activity, the surviving fraction and NF-κB-regulated effector protein expression were determined by electrophoretic mobility shift assay, clonogenic survival assay and western blotting, respectively. The therapeutic efficacy was evaluated in SAS/luc tumor-bearing mice by caliper measurement and bioluminescence imaging. Curcumin enhanced SAS/luc radiosensitivity through the inhibition of radiation-induced NF-κB activity and expression of effector proteins both in vitro and in vivo. With 4 Gy or greater radiation doses, synergistic effects of curcumin were observed. The combination group (curcumin plus radiation) had significantly better tumor control compared with that of curcumin or radiation alone. No significant body weight change of mice was found throughout the entire study. In conclusion, curcumin is a radiosensitizer against OSCC with negligible toxicity.

A simple algorithm for subregional striatal uptake analysis with partial volume correction in dopaminergic PET imaging.

OBJECTIVE: In positron emission tomography (PET) of the dopaminergic system, quantitative measurements of nigrostriatal dopamine function are useful for differential diagnosis. A subregional analysis of striatal uptake enables the diagnostic performance to be more powerful. However, the partial volume effect (PVE) induces an underestimation of the true radioactivity concentration in small structures. This work proposes a simple algorithm for subregional analysis of striatal uptake with partial volume correction (PVC) in dopaminergic PET imaging. METHODS: The PVC algorithm analyzes the separate striatal subregions and takes into account the PVE based on the recovery coefficient (RC). The RC is defined as the ratio of the PVE-uncorrected to PVE-corrected radioactivity concentration, and is derived from a combination of the traditional volume of interest (VOI) analysis and the large VOI technique. The clinical studies, comprising 11 patients with Parkinson's disease (PD) and 6 healthy subjects, were used to assess the impact of PVC on the quantitative measurements. Simulations on a numerical phantom that mimicked realistic healthy and neurodegenerative situations were used to evaluate the performance of the proposed PVC algorithm. In both the clinical and the simulation studies, the striatal-to-occipital ratio (SOR) values for the entire striatum and its subregions were calculated with and without PVC. RESULTS: In the clinical studies, the SOR values in each structure (caudate, anterior putamen, posterior putamen, putamen, and striatum) were significantly higher by using PVC in contrast to those without. Among the PD patients, the SOR values in each structure and quantitative disease severity ratings were shown to be significantly related only when PVC was used. For the simulation studies, the average absolute percentage error of the SOR estimates before and after PVC were 22.74% and 1.54% in the healthy situation, respectively; those in the neurodegenerative situation were 20.69% and 2.51%, respectively. CONCLUSIONS: We successfully implemented a simple algorithm for subregional analysis of striatal uptake with PVC in dopaminergic PET imaging. The PVC algorithm provides an accurate measure of the SOR in the entire striatum and its subregions, and improves the correlation between the SOR values and the clinical disease severity of PD patients.

Imaging, autoradiography, and biodistribution of (188)Re-labeled PEGylated nanoliposome in orthotopic glioma bearing rat model.

The (188)Re-labeled pegylated nanoliposome (abbreviated as (188)Re-Liposome) was prepared and evaluated for its potential as a theragnostic agent for glioma. (188)Re-BMEDA complex was loaded into the pegylated liposome core with pH 5.5 ammonium sulfate gradient to produce (188)Re-Liposome. Orthotopic Fischer344/F98 glioma tumor-bearing rats were prepared and intravenously injected with (188)Re-Liposome. Biodistribution, pharmacokinetic study, autoradiography (ARG), histopathology, and nano-SPECT/CT imaging were conducted for the animal model. The result showed that (188)Re-Liposome accumulated in the brain tumor of the animal model from 0.28%±0.09% injected dose (ID)/g (n=3) at 1 hour to a maximum of 1.95%±0.35% ID/g (n=3) at 24 hours postinjection. The tumor-to-normal brain uptake ratio (T/N ratio) increased from 3.5 at 1 hour to 32.5 at 24 hours. Both ARG and histopathological images clearly showed corresponding tumor regions with high T/N ratios. Nano-SPECT/CT detected a very clear tumor image from 4 hours till 48 hours. This study reveals the potential of (188)Re-Liposome as a theragnostic agent for brain glioma.

Automated striatal uptake analysis of ¹8F-FDOPA PET images applied to Parkinson's disease patients.

OBJECTIVE: 6-[(18)F]Fluoro-L: -DOPA (FDOPA) is a radiopharmaceutical valuable for assessing the presynaptic dopaminergic function when used with positron emission tomography (PET). More specifically, the striatal-to-occipital ratio (SOR) of FDOPA uptake images has been extensively used as a quantitative parameter in these PET studies. Our aim was to develop an easy, automated method capable of performing objective analysis of SOR in FDOPA PET images of Parkinson's disease (PD) patients. METHODS: Brain images from FDOPA PET studies of 21 patients with PD and 6 healthy subjects were included in our automated striatal analyses. Images of each individual were spatially normalized into an FDOPA template. Subsequently, the image slice with the highest level of basal ganglia activity was chosen among the series of normalized images. Also, the immediate preceding and following slices of the chosen image were then selected. Finally, the summation of these three images was used to quantify and calculate the SOR values. The results obtained by automated analysis were compared with manual analysis by a trained and experienced image processing technologist. RESULTS: The SOR values obtained from the automated analysis had a good agreement and high correlation with manual analysis. The differences in caudate, putamen, and striatum were -0.023, -0.029, and -0.025, respectively; correlation coefficients 0.961, 0.957, and 0.972, respectively. CONCLUSIONS: We have successfully developed a method for automated striatal uptake analysis of FDOPA PET images. There was no significant difference between the SOR values obtained from this method and using manual analysis. Yet it is an unbiased time-saving and cost-effective program and easy to implement on a personal computer.

GMP production of [18F]FDOPA and issues concerning its quality analyses as in USP "Fluorodopa F 18 Injection".

INTRODUCTION: Lately, 6-[(18)F]fluoro-L: -DOPA (FDOPA) has found increase in its clinical demand for whole-body positron emission tomography (PET) scans, and two key issues in fulfilling this demand are the difficulties in producing FDOPA under the recently imposed PET drug good manufacturing practice (GMP) regulations and in providing it in the quality meeting the terms of major compendia. This paper describes the approaches for the GMP production of FDOPA and for the product testing to meet the standard of United States Pharmacopeia (USP) "Fluorodopa F 18 Injection." METHODS: FDOPA was produced by the carrier-added electrophilic aromatic substitution reaction in the facility complying Pharmaceutical Inspection Cooperation Scheme clean room standard. The special aseptic handling technique was applied to minimize the bioburden. The product quality control followed all testing items and procedures, including three different settings of HPLC. RESULTS: The process yielded FDOPA average 2.60 ± 0.26 GBq (N = 22) in every batch. All qualities of the product were within the specifications described in the USP "Fluorodopa F 18 Injection." The entire production was audited by the government authority and certified to comply with the latest PET drug GMP regulation. CONCLUSION: Our efforts in producing FDOPA following all aspects of GMP requirements have resulted in a product with the USP quality and certified as GMP complied. The routine production yields enough doses for three to four whole-body scans in each batch. The issues discussed in the report provide good reference for producers planning in routine production for PET drugs that are not commonly produced or with complicated compendial quality control tests.

An efficient and aseptic preparation of "sodium fluoride ((18)F) injection" in a GMP compliant facility.

INTRODUCTION: "Sodium fluoride ((18)F) injection" is an isotonic NaCl solution containing [(18)F]NaF to be used as bone imaging agent. Although its NDA was approved by the US FDA in 1972, it has not been commercially available since 1975 due to mostly the popularity of (99m)Tc-MDP. Recently, advances in PET/CT technology and the often interrupted (99m)Tc supply have led to the renewed interest in the use of [(18)F]NaF to detect bone metastases in cancer patients. This report introduces an efficient, low-cost and aseptic preparation of "Sodium fluoride ((18)F) injection" for PET scan. METHOD: (18)F-Fluoride in target water from cyclotron was adsorbed onto four different forms of anion-exchange resins then desorbed by isotonic NaCl solution into the product vial. One of the resins that yielded the product at the suitable pH was used for the aseptic preparation. The components for this setup, including stopcocks, extension tubes, etc., were all single-use, individually packed and sterile. The process was done in a lead-line isolator maintained in grade A (PIC/S) aseptic condition. The quality of the obtained "Sodium fluoride ((18)F) injection" was analyzed according to its monograph in the European Pharmacopoeia (EP). RESULTS: The resin in the chloride form yielded the product of pH 6.7 and was chosen for the subsequent preparation. The radiochemical yield was quantitative. The product met all criteria specified in EP, including biological, physical and chemical specifications. CONCLUSIONS: This method is an efficient, space-saving and extremely low-cost operation that easily performed in an aseptic environment meeting GMP standard. The quality of the "Sodium fluoride ((18)F) injection" so yielded meets EP specifications. This setup provides hospital with facility meeting GMP standard a cost effective and efficient method for "Sodium fluoride ((18)F) injection" production without the need for the expensive automatic module and extra QC instrument.

[18F]FBAU 3',5'-dibenzoate, a lipophilic prodrug, enhances brain uptake of the cell proliferation tracer [18F]FBAU.

INTRODUCTION: 1-(2-deoxy-2-[(18)F]fluoro-beta-D-arabinofuranosyl)-5-bromouracil ([(18)F]FBAU) is a cell proliferation tracer. However, it does not pass readily through the blood-brain barrier. We synthesized a lipophilic prodrug of [(18)F]FBAU that was intended to enhance brain uptake of [(18)F]FBAU to improve the imaging of brain cell proliferation. METHODS: [(18)F]FBAU was synthesized according to the methods described by Alauddin [J Med Chem 39 (1996) 2835-2843]. The prodrug, 1-(2-deoxy-3,5-O-dibenzoyl-2-[(18)F]fluoro-beta-D-arabinofuranosyl)-5-bromouracil ([(18)F]FBAU 3',5'-dibenzoate), was purified from an intermediate of [(18)F]FBAU. Their lipophilicity was determined by performing octanol/water partition coefficient (log P) measurements. In vitro metabolic fates of the prodrug were examined in rat and mouse plasma and brain homogenates. Brain uptake was determined following iv injection of the radiotracers by killing animals at various time points and dissecting and counting the radioactivity accumulation in the various tissues. RESULTS: Values of log P for [(18)F]FBAU 3',5'-dibenzoate and [(18)F]FBAU were 3.95 and -0.35, respectively. In rat plasma, the prodrug was gradually hydrolyzed to [(18)F]FBAU. Thirty minutes after mixing [(18)F]FBAU 3',5'-dibenzoate in the plasma, 25% of the prodrug had been hydrolyzed. The hydrolysis went more slowly in brain homogenates. At 15 min post injection, relative to animals injected with [(18)F]FBAU, brain uptake of radioactivity in animals injected with [(18)F]FBAU 3',5'-dibenzoate was increased by 150% (P=.005) and 78% (P=.037) in rats and mice, respectively. At 60 min post injection, the radioactive contents extracted from the brain were mostly [(18)F]FBAU. CONCLUSION: The synthesized novel prodrug [(18)F]FBAU 3',5'-dibenzoate has enhanced brain uptake in rodents, suggesting it may be useful as an imaging agent for tracing brain cell proliferation.

A crossed molecular beam study on the reaction of boron atoms with methylacetylene and partially deuterated methylacetylene.

The reactions of ground-state boron atoms, B((2)P(j)), with methylacetylene, CH3CCH(X(1)A(1)), and its [D3]-substituted isotopomer, CD3CCH(X(1)A(1)), are studied under single collision conditions using the crossed molecular beam technique at collision energies of 21.6 and 21.9 kJ mol(-1), respectively. Utilizing the CD3CCH reactant, detailed information on the dynamics is obtained. The reaction followed indirect scattering dynamics and proceeded through at least two reaction channels via atomic deuterium and hydrogen atom elimination pathways leading eventually to two isotopomers, that is, the C(2v) symmetric D2CCCBH(X(1)A(1)) and D2CCCBD(X(1)A(1)) structures via statistical and non-statistical reaction pathways, respectively.

Kimura's disease with generalized lymphadenopathy demonstrated by positron emission tomography scan.

Kimura's disease is a chronic inflammatory disorder that occurs mainly in Asian patients. Most imaging studies focus on the loco-regional involvement of this disorder. Images of the whole body fluorine-18 fluorodeoxyglucose positron emission tomography (18F-FDG PET) scan have not been reported in the literature before. The possibility of lymphoid clonality is also discussed frequently despite its clinically benign course. We present a patient of Kimura's disease initially assessed by whole body 18F-FDG PET study and proved by pathologic findings. 18F-FDG-PET scan showed diffusely intense uptake in the neck, axillary, pelvic and inguinal nodal regions bilaterally, as well as in the mediastinal, celiac region. The flow cytometric analysis of lymph node tissue confirmed the absence of clonality. The image of 18F-FDG-PET in Kimura's disease can closely resemble that seen in neoplastic disorders such as lymphoma or metastatic lymphadenopathy. It should be taken into consideration as a differential diagnosis for a generalized lymphadenopathy.

Autoradiographic visualization of corticotropin releasing hormone type 1 receptors with a nonpeptide ligand: synthesis of [(76)Br]MJL-1-109-2.

A high-affinity, nonpeptide radioligand for the CRHR1 was synthesized and showed distribution in rat brain consistent with CRHR1 using in vitro autoradiography. This is the first nonpeptide radiotracer combining high affinity and appropriate lipophilicity that penetrates the blood-brain barrier and hence has the potential to be used for PET imaging studies. In vivo visualization of changes in the CRH1 receptor or its occupancy would further the understanding of the pathophysiology of stress related diseases.

Fluoro-, bromo-, and iodopaclitaxel derivatives: synthesis and biological evaluation.

Paclitaxel (Taxol) is a clinically important chemotherapeutic agent. We describe the synthesis of fluoro-, bromo-, and iodopaclitaxel and their [(18)F]fluoro-, [(76)Br]bromo-, and [(124)I]iodo- analogues. [(18)F]Fluoropaclitaxel shows high uptake and rapid clearance from tissues in rats. Preadministration of paclitaxel in normal rats significantly increases (p < 0.005) retention of [(18)F]fluoropaclitaxel and [(76)Br]bromopaclitaxel in blood (33.0%), heart (32.0%), lung (37.6%) kidney (142.4%); and blood (33.4%), lung (42.3%), kidney (62.4%), respectively. [(18)F]Fluoropaclitaxel uptake in the brain of mdr1a/1b(-/-) mice is increased 1400% (p < 1.3e-07) relative to wild-type controls. Preadministration of paclitaxel or XR9576, a modulator, had little effect on the biodistribution in these mdr1a/1b(-/-) mice. As a result, [(18)F]fluoropaclitaxel will be a useful radiopharmaceutical for the study of multidrug resistant tumors.

Evaluation of [76Br]FBAU 3',5'-dibenzoate as a lipophilic prodrug for brain imaging.

[76Br]FBAU is a potential PET tracer for assessing proliferation. This study proposes that [76Br]FBAU 3',5'-dibenzoate has higher blood-brain-barrier permeability than [76Br]FBAU itself and thus might be better suited for applications in the brain. The brain uptake indexes of the two compounds measured after carotid injection (29.6 +/- 13.9 for [76Br]FBAU 3',5'-dibenzoate, versus 10.0 +/- 8.7 for [76Br]FBAU) support this claim. Biodistribution study also showed that the brain accumulation of activity was higher in rats injected with [76Br]FBAU 3',5'-dibenzoate than with [76Br]FBAU (0.119+/-0.023 DUR at 1 h, versus 0.061 +/- 0.006). [76Br]FBAU 3',5'-dibenzoate was relatively stable in rat plasma, gradually being hydrolyzed to [76Br]FBAU exponentially with a calculated half-life of 0.8 h. DNA incorporation of [76Br]FBAU was also confirmed. The results presented support the hypothesis that the 3',5'-dibenzoate can act as a prodrug for FBAU and deliver more radiolabeled nucleoside to the brain.

Improved renal clearance and tumor targeting of 99mTc-labeled anti-Tac monoclonal antibody Fab by chemical modifications.

This study was undertaken to improve the renal clearance and tumor targeting properties of 99mTc-labeled humanized anti-Tac (HuTac) monoclonal antibody Fab fragments using two chemical approaches: 1) labeling with a renal secretion agent 99mTc-mercaptoacetyltriglycine (MAG3) and 2) lowering its isoelectric point (pI) by acylation. HuTac Fab (3.3 mg/mL) was reacted with a trifluorophenyl ester (TFP) of 99mTc-MAG3 alone or was additionally reacted with TFP-glycolate to reduce the pI. In Balb/c mice, 99mTc-MAG3-Fab (pI > 9.3) rapidly accumulated in the kidneys (177% injected dose [ID]/g at 15 min) and then gradually cleared out of the kidneys. In contrast, the glycolation (pI 4.6 approximately 6.6) drastically reduced the renal uptake (31% ID/g) and also the whole-body retention (82% ID vs 101% for the nonglycolated) at 15 min, indicating that the glycolated 99mTc-MAG3-Fab (pI 4.6 approximately 6.6) was rapidly excreted. The glycolated remained in the blood longer than the nonglycolated (1.2% vs 0.3% ID/g at 360 min), but this effect was less drastic than the effect shown on the renal uptake. In nude mice bearing receptor-positive (ATAC4) tumors, the glycolated 99mTc-MAG3-Fab increased the peak tumor uptake to 14.8% ID/g from 8.3% ID/g for 99mTc-MAG3-Fab, whereas the glycolation resulted in a drastic reduction of the renal uptake at 15 min. We demonstrated that the renal clearance and the tumor targeting of Fab could be optimized by chemical modifications.