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2 Table 1. Physiochemical Properties of Three Blood Pool Contrast Agents Properties Gadomer-17 Gadofluorine M Ferucarbotran MW (kd) Gd-Con (L/mmol) Size (nm) 21 T1/T2 RR 18.7/ / /60.0 (L.mmol.sec -1 ) Elimination urine urine (32%) RES feces (66%) (liver, spleen) Acute tolerance >30 5 (mmol/kg) Recommended dose for MRI (mmol/kg) MW: molecular weight, Gd-Con: Gadolinium concentration RR: relaxivity ratio at 20 MHz 40 plasma, RES: Reticuloendothelial system Table 2. Signal Difference to Noise Ratios of Three Blood Pool Contrast Agents and Gd-DTPA Contrast Agents SDNR (mean(sd) /Dose (mmol/kg) Precontrast Maximum Gadopentetate Demeglumine Gadomer Gadofluorine M Ferucarbotran Fig. 1. Graph shows aorta-to-tissue SD- NR from equilibrium phase MRA in the rabbits before and after injection of Gd-DTPA 0.1mmol/kg, Gadomer mmol/kg, 0.1 mmol/kg, Gadofluorine M 0.05 mmol/kg, 0.1 mmol/kg, Ferucarbotran 0.1 mmol/kg. The SDNRs are increased over nonenhanced values for all dose groups and the SDNRs are higher than that of the Gd-DTPA. Vessel enhancement with agents decreases monotonically over time except Ferucarbotran. =Gd-DTPA 0.1 mmol/kg, =Gadomer mmol/kg, =Gadomer mmol/kg, =Gadofluorine M 0.05 mmol/kg, * =Gadofluorine M 0.1 mmol/kg, =Ferucarbotran 0.1 mmol/kg
3 대한영상의학회지 2004;51: 입효과가 없고 비교적 균일한 신호강도를 보이는 부위를 선택 하였으며 시간에 따른 여러 영상의 같은 부위에서 측정하였 다. SDNR은(SIaorta SItissue)/SDair로 정의하여 계산하였으 며 SDNR은 4마리의 토끼에서의 평균 값으로 mean±sd으로 표시하여 Gd-DTPA와 비교하였다. 결 과 Fig. 1에서 각각의 용량과 종류별 조영제의 시간에 따른 평 A 균 SDNR을 그래프로 표시하였으며 Table 2에서는 각 조영 제의 조영 전, 조영 후 최고값의 SDNR을 4마리 토끼에서의 평균값인 mean±sd으로 표시하였다. Gadomer-17, Gadofluorine M, Ferucarbotran의 조영 후 최고값의 SDNR은 0.1 mmol/kg Gd-DTPA와 비교하였을 때 Gadomer mmol/kg, 0.1 mmol/kg에서 각각 35%, 124% 증가하였고, Gadofluorine M은 0.05 mmol/kg, 0.1 mmol/kg에서 각각 63%, 250% 증가하였으며, Ferucarbotran 는 0.1 mmol/kg에서 88%의 증가를 보였다. 또한 Gd-DTPA B C D E F Fig. 2. Coronal maximum intensity projection images from three-dimenional SPGR MR angiograms obtained in rabbit after intravenous injection of 0.1 mmol/kg Gd-DTPA. (A) 1minute (B) 5 minutes (C) 10minutes (D) 20minutes (E) 30minutes (F) 24 hour. These images show initial vessel enhancement with rapid loss of vessel enhancement. 501
4 임수미 외: 새로운 혈액저류 조영제를 이용한 평형기 자기공명 혈관조영술 를 이용한 MRA에서는 복부 대동맥이 5분 영상에서 까지만 (Fig. 2) 보이는 것과 비교하여 Gadomer-17은 20분까지(Fig. 3) Gadofluorine M과 Ferucarbotran에서는 30분까지도(Fig. 4, 5) 복부 대동맥을 잘 볼 수 있었다. 모든 조영제에서 조영제 주입 후의 SDNR이 조영제 주입 전 과 비교하여 확연한 증가를 보였고 시간 따라 서서히 감소하 였으며 3가지 조영제의 SDNR이 Gd-DTPA와 비교하였을 때 모두 증가하였다. Ferucarbotran에서는 30분까지 SDNR이 점 A 차적으로 증가하여 다른 조영제와의 차이를 보였다(Fig. 5). 고 찰 3가지의 새로운 혈액저류 조영제를 이용하여 토끼에서 좋 은 영상의 평형기 자기공명혈관조영술을 얻을 수 있었으며 Gd-DPTA와 비교하였을 때 복부 대동맥에서의 SDNR이 더 높고 오랫동안 지속되었다. B C D E F Fig. 3. Coronal maximum intensity projection images from three-dimensional SPGR MR angiograms obtained in rabbit after intravenous injection of 0.1 mmol/kg Gadomer-17. (A) 1 minute (B) 5 minutes (C) 10 minutes (D) 20minutes (E) 30minutes (F) 24 hour. These images show strong initial vessel enhancement and vessel contrast decreases slowly, and vessels remains visible up to 20 minutes after contrast material application. Gadomer-17 provided sequential enhancement of renal cortex, medulla and pelvis with time. 502
5 대한영상의학회지 2004;51: 사용한 조영제는 가돌리늄을 기본으로 한 혈액저류 조영제 인 Gadomer-17, Gadofluorine M과 산화철을 기본으로 한 Ferucarbotran였고 두종류의 조영제는 배설경로, T1/T2 이완 율, 자화율과 화학적 구조 등에 있어 서로 다르다. Gadomer17의 Mhz 혈장에서의 T1/T2 이완율(relaxivity ratio)은 18.7/29.0 L.mmol-1.sec-1이고 다른 가돌리늄 중합체 와 비슷하며 수지상 물질 표면에 24개의 가돌리늄 복합체를 포함하고 있다(14, 15). 중심부인 트리메소일 트리아마이드 (trimesoyl triamide)와 18개의 라이신(lysine) 잔여물로 이루 A 어져 있고 24 폴리아민을 형성하며 24 자유 아미노산 그룹이 tetraazacyclododecanetetraacetic acid gadolinium chelate에 연결되어 있다. 이 물질은 동물실험에서 독성이 낮고 모두 신 장으로 배설되며 평균치사량이 약 10 mmol/kg, 급성내성이 30 mmol/kg이상이다. 실질적인 분자량은 17 kd이나 둥근 모 양으로 약 30 kd의 분자량을 가진다. 이러한 높은 분자량은 간질 내로의 확산을 늦추며 가돌리늄과 비교하였을 때 0.5 T 에서 그 확산 속도는 약 3.7배가 느리다. 이러한 이유로 Gadomer-17은 20분까지 평형기 MRA에서 복부 대동맥의 조 B C D E F Fig. 4. Coronal maximum intensity projection images from three-dimensional SPGR MR angiograms obtained in rabbit after intravenous injection of 0.1 mmol/kg Gadofluorine M. (A) 1minute (B) 5 minutes (C) 10minutes (D) 20minutes (E) 30minutes (F) 24 hour. These images show more improved vessel contrast, as compared with the Gadomer-17 in Fig. 3, and arteries remain visible up to 30 minutes after contrast material application. 503
6 임수미 외: 새로운 혈액저류 조영제를 이용한 평형기 자기공명 혈관조영술 영이 가능하였다. Gadofluorine M의 Mhz 혈장에서의 T1/T2 이완 율는 15.9/21.1 L.mmol-1.sec-1이며 물질의 1/3은 신장으로, 2/3는 변으로 배설되며 분자량이 1528 kd로 Gadomer-17의 50배에 이른다. Gadofluorine M은 혈장 제거 속도가 Gadomer-17보다 느리며 평형기 MRA에서 30분까지 복부동 맥을 볼 수 있었고 SDNR은 Gd-DTPA와 비교하였을 때 250%의 증가를 보였다. 시간에 따른 SDNR은 Gadomer-17 이나 Gadofluorine M A 에서 모두 1분 후부터 천천히 감소하였다. Gadofluorine M 0.1 mmol/kg의 경우 1분보다 5분에서 SDNR이 약간 높아 다른 조영제와 다른 결과를 보였으며 이는 측정 오차의 가능성 및 신장으로의 배설이 적음으로 인해 생기는 조영제 자체의 특성 등의 원인을 생각해 볼 수 있으며 좀더 자세한 연구가 필요한 부분으로 생각된다. Gadofluorine M은 Gadomer-17과 Ferucarbotran 과 비교하였을 때 SDNR이 높고 비교적 오랫 동안 혈관 내 머물러 있는 등 평형기 MRA에 유리한 장점을 가지고 있어 인체 내 축적되지 않고 부작용을 일으키지 않는 B C D E F Fig. 5. Coronal maximum intensity projection images from three-dimensional SPGR MR angiograms obtained in rabbit after intravenous injection of 0.1 mmol/kg Ferucarbotran. (A) 1minute (B) 5 minutes (C) 10 minutes (D) 20 minutes (E) 30 minutes (F) 24 hour. Aorta-to-tissue SDNR increased with time for 30 minutes in Ferucarbotran. 504
7 1. Snidow JJ, Aisen AM, Harris VJ, Trerotola SO, Johnson MS, Sawehuk AP, et al. Iliac artery MR angiography: comparison of three-dimensional gadolinium-enhanced and two-dimensional time-of flight techniques. Radiology 1995;196: Maki JH, Chenevert TL, Prince MR. Contrast-enhanced MR angiography. Abdom Imaging 1998;23: Parker DL, Tsuruda JS, Goodrich KC, Alexander AL, Buswell HR. Contrast-enhanced magnetic resonance angiography of cerebral arteries. A review. Invest Radiol 1998;33: Prince MR, Narasimham DL, Stanley JC, Chenevert TL, Williams DM, Marx MV, et al. Breath-hold gadolinium-enhanced MR angiography of the abdominal aorta and its major branches. Radiology 1995;197: Wang SC, Wikstrom MG, White DL, Klaveness J, Holtz E, Rongved P, et al. Evaluation of Gd-DTPA-labeled dextran as an intravascular MR contrast agent: imaging characteristics in normal rat tissues. Radiology 1990;175: Bogdanov AA Jr, Weissleder R, Frank HW, Bogdanova AV, Nossif N, Schaffer BK, et al. A new macromolecule as a contrast agent for MR angiography: preparation, properties, and animal studies. Radiology 1993;187: Adam G, Neuerburg J, Spuntrup E, Muhler A, Scherer K, Gunther RW. Dynamic contrast-enhanced MR imaging of the upper ab- enhancement properties of gadobutrol, gadolinium-dtpa- domen: polylysine, and gadolinium-dtpa-cascade-polymer. Magn Reson Med 1994;32: McLachlan SJ, Morris MR, Lucas MA, Fisco RA, Eakins MN, Fowler DR, et al. Phase I clinical evaluation of a new iron oxide MR contrast agent. J Magn Reson Imaging 1994;4: Mayo-Smith WW, Saini S, Slater G, Kaufman JA, Sharma P, Hahn PF. MR contrast material for vascular enhancement: value of su- iron oxide. AJR Am J Roentgenol 1996;166: Lauffer RB, Parmelee DJ, Dunham SU, Ouellet HS, Dolan RP, perparamagnetic Witte S, et al. MS-325: albumin-targeted contrast agent for MR angiography. Radiology 1998;207: Grist TM, Korosec FR, Peters DC, et al. Steady-state and dynamic MR angiography with MS-325: initial experience in humans. Radiology 1998;207: Adam G, Muhler A, Spuntrup E, Neuerburg J, Kilbinger M, Bauer H, et al. Differentiation of spontaneous canine breast tumors using dynamic magnetic resonance imaging with 24-Gadolinium-DTPAcascade-polymer, a new blood-pool agent. Preliminary experience. Invest Radiol 1996;31: Roberts HC, Saeed M, Roberts TP, Muhler A, Shames DM, Mann JS, et al. Comparison of albumin-(gd-dtpa) 30 and Gd-DTPA-24- cascade-polymer for measurements of normal and abnormal microvascular permeability. J Magn Reson Imaging 1997;7:
8 14. Clarke SE, Weinmann HJ, Dai E, Lucas AR, Rutt BK. Comparison of two blood pool contrast agents for 0.5-T MR angiography: experimental study in Rabbits. Radiology 2000;214: Marchal G, Bosmans H, Van Hecke P, Speck U, Aerts P, Vanhoenacker P, et al. MR angiography with gadopentetate dimeglumine-polylysine: evaluation in rabbits. AJR Am J Roentgenol 1990;155: Engelbrecht MR, Saeed M, Wendland MF, Canet E, Oksendal AN, Higgins CB. Contrast-enhanced 3D-TOF MRA of peripheral vessels: intravascular versus extracellular MR contrast media. J Magn Reson Imaging 1998;8: Li D, Dolan RP, Walovitch RC, Lauffer RB. Three-dimensional MRI of coronary arteries using an intravascular contrast agent. Magn Reson Med 1998;39: Equilibrium Phase MR Angiography Using New Blood Pool Contrasts: Experimental Study in Rabbits 1 Soo Mee Lim, M.D., Hye-Young Choi, M.D., Yoo Kyung Kim, M.D., Do Yeon Kim, M.D., Min Sun Lee, M.D. 1 Department of Radiology, Ewha Womans University, College of Medicine Purpose: The purpose of this study was to evaluate the usefulness of three experimental blood pool contrast agents for equilibrium phase magnetic resonance angiography. Materials and Methods: MR angiography was performed in 21 rabbits before and 1, 5, 10, 20 and 30 minutes and 24 hours after the injection of gadolinium-based blood pool contrast agents (Gadomer-17, Gadofluorine M,) and superparamagnetic iron oxide blood pool agent (Ferucarbotran). 3D TOF SPGR images of the thoracic and abdominal aorta (and involving the renal arteries) were obtained. The signal difference-to noise ratios (SDNRs) were measured over time in the aorta. These images were then compared to that of images with Gd- DTPA. Results: MR angiography with the three blood pool agents yielded excellent visualization results of the rabbit abdominal aorta. At the same dose, the three agents provided a significant increase of the aorta-to-tissue SDNR in comparison with that achieved with the Gd-DTPA (a 250% increase for Gadomer-17, a 124% increase for Gadofluorine and a 88% increase for Ferucarbotran). The SDNRs using Ferucarbotran especially showed continuously increasing values to 30 minutes after the injection of contrast agent. Conclusion: The three blood pool agents were found to be very useful contrast agents for equilibrium phase MR angiography. Index words : Magnetic resonance (MR) Angiography Contrast media, experimental studies Address reprint requests to : Soo Mee Lim, M.D., Department of Radiology, Ewha Womans University Mokdong Hospital, College of Medicine, Mok-dong, Yangcheon-gu, Seoul , Korea. Tel Fax soomee@ewha.ac.kr 506
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