Symmetrical Skin Lesions on the Gluteal Region in a Patient with Anti-Laminin-332 Mucous Membrane Pemphigoid

Mucous membrane pemphigoid (MMP), previously called cicatricial pemphigoid, is a rare subepidermal immunobullous disorder that primarily affects the mucous membranes (1,2). MMP is divided into two major subtypes, anti-BP180-type MMP and anti-laminin-332 (previously called laminin 5 or epiligrin) MMP. Anti-laminin-332 MMP is known to be associated with malignant tumors (3), which may cause overexpression of autoantibodies and induce autoimmunity to laminin-332 (4). MMP primarily affects the mucous membranes, and widespread skin lesions are rare. In MMP, circumscribed skin lesions have been previously reported as occurring on the head, neck, and upper trunk (5). We report a case of anti-laminin-332 MMP presenting with symmetrical skin lesions characteristic of MMP on the weightbearing areas of the gluteal regio

Symmetrical Skin Lesions on the Gluteal Region in a Patient with Anti-Laminin-332 Mucous Membrane Pemphigoid

Mucous membrane pemphigoid (MMP), previously called cicatricial pemphigoid, is a rare subepidermal immunobullous disorder that primarily affects the mucous membranes (1,2). MMP is divided into two major subtypes, anti-BP180-type MMP and anti-laminin-332 (previously called laminin 5 or epiligrin) MMP. Anti-laminin-332 MMP is known to be associated with malignant tumors (3), which may cause overexpression of autoantibodies and induce autoimmunity to laminin-332 (4). MMP primarily affects the mucous membranes, and widespread skin lesions are rare. In MMP, circumscribed skin lesions have been previously reported as occurring on the head, neck, and upper trunk (5). We report a case of anti-laminin-332 MMP presenting with symmetrical skin lesions characteristic of MMP on the weightbearing areas of the gluteal regio

Efficient synthesis and chiral separation of 11C-labeled ibuprofen assisted by DMSO for imaging of in vivo behavior of the individual isomers by positron emission tomography

The pharmacological mechanisms focusing on chiral isomer of ibuprofen are not fully understood. Only the (S)-isomer of ibuprofen inhibits cyclooxygenases, which mediates the generation of prostanoids and thromboxanes. Consequently, (S)-isomers represent a major promoter of the anti-inflammatory effect,and the effects of the (R)-isomers have not been widely discussed. However, more recently, the cyclooxygenase-independent pharmacological effects of ibuprofen have been lucidated. Pharmacokinetic studies with individual isomers of ibuprofen by positron emission tomography should aid our understanding of the pharmacological mechanisms of ibuprofen. The efficient 11C-labeling of ibuprofen for chiral separationvia the TBAF-promoted a-[11C]methylation was achieved by using DMSO rather than THF as the reaction solvent. The robust production of the radiochemically labile 11C-labeled ibuprofen ester was realized by the protective effect of DMSO on radiolysis. After intravenous injection of each enantiomer of [11C]ibuprofen, significantly high radioactivity was observed in the joints of arthritis mice when compared to the levels observed in normal mice. However, the high accumulation was equivalent between the enantiomers, indicating that ibuprofen is accumulated in the arthritic joints regardless of the expression of cyclooxygenases

Preparation and PET study of individual isomers of [11C]ibuprofen

the 19th International Symposium on Radiopharmaceutical Sciences, the ISRS 201

Sulfate conjugation of [11C]PBB3, a Tau imaging agent, in the brain

Introduction[11C]PBB3, a Tau imaging agent, is rapidly metabolized to form a sulfate conjugate ([11C]PBB3-sulfate) in peripheral tissues by sulfotransferase (SULT).1 After the administration of [11C]PBB3 to mice, [11C]PBB3-sulfate was observed also in the brain. The previous report concluded that it was due to the influx of [11C]PBB3-sulfate from blood to brain. However, it is known that SULT is expressed in the brain and [11C]PIB which possesses 6-hydroxybenzothiazole as a fundamental structure (Fig 1) is sulfated in the rat brain.2 It was therefore expected that [11C]PBB3, a [11C]PIB derivative, would be sulfated in the brain. In this study, the sulfate conjugation of [11C]PBB3 in the brain was investigated because the conjugation might affect the kinetic analysis of Tau imaging with [11C]PBB3. In addition, the hydrolysis of [11C]PBB3-sulfate to form parent [11C]PBB3 in the brain was investigated as sulfate conjugates can be hydrolyzed by sulfatase which is expressed in the brain.Materials & MethodsSulfate conjugation of [11C]PBB3 in the brain was evaluated by adding [11C]PBB3 and a sulfate donor, 3\u27-phosphoadenosine-5\u27-phosphosulfate (PAPS) to the brain homogenate sample. In mice samples (cerebrum, C57BL/6, 8 wo, n=3), reactions were carried out at 37°C for 30 min. In samples of a rhesus monkey (frontal cortex, Macacca mulatta, male, 23 yo), reactions were carried out at 37°C and the conjugates generated were analyzed at 5, 15, 30 min after starting reaction. In addition to the crude homogenate (around 0.2 g/mL for mice, 0.16 g/mL for monkey), the sulfate conjugation in the supernatant of homogenate was investigated. The conjugation was analyzed using radio-TLC. Similarly, [11C]PBB3-sulfate, which was prepared by O-sulfation of [11C]PBB3 using sulfur trioxide pyridine complex, was incubated in the mice brain homogenate at 37°C for 30 min to evaluate its hydrolysis.ResultsThe sulfate conjugation of [11C]PBB3 was observed in the mice brain samples with 30 min reaction time, and only 7.7±0.44% and 9.2±0.30% of [11C]PBB3 was conjugated in the crude homogenate and supernatant, respectively (Fig 2A). Meanwhile, [11C]PBB3-sulfate was slowly hydrolyzed to form [11C]PBB3 in the brain sample (3.1±0.13% in the crude homogenate and 3.7±0.20% in the supernatant, Fig 2B).The conjugation rates of [11C]PBB3 in the monkey brain samples were much faster than that in the mice brain samples. The conjugation in the crude homogenate of monkey brain followed first order manner (r2=1.0) up to 91% decrease of [11C]PBB3 and the rate was estimated to be 0.49 min–1(g/mL)–1. The first order kinetics suggested that the hydrolysis rate of [11C]PBB3-sulfate in the monkey brain was much slower than the conjugation rate. Indeed, the conjugation rate and the hydrolysis rate in the supernatant prepared from 0.16 g/mL of monkey brain homogenate were estimated to be 0.35 min-1 and 0.013 min-1, respectively (Fig 3).DiscussionIn mice, [11C]PBB3 slowly but significantly underwent sulfate conjugation in the brain. Therefore, a part of [11C]PBB3-sulfate observed in the mouse brain after [11C]PBB3 administration would be the metabolite generated in the brain. On the other hand, the sulfate conjugation of [11C]PBB3 was quite rapid and apparently irreversible in the monkey brain samples. In this study, large Interspecies differences regarding the sulfate conjugation of [11C]PBB3 in the brain was observed. Therefore, further investigation about the conjugation of [11C]PBB3 in the human brain would be required.References1.Hashimoto H, Kawamura K, Takei M et al. [2015] Nucl. Med. Biol. 42: 905–9102.Cole GB, Keum G, Liu J et al. [2010] Proc. Natl. Acad. Sci. USA 107: 6222–6227The XII International Symposium of Functional Neuroreceptor Mapping of the Living Brai

Upregulation of striatal metabotropic glutamate receptor subtype 1 (mGluR1) in rats with excessive glutamate release induced by N-acetylcysteine

Aim of this study is to investigate the changes in expression of metabotropic glutamate (Glu) receptor subtype 1 (mGluR1), a key molecule involved in neuroexcitetoxicity, during excessive Glu release in the brain by PET imaging. An animal model of excessive Glu release in the brain was produced by intraperitoneally implanting an Alzet osmotic pump containing N-acetylcysteine (NAC), an activator of the cysteine/Glu antiporter, into the abdomen of rats. Basal Glu concentration in the brain was measured by microdialysis, which showed that basal Glu concentration in NAC-treated rats (0.31 µM) was higher than that in saline-treated rats (0.17 µM) at day 7 after the implantation of the osmotic pump. Similarly, PET studies with [11C]ITDM, a useful radioligand for mGluR1 imaging exhibited that the striatal binding potential (BPND) of [11C]ITDM for mGluR1 in PET assessments was increased in NAC-treated animals at day 7 after implantation (2.30) compared with before implantation (1.92). The dynamic changes in striatal BPND during the experimental period were highly correlated with basal Glu concentration. In conclusion, density of mGluR1 is rapidly upregulated by increases in basal Glu concentration, suggesting that mGluR1 might to be a potential biomarker of abnormal conditions in the brain