PET Imaging of Bacterial Infections with Fluorine-18Labeled Maltohexaose Xinghai Ning, Wonewoo Seo, Seungjun Lee, Kiyoko Takemiya, Mohammad Rafi, Xuli Feng, Daiana Weiss, Xiaojian Wang, Larry Williams, Vernon M. Camp, Malveaux Eugene,W. Robert Taylor,* Mark Goodman,* and Niren Murthy* Impact factor:11.261 / 21 October 2014 指導老師 林宏榮老師 鄭伯智老師 學生 林秀鈴
PET/CT http://www2.edah.org.tw/pet/first.htm 2/24
造影原理 正常細胞消耗更大量的葡萄糖來做分裂的能源 因此較多量葡萄糖會聚集於代謝特別旺盛的癌症細胞組織 FDG CT 是人體組織密度分佈的解剖影像在 PET/CT 掃描中 能提供解剖定位 衰減校正與輔助影像診斷的功能 CT 利用正子與電子發生互毀效應時激發的 γ- 射線在 PE 器內 兩個相對的偵測器幾乎是 同時 偵測到這一對 γ- 光子 PET FDG PET/CT 在癌症的應用 3/24
臨床前動物實驗常見造影技術與特性分析 簡介電腻斷層掃描 // 正子斷層掃描 // 單光子放射斷層掃描在臨床前動物實驗的應用 陳仁焜 博士 / 中央研究院物理研究所 4/24
PET 簡介電腻斷層掃描 // 正子斷層掃描 // 單光子放射斷層掃描在臨床前動物實驗的應用 陳仁焜 博士 / 中央研究院物理研究所 5/24
Bacterial Infections Bacterial infections cause significant mortality and worldwide In the UK, the frequency of drug-resistant bacteria increased 20-fold in the past 10 years Infections are currently diagnosed by culturing of tissue biopsies or blood samples A major limitation preventing the effective treatment of bacterial infections is an inability to image them in vivo with accuracy and sensitivity. ScienceTranslationalMedicine 22 October 2014 Vol 6 Issue 259 259fs43 6/24
Bacterial Probes Positron emission tomography (PET) imaging has the potential to significantly improve the diagnosis of bacterial infections because of its unparalleled sensitivity. Recently, three different PET contrast agents were developed to image bacterial infections in vivo, via PET: 18F-maltose,18F-maltohexaose, and 18F-2-fluorodeoxy sorbitol (FDS). ScienceTranslationalMedicine 22 October 2014 Vol 6 Issue 259 259fs43 7/24
FDG -18 去氧葡萄糖 (FDG) 為葡萄糖的類似物 在體內 會參與葡萄糖的攝取 氟 -18 物理半衰期為 109 分鐘 衰變時放出的正子會轉變成兩股角度為 180 之 511 kev 加馬射線 核子醫學利用 FDG 與葡萄糖相同攝取 機轉 可以作為惡性腫瘤 心肌梗塞及癲癇等葡萄糖攝取異 常病灶的診斷 由於診斷靈敏度及準確性明顯高於其 他醫學影像技術 因此 FDG 被全球核醫學界譽為世紀 核醫造影劑 氟 http://www.iner.gov.tw/rpc/intro/f-18_fdg.htm 8/24
Maltohexaose Maltohexaose is a major source of glucose for bacteria Maltodextrin transporters internalize substrates at very high rates and tolerate large modifications to their substrates ScienceTranslationalMedicine 22 October 2014 Vol 6 Issue 259 259fs43 9/24
Maltodextrin-based imaging probes (MDPs) (1/2) MDPs also have high specificity for bacteria because mammalian cells do not express the maltodextrin transporte MDPs are composed of (1-4)-linked glucose oligomers, which are hydrophilic and membrane impermeable; therefore, MDPs are efficiently cleared from uninfected tissues in vivo, leading to a low background. 10/24
Maltodextrin-based imaging probes (MDPs) (2/2) NATURE MATERIALS,VOL 10,AUGUST 2011 11/24
Synthesis of MH18F Scheme 1. brosylate with an 87 % radio- chemical purity based on radiometric HPLC The protocol for the preparation of MH18F had a synthesis time of 100 minutes 12/24
High specificity of MH19F for bacteria Bacteria robustly accumulate MH19F The uptake of EC+MH and LamB is significantly reduced hepatocytes have negligible uptake Bacteria and mammalian cells were incubated for one hour with MH19F at a concentration of 500 µm Figure 1. EC E. coli LamB LamB mutation (Blocks maltose utilization) 13/24
The ability of MH18F to image bacterial infections in rats. Figure 2. Rats infected with E. coli (107 CFUs) 2hr Injected with 250 µci of MH18F through the tail vein Infected muscles can be easily visualized after 90 min EC E. coli(infected muscle) HT healthy tissue 14/24
Time activity curves Infected muscle has an 8.5-fold increase in radioactivity over PBS-injected muscle. Figure 2. 15/24
The ability of MH18F to image earlystage bacterial infections E. coli (105 CFUs) were injected into the left triceps muscle imaged with MH18F as described above ROI ratio expressed as the target or control to background ratio Figure 3. MH18F generates a 2.7-fold increase in radioactivity in infected muscles 16/24
Biodistribution study (1/2) Figure 4. Rats infected with E. coli (109 CFUs) and intravenously injected with either MH18F or 18FDG 1hr Measured various organs radioactivity between infected versus healthy muscles accumulation MH18F generated a 30-fold difference 18FDG generatedy a 1.5-fold difference 17/24
Biodistribution study (2/2) Figure 4. in infected rats the ratio of accumulation MH18F 18 FDG other reported PET contrast agents infected muscle liver 5 1 0.3 1 Less than 1 1 18/24
Distinguish between live versus dead Rats infected with 10 bacteria live and dead E. coli 9 imaged with MH18F using a micro- PET/CT Figure 5. MH18F does not accumulate in dead bacteria E. coli infected tissues had a 7-fold increase in radioactivity over muscles treated with dead bacteria 18FDG cannot discriminate live or dead bacteria 18FDG accumulates in tissues infected with both live and dead bacteria 19/24
Antibiotics ampicillin ciprofloxacin 20/24
Measure drug resistance and monitor the therapeutic effect of a1) Rats infected with 10 CFUs of antibiotics(1/2) ampicillin-resistant E. coli (DREC) 9 and wild-type E. coli (EC) treated with ampicillin imaged with MH18F using a micropet/ct b1) Rats infected with DREC and EC treated with ciprofloxacin imaged with MH18F using a micropet/ct Figure 6. 21/24
Measure drug resistance and monitor the therapeutic effect of antibiotics(2/2) DREC generated a 10-fold increase in radioactivity over EC DREC and EC infected muscles have weak accumulation of MH18F Figure 6. 22/24
Conclusions MH18F can be synthesized in one radiochemical step from clinically available K18F and therefore has the potential to rapidly enter into clinical trials. We have presented a bacteria-targeted PET tracer termed MH18F, which can image bacteria in vivo with a sensitivity and specificity. 23/24
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