Appropriate collimators in a small animal SPECT scanner with CZT detector

Objective: Almost all small animal SPECT is performed with pinhole collimators (PH), including single-PH (SPH) and multi-PH (MPH). In the clinical study, not only PH but also parallel-hole collimator (PAH) is often used in planar and SPECT imaging. However, there have been no comparative studies on image quality with various collimators on the small animal imaging. This study compared the basic characteristics of PH and PAH in small animal imaging. Methods: Performance of planar and SPECT images was evaluated using 99mTcO4 - and SPH, MPH and PAH with low energy and high resolution on the SPECT/CT scanner FX3200. We measured sensitivity, resolution, concentration linearity and uniformity. Planar imaging of mice with 99mTc-labeled mercaptoacetyltriglycine (99mTc-MAG3) was performed using SPH and PAH. SPECT imaging with 99mTc-methylene diphosphonate (99mTc-MDP) was performed using all collimators. Results: With SPH, MPH and PAH, sensitivity was 43.5, 211.2 and 926.5 cps/MBq, respectively, and spatial resolution was 0.60/0.56, non/0.96, 5.20/5.34 mm full-width half maximum (planar/SPECT), respectively. There were marked correlations between the radioactivity counts on images and radioactivity with all collimators. Values of % standard deviation on planar imaging showed small differences between the SPH and PAH, while the values were the smallest on SPECT imaging with MPH. On imaging of mice, SPH yielded high-quality 99mTc-MAG3-planar images when compared with PAH. MPH yielded sharper 99mTc-MDP-SPECT images than SPH and PAH. Conclusions: The characteristics of PH and PAH differed on small animal imaging. Although sensitivity was higher with PAH, PH showed higher resolution. Among the PH collimators, SPH was more appropriate for planar imaging, and MPH was more suitable for SPECT imaging in a small animal imaging scanner with CZT detector. © 2013 The Japanese Society of Nuclear Medicine.Thesis of Yusuke Higaki / 檜垣 佑輔 博士論文 金沢大学医薬保健学総合研究科（保健学専攻

Usefulness of competitive inhibitors of protein binding for improving the pharmacokinetics of 186Re-MAG3-conjugated bisphosphonate (186Re-MAG3-HBP), an agent for treatment of painful bone metastases

金沢大学学際科学実験センターアイソトープ総合研究施設Purpose: We have developed a 186Re-mercaptoacetylglycylglycylglycine complex-conjugated bisphosphonate (186Re-MAG3-HBP) for the treatment of painful bone metastases. We assumed competitive inhibitors of protein binding to be useful for procuring a favorable biodistribution of 186Re-MAG3-HBP for the palliation of bone pain because it has been reported that the concurrent administration of 99mTc-MAG3 and drugs with high affinity for serum protein produced competitive displacement at specific binding sites and enhanced total clearance and tissue distribution. Methods: The displacement effects of several protein-binding inhibitors on the protein binding of 186Re-MAG3-HBP were investigated. Biodistribution experiments were performed by intravenously administering 186Re-MAG3-HBP into rats with ceftriaxone as a competitive protein-binding inhibitor or saline. Results: The protein binding of 186Re-MAG3-HBP in rat serum, human serum, and a human serum albumin solution was significantly decreased by the addition of ceftriaxone, which has high affinity for binding site I on serum albumin. In the biodistribution experiments, pretreatment with ceftriaxone enhanced the clearance of the radioactivity of 186Re-MAG3-HBP in blood and nontarget tissues but had no effect on accumulation in bone. Conclusions: The findings suggested that the use of protein-binding competitive inhibitors would be effective in improving the pharmacokinetics of radiopharmaceuticals with high affinity for serum protein. © 2008 Springer-Verlag

A Critical Role of Fatty Acid Binding Protein 4 and 5 (FABP4/5) in the Systemic Response to Fasting

During prolonged fasting, fatty acid (FA) released from adipose tissue is a major energy source for peripheral tissues, including the heart, skeletal muscle and liver. We recently showed that FA binding protein 4 (FABP4) and FABP5, which are abundantly expressed in adipocytes and macrophages, are prominently expressed in capillary endothelial cells in the heart and skeletal muscle. In addition, mice deficient for both FABP4 and FABP5 (FABP4/5 DKO mice) exhibited defective uptake of FA with compensatory up-regulation of glucose consumption in these tissues during fasting. Here we showed that deletion of FABP4/5 resulted in a marked perturbation of metabolism in response to prolonged fasting, including hyperketotic hypoglycemia and hepatic steatosis. Blood glucose levels were reduced, whereas the levels of non-esterified FA (NEFA) and ketone bodies were markedly increased during fasting. In addition, the uptake of the 125I-BMIPP FA analogue in the DKO livers was markedly increased after fasting. Consistent with an increased influx of NEFA into the liver, DKO mice showed marked hepatic steatosis after a 48-hr fast. Although gluconeogenesis was observed shortly after fasting, the substrates for gluconeogenesis were reduced during prolonged fasting, resulting in insufficient gluconeogenesis and enhanced hypoglycemia. These metabolic responses to prolonged fasting in DKO mice were readily reversed by re-feeding. Taken together, these data strongly suggested that a maladaptive response to fasting in DKO mice occurred as a result of an increased influx of NEFA into the liver and pronounced hypoglycemia. Together with our previous study, the metabolic consequence found in the present study is likely to be attributed to an impairment of FA uptake in the heart and skeletal muscle. Thus, our data provided evidence that peripheral uptake of FA via capillary endothelial FABP4/5 is crucial for systemic metabolism and may establish FABP4/5 as potentially novel targets for the modulation of energy homeostasis

タンカンナイ シュヨウセン オ ミトメ ゲンパツセイ カンナイ タンカンガン トノ カンベツ オ ヨウシタ イジセイ ダイチョウガン カンテンイ ノ 1セツジョレイ

The patient was a 68-year-old man who had undergone right hemicolectomy for ascending colon cancer, and pulmonary resection for lung metastases. After 10 months of operations, abdominal computed tomograms revealed a liver tumor with a biliary tumor thrombus in the segment 5 and a localized dilation of the intrahepatic bile duct. Endoscopic retrograde cholangiopancreatography showed obstruction, 2cm long, of the intrahepatic bile duct （B5） and dilation of the peripheral duct. Cytological examination of extracted bile showed adenocarcinoma. A right hepatic lobectomy was performed under the diagnosis of metastatic liver tumor with tumor development in the intrahepatic bile duct or intrahepatic cholangiocarcinoma. The resected specimen showed massive infiltration of the tumor into intrahepatic bile duct （B5） with forming a tumor thrombus. Histologically, the tumor was moderately differentiated adenocarcinoma, similar to the ascending colon cancer. The final diagnosis was liver metastasis of ascending colon cancer with intrabiliary tumor growth

Critical amino acids in human DNA polymerases η and κ involved in erroneous incorporation of oxidized nucleotides

Oxidized DNA precursors can cause mutagenesis and carcinogenesis when they are incorporated into the genome. Some human Y-family DNA polymerases (Pols) can effectively incorporate 8-oxo-dGTP, an oxidized form of dGTP, into a position opposite a template dA. This inappropriate G:A pairing may lead to transversions of A to C. To gain insight into the mechanisms underlying erroneous nucleotide incorporation, we changed amino acids in human Polη and Polκ proteins that might modulate their specificity for incorporating 8-oxo-dGTP into DNA. We found that Arg61 in Polη was crucial for erroneous nucleotide incorporation. When Arg61 was substituted with lysine (R61K), the ratio of pairing of dA to 8-oxo-dGTP compared to pairing of dC was reduced from 660:1 (wild-type Polη) to 7 : 1 (R61K). Similarly, Tyr112 in Polκ was crucial for erroneous nucleotide incorporation. When Tyr112 was substituted with alanine (Y112A), the ratio of pairing was reduced from 11: 1 (wild-type Polκ) to almost 1: 1 (Y112A). Interestingly, substitution at the corresponding position in Polη, i.e. Phe18 to alanine, did not alter the specificity. These results suggested that amino acids at distinct positions in the active sites of Polη and Polκ might enhance 8-oxo-dGTP to favor the syn conformation, and thus direct its misincorporation into DNA