99Mo/99mTc 방사성동위원소 발생기 개발 및 응용 = Developments and appications of Mo-99/Tc-99m radionuclide generator

다국어 초록 (Multilingual Abstract)

Technetium-99m (99mTc) is a radioisotope used to diagnose various diseases and is the most essential radioisotope in the diagnosis field of nuclear medicine, whereby 80% of nuclear medicine diagnosis worldwide uses this radioactive isotope.
99mTc is generally portable and produced by 99Mo/99mTc generator which is simple to operate.
Although many research studies on the conventional 99Mo/99mTc generator had been conducted for a long period of time, all are restricted to tests for medical effectiveness of the eluted Na99mTcO4. However, there had been incomplete studies on the adsorption behavior of alumina in Na299MoO4, which plays a pivotal role in high-efficiency elution of Na99mTcO4, and on elution behavior according to types of alumina when Na99mTcO4 is eluted.
Therefore, this present study tested the adsorption behavior of Na299MoO4 along the chromatography column packed with alumina, elution behavior of Na99mTcO4, and medical effectiveness of Na99mTcO4 the eluted from the generator. Furthermore, through chemical research methods for the production of 99mTc-labeled compounds which are imaging agents for hypoxia cells, we investigated their potential to be used as diagnostic imaging agents for nuclear medicine.

The results of this present study were the following.

First, results measuring the loading quantity and rate with Fission-99Mo on alumina, known as 99Mo adsorbent, showed that loading with 99Mo on acidic alumina 1 was possible as much as 24 Ci and that loading rate of 99Mo was above an average of 99%, showing a very high loading efficiency.
Moreover, according to results that tested the loading efficiency and distribution of Na99MoO4 along the interior of the adsorption column, column packed only with acidic alumina showed high adsorption from the beginning, whereas column packed with neutral alumina and basic alumina showed decreased initial loading efficiency.

Second, results testing the elution rate and distribution of 99mTc in the adsorption column showed high elution rate of an average 91.19%. It was determined that its elution speed was quick in the order of basic alumina > neutral alumina > acidic alumina.
In addition, results testing column distribution of Na99mTcO4, elution rate of column packed only with acidic alumina was 90.90%, showing a lower elution rate compared to column packed with neutral and basic alumina. According to results that determined the distribution in the column before and after elution, Na99mTcO4 re-adsorbed along the column as it eluted.
These results showed that adsorbent for 99Mo/99mTc generator was not only packed with pure acidic alumina but also packed with a mixture of neutral and basic alumina to exhibit effects of reducing re-adsorption and non-radioactivity.

Third, results of quality test of 99Mo/99mTc generator showed that the eluted Na99mTcO4 solution was colorless and maintained a transparent state. Although the pH of the eluted solution was 6.4-7.8, which were values that satisfied the European Pharmacopoeia standards of pH 4.5-8.0, column packed with basic alumina was unsuitable according to Korean Pharmacopoeia standards (4.0-7.0). Furthermore, there were no impurities even in radionuclidic purity tests, and the value of 99Mo Breakthrough (99Mo/99mTc Radio) test was below the Korean Pharmacopoeia standard of 0.15 μCi/mCi. Radionuclidic purity of Na99mTcO4 in the eluted solution was above 95%, and chemical purity of aluminum concentration in the Na99mTcO4 solution did not exceed the standard value of 10 μg/ml. Sterility test and heat release rate test also showed values that satisfied the Korean Pharmacopoeia standards.

Fourth, we generated 99% pure NIAP, which are imaging agents for hypoxic cells, that was determined through NMR, Lc-MS, UV/Vis spectroscopy, and HPLc. Moreover, results from testing the coordination bond of Na99mTcO4 and NIAP which are target compounds for hypoxia cells, showed that the optimized conditions for coordination bond above 95% radiochemical purity were a reaction temperature at 80℃ and a reaction time of 20 min, taking into account the 6-hour physical half-life of 99mTc and settling time of patients after injection.

Fifth, according results of vivo distribution and imaging experiments of 99mTc-NIAP in mouse, the amount of tumor uptake of 99mTc-NIAP increased with time. Results from injecting 99mTc-NIAP into BALB/c mouse model transplanted with HCT116 cells and obtaining images through SPECT showed characteristic accumulation on the tumor 1 h after injection. In terms of expenses and comparison with PET-CT that uses F-18 FDG, 99mTc can be utilized in the future as a good alternative for diagnostic imaging.

keywords : Alumina, 99Mo/99mTc generator , behavior of Na299MoO4 , hypoxia cell, nuclear medicine

목차 (Table of Contents)

• CHAPTER 1. 99Mo/99mTc 방사성동위원소 발생기 개발
• Ⅰ.서론 1
• Ⅱ.이론적 배경 5
• 1.99Mo/99mTc의 특성 7
• 2. 99Mo의 생산 12
• 3. 99Mo/99mTc의 분리기술 19
• 4. Fission 99Mo 알루미나 흡착 특성 25
• 5. 99Mo/99mTc 발생기 품질시험 26
• Ⅲ.실험 및 방법 27
• 1. 실험재료 및 장비 27
• 1) 실험재료 27
• 2) 실험장비 27
• 2.실험 방법 28
• 1) 흡착제의 구성 28
• 2) Na299MoO4의 흡착량 및 흡착률 측정실험 30
• 3) Na99mTcO4의 용출률 실험 33
• 4) 99Mo/99mTc 발생기의 품질시험 34
• 5) 99Mo/99mTc 발생기 시작품 제작 41
• Ⅳ.연구결과 및 고찰 43
• 1.Na299MoO4의 흡착량・률 및 분포 실험 43
• 1) 99Mo 최대흡착량・률 실험 43
• 2) 세척 수 및 세척방향에 따른 99mTc 탈착실험 45
• 3) 흡착 칼럼 내부의 Na299MoO4 흡착효율 및 분포 실험 47
• 2.Na99mTcO4의 용출률 및 칼럼 분포 실험 49
• 1) Na99mTcO4의 용출률 실험 49
• 2) Na99mTcO4의 칼럼 분포 실험 52
• 3 99Mo/99mTc 발생기의 품질시험 54
• 1) 성상시험 54
• 2) pH 시험 54
• 3) 방사성핵종순도 시험 54
• 4) 방사화학적 순도 시험 57
• 5) 화학적 순도 시험 59
• 6) 무균 시험 60
• 7)발열성물질 시험 61
• 4.99Mo/99mTc 발생기 시작품 제작 62
• Ⅴ.결론 66
• CHAPTER 2. 저산소증 표적영상진단제 개발
• Ⅰ.서론 69
• Ⅱ.이론적 배경 72
• 1.저산소증 72
• 2. 저산소증 방사성의약품 74
• Ⅲ. 실험 및 방법 79
• 1.실험재료 및 장비 79
• 1) 실험재료 79
• 2) 실험장비
• 2. 실험방법81
• 1) L-aspartic와 Na99mTcO4-와 배위결합81
• 2) 저산소증 표적 영상진단제 (99mTc-NIAP) 제조 방법 83
• 3) mouse에서의 생체분포 실험 및 Image 평가 실험89
• Ⅳ. 연구결과 및 고찰 91
• 1. L-aspartic와 Na99mTcO4-와 배위결합91
• 1) Na99mTcO4와 SnCl2·2H2O의 영향91
• 2) L-asp와 SnCl2·2H2O의 농도의 영향 93
• 3) pH의 영향 96
• 4) 반응시간과 온도에 의한 영향 97
• 5) L-asp와 99mTc의 배위결합 구조 99
• 2. 저산소증 표적 영상단제 제조 100
• 1 )저산소증 세포표적화합물 합성 100
• 2) 방사성테크네튬과 저산소증 세포 표적화합물과(NIAP)의
• 배위결합 106
• 3) mouse에서의 생체분포 실험 및 영상시험 109
• Ⅴ. 결론 111
• 참 고 문 헌 112

참고문헌 (Reference)

1. Bio-MedicalPhotonics, 이병일, pp.252-278, , 2008

2. NuclearMedicine,3rdedition, 정재민, pp.123-1696, , 2008

3. 핵의학-분자영상의학, 이재태, 고문사, pp.113-154, , 2003