神經醫學造影放射藥物發展

 
林口長庚醫院 分子影像中心 魏孝萍,林昆儒,閻紫宸 醫師
 
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前言

核子醫學使用半衰期適中的放射性同位素標幟藥物,配合先進造影設備及影像重組技術,已廣泛用於臨床檢查生理的改變與疾病的發展。由於所使用的放射性同位素衰變模式的差異因而發展出 正子掃描 (PET SCAN)   以及單光子放射電腦斷層造影 (single-photon emission computed tomography; SPECT)。用於 正子掃描 (PET SCAN)  的放射藥物所標幟的放射核種包括碳-11、氮-13、氧-15及氟-18等,衰變時會釋出正子; 正子掃描 (PET SCAN)  即以偵測正子與電子發生互毀反應 (annihilation) 釋出的 511 keV光子,由於偶合電路的設計使PET具備高靈敏度與高解析度的造影優勢。SPECT則使用鎝-99m、碘-123、鉈-201、鎵-67、銦-111等衰變時釋放加馬射線的放射核種標幟的放射藥物, SPECT攝影機需要.直儀 (collimator) 來消除散射加馬射線,造影的靈敏度與解析度不及PET,但設備與放射藥物的費用較 正子掃描 (PET SCAN)  低廉,對於當前核醫檢查仍佔有重要地位。
 

血腦屏障

早期核醫影像診斷腦部疾病僅限於檢查血腦屏障 (blood-brain barrier; BBB)的完整性,使用的放射藥物必須依賴疾病或外傷所引起的的BBB破損才能進入腦內並被檢出。1980年代發展的局部腦血流灌注造影 (brain perfusion imaging) 開始用到能透過BBB、隨腦血流分佈並滯留腦內的放射藥物,包括SPECT造影使用的鎝-99m-HMPAO [1]、鎝-99m-ECD [2]、碘-123-IMP [3],以及PET使用的氧-15水 [4] 等。隨著迴旋加速器 (cyclotron) 的普遍化,被譽為世紀分子的氟-18-FDG (氟化去氧葡萄糖) 也大量用於PET檢查疾病引起的腦部葡萄糖攝取與代謝差異 [5]。
 

神經受體 (receptor)及轉運體 (transporter) 造影

過去十年在發展中樞神經系統特定神經受體 (receptor)及轉運體 (transporter) 造影用放射藥劑有顯著進展。由於早期的PET應用以神經醫學研究為主,因此許多神經受體造影多由PET開始,再延伸到SPECT造影劑的發展與應用。腦多巴胺神經系統的放射性造影劑研發尤其蓬勃,此與帕金森氏病 (Parkinson’s disease; PD) 以及精神分裂症 (schizophrenia) 的病因及治療機制有關。氟-18-FDOPA [6]及放射性同位素標幟古柯鹼 (cocaine) 衍生物被用來檢查與帕金森氏病及動作障礙疾病有關的腦多巴胺神經退化;氟-18-FDOPA PET影像顯示多巴胺神經細胞合成多巴胺的生化機轉,而放射性同位素標幟古柯鹼類似物則為選擇性結合於多巴胺神經節前細胞膜上的轉運體,兩者攝取機制不同,但都能顯現多巴胺神經節前細胞的功能是否完整。這些放射性同位素標幟古柯鹼類似物包括用於PET造影的碳-11-FECIT [7]、氟-18-CFT [8]、氟-18-FPCIT [9]及氟-18-FECNT [10] 等,以及用於SPECT造影的碘-123-IPT [11]、碘-123-β-CIT [12]、碘-123-PE2I [13]、碘-123-FPCIT [14]及鎝-99m-TRODAT-1 [15]等;其中碘-123-FPCIT已於歐洲由GE HealthCare以DatSacn之名上市,鎝-99m-TRODAT-1 已於國內上市,國外由GE HealthCare進行臨床試驗中。
 

腦多巴胺神經系統

針對腦多巴胺神經節後細胞膜上的受體造影,可分為D1受體造影劑及D2/D3受體造影劑兩大類,其中又以D2/D3受體造影劑的研究最為普遍,此與D2受體為主要精神分裂症治療藥的作用位置有很大關聯。文獻發表的D1受體造影劑只有PET造影用的碳-11-SCH 23390 [16]及碳-11-NNC 756 [17];D2/D3受體造影劑則包括用於PET造影的碳-11-raclopride [18]、碳-11-NMSP [19]、氟-18-FMB [20]、氟-18-FIDA-2 [21]、氟-18-DMFP [22]等,以及用於SPECT造影的碘-123-IBZM [23]、碘-123-IBF [24]、碘-123-epidepride [25]、碘-123-FIDA-2 [21]等。
 

情緒與精神狀態有關的血清胺造影

與情緒與精神狀態有關的血清胺 (serotonin) 神經系統的造影研究,近年亦有顯著發展,許多憂鬱症治療藥物的作用即為抑制血清胺轉運體或調控血清胺受體的機能,因此以核分子影像研究血清胺神經系統的發展如雨後春筍。研究血清胺轉運體的放射性造影劑包括用於PET的碳-11-McN 5652 [26]、碳-11-β-CIT [27]、碳-11-nor-βCIT [28]、碳-11-ADAM [29]、碳-11-DAPA [30]、碳-11-AFM [31]、碳-11-DASB [32]、碳-11-MADAM [33]、氟-18-FADAM [34]等,以及用於SPECT造影的碘-123-β-CIT [35]、碘-123- nor-βCIT [36]、碘-123-ADAM [37]等。腦血清胺神經受體造影可分為 5-HT1A受體及5-HT2A受體兩大類造影劑。5-HT1A受體造影劑包括用於PET的碳-11-WAY 100635 [38]、碳-11-DWAY 100635 [39]、氟-18-MPPF [40]、氟-18-DMPPF [41]等;文獻報導鎝-99m-DWAY以體外自動顯影 (in-vitro autoradiography) 顯現5-HT1A受體的分佈,但無後續體內造影的進展。至於5-HT2A受體造影劑則包括用於PET的碳-11-NMSP [42]、碳-11-MDL 100907 [43]、氟-18-setoperone [44]、氟-18-altanserin [45]等,以及用於SPECT造影的碘-123-5-iodo-R91150 [46]。
 

失憶症 (dementia) 有關造影研究

與失憶症 (dementia) 有關造影研究近年集中在與阿爾茲海漠氏症 (Alzheimer's disease) 病理息息相關的 β-amyloid plaques及tangles的造影。氟-18-FDDNP [47]、碳-11-PIB [48]、碳-11-SB-13 [49]的陸續出現為分子影像診斷阿爾茲海漠氏症帶來曙光,其中碳-11-PIB已授權給GE HealthCare作為未來藥物治療阿爾茲海漠氏症的療效評估指標。由於碳-11-PIB的物理半衰期只有20分鐘,不利於較長時間的造影程序,因此未來勢必會有氟-18標幟藥物的後續發展。在SPECT造影劑的研發方面,以賓州大學發展的碘-123-IMPY [50]最具發展潛力。
 
隨著能表現各種神經學疾病的動物模式的陸續建立,加上高解析度的動物造影用PET、SPECT結合CT、MRI影像設備與技術的發展,核醫腦造影已不再侷限於臨床檢查的工具。藉由不斷推陳出新的放射性造影劑研發,未來藉由動物造影研究發展出用於人類診斷及治療的新技術已經成為分子影像醫學的願景。
 

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