Takahiro Mukai

Clinical value of FDG-PET in the follow up of post-operative patients with endometrial cancer

Objective: The clinical usefulness of FDG-PET in the follow up of post-operative patients with endometrial cancer was retrospectively evaluated.Methods: Twenty-one post-operative patients with endometrial cancer received 30 FDG-PET examinations to evaluate recurrence or response to treatment. The findings of FDG-PET were compared with their serum levels of tumor markers, CT and/or MRI findings, and the final outcome. Results of FDG-PET were also correlated with the clinical course of each patient.Results: In detecting recurrent lesions and evaluating treatment responses, FDG-PET, with the help in anatomic information by CT/MRI, showed better diagnostic ability (sensitivity 100.0%, specificity 88.2%, accuracy 93.3%) compared with combined conventional imaging (sensitivity 84.6%, specificity 85.7%, accuracy 85.0%) and tumor markers (sensitivity 100.0%, specificity 70.6%, accuracy 83.3%). FDG-PET had no false-negative results, suggesting the possibility of its use as the first-line examination in a patient’s follow-up. FDG-PET could detect unknown lesions in 4 cases, and, as reported for other malignancies, FDG-PET affected the patient management in one-third of the cases. Furthermore, the results of FDG-PET correlated well with the clinical outcome of the patients, with patients with negative PET results tending to show disease-free courses.Conclusions: These results suggest that, despite the limited number of patients studied, FDG-PET was accurate in detecting recurrence and evaluating therapeutic response, and could afford important information in the management of post-operative patients with endometrial cancer. FDG-PET also appeared to have a possibility to predict the outcome of each patient.

Effect of molecular charges on renal uptake of 111In-DTPA-conjugated peptides

The effect of molecular charges on renal accumulation of 111In-DTPA-labeled low molecular weight (LMW) peptides was investigated using 111In-DTPA-octreotide derivatives as models to design radiolabeled peptides that are taken up less by renal cells. The N-terminal D-phenylalanine (Phe) of 111In-DTPA-D-Phe(1)-octreotide was replaced with L-aspartic acid (Asp), L-lysine (Lys), L-methionine (Met) or L-Phe. Cellulose acetate electrophoresis indicated that both 111In-DTPA-L-Phe(1)-octreotide and 111In-DTPA-L-Met(1)-octreotide showed similar net charges, whereas 111In-DTPA-L-alphaLys(1)-octreotide and 111In-DTPA-L-Asp(1)-octreotide had more positive and negative charges, respectively, at pH values similar to those in blood and glomerular filtrate. When injected into mice, significant differences were observed in the renal radioactivity levels. 111In-DTPA-L-alphaLys(1)-octreotide showed the highest radioactivity levels from 10 min to 6 h postinjection, whereas the lowest radioactivity levels were observed with 111In-DTPA-L-Asp(1)-octreotide at all the postinjection intervals. These findings indicated that the replacement of only one amino acid in 111In-DTPA-D-Phe(1)-octreotide significantly altered net molecular charges of the resulting peptides and that the net charges of the 111In-DTPA-octreotide derivatives significantly affected their renal uptake. Thus, an increase of negative charges in peptide molecules may constitute a strategy for designing 111In-DTPA-conjugated LMW peptides with low renal radioactivity levels.

Temporal Change in Human Nicotinic Acetylcholine Receptor After Smoking Cessation: 5IA SPECT Study

Nicotinic acetylcholine receptors (nAChRs) are of great interest because they are implicated in various brain functions. They also are thought to play an important role in nicotine addiction of smokers. Chronic (−)-nicotine, a nAChR agonist, treatment in mice and rats elicits a dose-dependent increase in nAChRs in the brain. Upregulation of nAChRs in postmortem human brains of smokers has also been reported. However, changes in nAChRs after cigarette smoking cessation in humans are poorly understood. The aim of this study was to detect the dynamic changes of nAChRs after smoking and smoking cessation in the brains of living subjects. Methods: We performed 5-123I-iodo-A-85380 (123I-5IA) SPECT on nonsmokers and smokers (n = 16) who had quit smoking for 4 h, 10 d, and 21 d and calculated and compared distribution volumes (Vt) of 123I-5IA. Results: The binding potential of nAChRs (Vt of 123I-5IA) in the brains of smokers decreased by 33.5% ± 10.5% after 4 h of smoking cessation, increased by 25.7% ± 9.2% after 10 d of smoking cessation, and decreased to the level of nonsmokers after 21 d of smoking cessation. Conclusion: Because the upregulation of the nAChRs of the smokers after chronic exposure of the nicotine was downregulated to the nonsmokers level by around 21 d after smoking cessation, the upregulation is a temporary effect. The decrease in nicotinic receptors to nonsmoker levels may be the breaking point during the nicotine withdrawal period.

18F-FDG and11C-methionine PET for evaluation of treatment response of lung cancer after stereotactic radiotherapy

This study was performed to investigate the feasibility of FDG- and L-[methyl-11C]methionine (Met)-PET for the follow up of lung cancer after stereotactic radiotherapy (SRT). Nine patients (pt) with solitary lung cancer underwent SRT. Met- and FDG-PET studies were performed one week before SRT and from one week to 8 months after SRT. Responses to SRT were complete in 2 pt and partial in 7 pt. Met- and FDG-PET scan showed high tracer uptake in all tumors before SRT. After SRT, standardized uptake values (SUV) of FDG and Met changed concordantly. Both decreased with time in 5 pt but did not decrease steadily in 4 pt, where 2 pt showed an increase at 1 to 2 weeks after SRT and 2 pt showed an increase at more than 3 months after SRT. The former appears to reflect the acute reaction to SRT and the latter radiation-induced pneumonitis. Although the addition of Met-PET did not provide additional information over FDG-PET, FDG- and Met-PET could be used to evaluate the treatment effect of SRT.

Comparison of myocardial blood flow during dobutamine-atropine infusion with that after dipyridamole administration in normal men.

OBJECTIVESnThe present study was designed to compare the absolute myocardial blood flow (MBF) after intravenous dipyridamole infusion with that during dobutamine-atropine administration in normal healthy male volunteers.nnnBACKGROUNDnBoth safety and usefulness of dobutamine-atropine stress in myocardial perfusion imaging have been reported. However, no information exists on whether the magnitude ofhyperemia achieved with dipyridamole and dobutamine-atropine is comparable.nnnMETHODSnMyocardial blood flow was measured with positron emission tomography and 15O-labeled water in 20 healthy young men (23 +/- 3 years) 1) at baseline, 2) after dipyridamole infusion (0.56 mg/kg over 4 min), and 3) during dobutamine (40 microg/kg/min) and atropine (0.25 to 1.0 mg) infusion.nnnRESULTSnThe MBF was significantly increased during dipyridamole infusion and during dobutamine-atropine stress compared with at rest (4.33 +/- 1.23 and 5.89 +/- 1.58 vs. 0.67 +/- 0.16 ml/min/g, respectively, p < 0.0001). Moreover, dobutamine-atropine infusion produced greater MBF compared with dipyridamole (p = 0.0011), while coronary vascular resistance did not differ significantly after dipyridamole administration and during dobutamine-atropine infusion (17.6 +/- 7.9 vs. 18.6 +/- 5.6 mm Hg/[ml/min/g], respectively).nnnCONCLUSIONSnNear maximal coronary vasodilatation caused by dipyridamole is attainable using dobutamine and atropine in young healthy volunteers. Dobutamine in conjunction with atropine is no less effective than dipyridamole in producing myocardial hyperemia.

Direct electrophilic radiofluorination of a cyclic RGD peptide for in vivo αvβ3 integrin related tumor imaging

Abstract The association of the α v β 3 integrin with tumor metastasis and tumor related angiogenesis has been suggested. Therefore, by imaging the α v β 3 receptor with PET, information concerning the tumor status could be obtained. Cyclic peptides including the RGD sequence, were radiolabeled by direct electrophilic fluorination with [ 18 F]AcOF. In tumor-bearing mice, the labeled peptides accumulated at the tumor with a high tumor to blood ratio. These findings suggest that an assessment of tumor characteristics may be obtained by using these 18 F-labeled peptides.

Plasma protein binding of 99mTc-labeled hydrazino nicotinamide derivatized polypeptides and peptides

6-Hydrazinopyridine-3-carboxylic acid (HYNIC) constitutes one of the most attractive reagents to prepare (99m)Tc-labeled polypeptides and peptides of various molecular weights in combination with two tricine molecules as coligands. Indeed, (99m)Tc-HYNIC-conjugated IgG showed biodistribution of radioactivity similar to that of (111)In-DTPA-conjugated IgG. However, recent studies indicated significant plasma protein binding when the (99m)Tc labeling procedure was expanded to low molecular weight peptides. In this study, pharmacokinetics of (99m)Tc-HYNIC-conjugated IgG, Fab and RC160 using tricine were compared with their radioiodinated counterparts to evaluate this (99m)Tc-labeling method. In mice, [(99m)Tc](HYNIC-IgG)(tricine)(2) and [(99m)Tc](HYNIC-Fab)(tricine)(2) showed persistent localization of radioactivity in tissues when compared with their (125)I-labeled counterparts. [(99m)Tc](HYNIC-IgG)(tricine)(2) eliminated from the blood at a rate similar to that of (125)I-labeled IgG, while [(99m)Tc](HYNIC-Fab)(tricine)(2) showed significantly slower clearance of the radioactivity than (125)I-labeled Fab. On size-exclusion HPLC analyses, little changes were observed in radiochromatograms after incubation of [(99m)Tc](HYNIC-IgG)(tricine)(2) in murine plasma. However, [(99m)Tc](HYNIC-Fab)(tricine)(2) and [(99m)Tc](HYNIC-RC160)(tricine)(2) demonstrated significant increases in the radioactivity in higher molecular weight fractions in plasma. Formation of higher molecular weight species was reduced when [(99m)Tc](HYNIC-RC160)(tricine)(2) was stabilized with nicotinic acid (NIC) to generate [(99m)Tc](HYNIC-RC160)(tricine)(NIC). [(99m)Tc](HYNIC-RC160)(tricine)(NIC) also demonstrated significantly faster clearance of the radioactivity from the blood than [(99m)Tc](HYNIC-RC160)(tricine)(2). These findings suggested that one of the tricine coligands in (99m)Tc-HYNIC-labeled (poly)peptides would be replaced with plasma proteins to generate higher molecular weight species that exhibit slow blood clearance. In addition, the molecular sizes of parental peptides played an important role in the progression of the exchange reaction of one of the tricine coligands with plasma proteins.

Evaluation of radioiodinated 5-iodo-3-(2(S)-azetidinylmethoxy)pyridine as a ligand for SPECT investigations of brain nicotinic acetylcholine receptors

Abstract5-Iodo-3-(2(S)-azetidinylmethoxy)pyridine (5IA), an A-85380 analog iodinated at the 5-position of the pyridine ring, was evaluated as a radiopharmaceutical for investigating brain nicotinic acethylcholine receptors (nAChRs) by single photon emission computed tomography (SPECT). [123/125I]5IA was synthesized by the iododestannylation reaction under no-carrier-added conditions and purified by high-performance liquid chromatography (HPLC) with high radiochemical yield (50%), high radiochemical purity (>98%), and high specific radioactivity (>55 GBq/μmol). The binding affinity of 5IA for brain nAChRs was measured in terms of displacement of [3H]cytisine and [125I]5IA from binding sites in rat cortical membranes. The binding data revealed that the affinity of 5IA was the same as that of A-85380 and more than seven fold higher than that of (−)-nicotine, and that 5IA bound selectively to the α4β2 nAChR subtype. Biodistribution studies in rats indicated that the brain uptake of [125I]5IA was rapid and profound. Regional cerebral distribution studies in rats demonstrated that the accumulation of [125I]5IA was consistent with the density of high affinity nAChRs with highest uptake observed in the nAChR-rich thalamus, moderate uptake in the cortex and lowest uptake in the cerebellum. Administration of the nAChR agonists (−)-cytisine and (−)-nicotine reduced the uptake of [125I]5IA in all regions studied with most pronounced reduction in the thalamus, and resulted in similar levels of radioactivity throughout the brain. [125I]5IA binding sites were shown to be saturable with unlabeled 5IA. Behavioral studies in mice demonstrated that 5IA did not show signs of behavioral toxicity. Furthermore, SPECT studies with [123I]5IA in the common marmoset demonstrated appropriate brain uptake and regional localization for a high-affinity nAChR imaging radiopharmaceutical. These results suggested that [123I]5IA is a promising radiopharmaceutical for SPECT studies of central nAChRs in human subjects.

Development of Injectable O-15 Oxygen and Estimation of Rat OEF

Cerebral metabolic rate for oxygen (CMRO2) and cerebral oxygen extraction fraction (OEF) are some of the most fundamental parameters to characterize the pathophysiologic status of cerebral tissue. Although O-15-labeled gases inhalation method is performed in clinical studies, application of the inhalation method on small animals requires too many intensive procedures. On this basis, the development of a new method to measure CMRO2 and OEF in small animals is of interest. This study was aimed at developing a method to assess CMRO2 and OEF using intravenously injectable oxygen (injectable 15O–O2) for small animals such as rats. Injectable 15O–O2, 72 MBq/mL of radioactivity, was obtained after 15O–O2 gas circulation into the artificial lung. OEF after injection of injectable 15O–O2 was calculated using the same equation as that applied to the bolus inhalation of 15O–O2 gas method. Values of 44 ± 4.5 mL · min−1 · 100 g−1 of CBF and 0.54 ± 0.11 of OEF were obtained (n = 13). This OEF value was well accordance with OEF evaluated by arterial-venous difference of oxygen concentration (0.57 ± 0.13). This method is useful to study the CMRO2 and OEF in small animals using an animal positron emission tomography system. It may accelerate the basic research of several cerebral perfusion diseases.

99mTc-HYNIC-derivatized ternary ligand complexes for 99mTc-labeled polypeptides with low in vivo protein binding

6-Hydrazinopyridine-3-carboxylic acid (HYNIC) is a representative agent used to prepare technetium-99m ((99m)Tc)-labeled polypeptides with tricine as a coligand. However, (99m)Tc-HYNIC-labeled polypeptides show delayed elimination rates of the radioactivity not only from the blood but also from nontarget tissues such as the liver and kidney. In this study, a preformed chelate of tetrafluorophenol (TFP) active ester of [(99m)Tc](HYNIC)(tricine)(benzoylpyridine: BP) ternary complex was synthesized to prepare (99m)Tc-labeled polypeptides with higher stability against exchange reactions with proteins in plasma and lysosomes using the Fab fragment of a monoclonal antibody and galactosyl-neoglycoalbumin (NGA) as model polypeptides. When incubated in plasma, [(99m)Tc](HYNIC-Fab)(tricine)(BP) showed significant reduction of the radioactivity in high molecular weight fractions compared with [(99m)Tc](HYNIC-Fab)(tricine)(2.) When injected into mice, [(99m)Tc](HYNIC-NGA)(tricine)(BP) was metabolized to [(99m)Tc](HYNIC-lysine)(tricine)(BP) in the liver with no radioactivity detected in protein-bound fractions in contrast to the observations with [(99m)Tc](HYNIC-NGA)(tricine)(2.) In addition, [(99m)Tc](HYNIC-NGA)(tricine)(BP) showed significantly faster elimination rates of the radioactivity from the liver as compared with [(99m)Tc](HYNIC-NGA)(tricine)(2.) Similar results were observed with (99m)Tc-labeled Fab fragments where [(99m)Tc](HYNIC-Fab)(tricine)(BP) exhibited significantly faster elimination rates of the radioactivity not only from the blood but also from the kidney. These findings indicated that conjugation of [(99m)Tc](HYNIC)(tricine)(BP) ternary ligand complex to polypeptides accelerated elimination rates of the radioactivity from the blood and nontarget tissues due to low binding of the [(99m)Tc](HYNIC)(tricine)(BP) complex with proteins in the blood and in the lysosomes. Such characteristics would render the TFP active ester of [(99m)Tc](HYNIC)(tricine)(BP) complex attractive as a radiolabeling reagent for targeted imaging.