Suthiram Janine, Ebenhan Thomas, Marjanovic-Painter Biljana, Sathekge Mike M, Zeevaart Jan Rijn
Radiochemistry, The South African Nuclear Energy Corporation (Necsa), Brits 0240, South Africa.
Department of Nuclear Medicine, University of Pretoria, Pretoria 0001, South Africa.
Pharmaceutics. 2021 Aug 25;13(9):1326. doi: 10.3390/pharmaceutics13091326.
Substance P (SP) is a small peptide commonly known as a preferential endogenous ligand for the transmembrane neurokinin-1 receptor. Nuclear Medicine procedures currently involve radiolabeled SP derivatives in peptide radioligand endotherapy of inoperable glioblastoma. Promising clinical results sparked the demand for facile production strategies for a functionalized 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid-[Thi, Met(O)]-SP to allow for rapid Gallium-68 or Bismuth-213 complexation. Therefore, we provide a simple kit-like radiotracer preparation method that caters for the gallium-68 activity eluted from a SnO generator matrix as well as preliminary results on the adaptability to produce [Bi]Bi-DOTA-[Thi, Met(O)]SP from the same vials containing the same starting material. Following a phase of radioanalysis for complexation of gallium-68 to DOTA-[Thi, Met(O)]SP and assessing the radiolabeling parameters, the vials containing appropriate kit-prototype material were produced in freeze-dried batches. The facile radiolabeling performance was tested and parameters for future human application were calculated to meet the criteria for theranostic loco-regional co-administration of activity doses comprising [Ga]Ga-DOTA-[Thi, Met(O)]SP mixed with [Bi]Bi-DOTA-[Thi, Met(O)]SP. [Ga]Ga-DOTA-[Thi, Met(O)]SP was prepared quantitatively from lyophilized starting material within 25 min providing the required molar activity (18 ± 4 GBq/µmol) and activity concentration (98 ± 24 MBq/mL), radiochemical purity (>95%) and sustained radiolabeling performance (4 months at >95% LE) as well as acceptable product quality (>95% for 120 min). Additionally, vials of the same starting materials were successfully adapted to a labeling strategy available for preparation of [Bi]Bi-DOTA-[Thi, Met(O)]SP providing sufficient activity for 1-2 human doses. The resultant formulation of [Ga]Ga-/[Bi]Bi-DOTA-[Thi, Met(O)]SP activity doses was considered of adequate radiochemical quality for administration. This investigation proposes a simple kit-like formulation of DOTA-[Thi, Met(O)]SP-a first-line investigation into a user friendly, straightforward tracer preparation that would warrant efficient clinical investigations in the future. Quantitative radiolabeling was accomplished for [Ga]Ga-DOTA-[Thi, Met(O)]SP and [Bi]Bi-DOTA-[Thi, Met(O)]SP preparations; a key requirement when addressing the specific route of catheter-assisted co-injection directly into the intratumoral cavities.
P物质（SP）是一种小肽，通常被认为是跨膜神经激肽-1受体的优先内源性配体。核医学程序目前在无法手术的胶质母细胞瘤的肽放射性配体治疗中涉及放射性标记的SP衍生物。有前景的临床结果引发了对功能化的1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸-[硫代，甲硫氨酸（O）]-SP简便生产策略的需求，以实现快速的镓-68或铋-213络合。因此，我们提供了一种简单的试剂盒样放射性示踪剂制备方法，该方法适用于从SnO发生器基质中洗脱的镓-68活性，以及关于从含有相同起始材料的相同小瓶中制备[铋]铋-DOTA-[硫代，甲硫氨酸（O）]SP的适应性的初步结果。在对镓-68与DOTA-[硫代，甲硫氨酸（O）]SP的络合进行放射性分析并评估放射性标记参数的阶段之后，含有适当试剂盒原型材料的小瓶以冻干批次生产。测试了简便的放射性标记性能，并计算了未来人体应用的参数，以满足包含[镓]镓-DOTA-[硫代，甲硫氨酸（O）]SP与[铋]铋-DOTA-[硫代，甲硫氨酸（O）]SP混合的活性剂量的治疗诊断局部区域联合给药标准。[镓]镓-DOTA-[硫代，甲硫氨酸（O）]SP在25分钟内由冻干的起始材料定量制备，提供所需的摩尔活度（18±4 GBq/μmol）和活度浓度（98±24 MBq/mL）、放射化学纯度（>95%）和持续的放射性标记性能（4个月时>95%的放化纯）以及可接受的产品质量（120分钟时>95%）。此外，相同起始材料的小瓶成功地适应了可用于制备[铋]铋-DOTA-[硫代，甲硫氨酸（O）]SP的标记策略，为1-2个人剂量提供了足够的活性。所得的[镓]镓-/[铋]铋-DOTA-[硫代，甲硫氨酸（O）]SP活性剂量制剂被认为具有足够的放射化学质量用于给药。本研究提出了一种简单的试剂盒样DOTA-[硫代，甲硫氨酸（O）]SP制剂——对用户友好、直接的示踪剂制备的首次研究，这将保证未来高效的临床研究。[镓]镓-DOTA-[硫代，甲硫氨酸（O）]SP和[铋]铋-DOTA-[硫代，甲硫氨酸（O）]SP制剂实现了定量放射性标记；这是直接通过导管辅助共同注射到瘤内腔的特定途径时的关键要求。
