背景:放射性杂交前列腺特异性膜抗原(rhPSMA)配体,例如18F-rhPSMA-7,是前列腺癌临床开发中的一类新型治疗诊断药物。我们比较了18F-rhPSMA-7与单一非对映异构体形式的临床前剂量测定和人类生物分布,18F-rhPSMA-7.3。
方法:用在注射25.6±3.6MBq18F-rhPSMA-7或28.5±4.8MBq18F-rhPSMA-7.3后多个时间点(10-300分钟)处死的SCID小鼠进行临床前剂量测定(n=每个时间点3-6只小鼠)。心,肺,肝脏,脾,脾胰腺,脂肪,胃,小肠,大肠,肾,肌肉,骨头,膀胱,睾丸,尾巴,收集脑组织,收集尿液和血液样本。计算每克注射剂量的百分比。吸收剂量用OLINDA/EXM1.0估算。使用18F-rhPSMA-7(n=47)和18F-rhPSMA-7.3(n=33)PET/CT检查来估计人类生物分布。平均(范围)注射活动为324(236-424)MBq与345(235-420)MBq,18F-rhPSMA-7和18F-rhPSMA-7.3的采集时间分别为84(42-166)和76(59-122)分钟。SUVmean被确定为背景(臀肌),正常器官(唾液腺,血池,肺,肝脏,脾,脾胰腺,十二指肠,肾,膀胱,骨)和多达三个代表性的肿瘤病变。定性分析评估图像质量,非特异性血池活动,和使用3/4点量表在骨/骨髓中的背景摄取。
结果:临床前剂量测定显示,在3.5h和1h膀胱排尿间隔,18F-rhPSMA-7的外推总有效剂量分别为26.6和12.2µSv/MBq,18F-rhPSMA-7.3的外推总有效剂量分别为21.7和12.8µSv/MBq.两种药物的人体生物分布在其他PSMA配体中是典型的,并且彼此大致相似;SUVmean分别为16.9和16.2(腮腺),19.6对19.9(颌下腺),2.0对1.9(血池,p<0.005),0.7对0.7(肺),7.0对7.3(肝脏),9.1对8.4(脾),32.4对35.7(肾),2.5对2.8(胰腺),10.9对11.0(十二指肠),对于18F-rhPSMA-7和18F-rhPSMA-7.3,分别为1.1对1.3(骨)和4.6对2.0(膀胱;p<0.001)。18F-rhPSMA-7.3(32.5±42.7,n=63个病灶)的肿瘤SUV均值高于18F-rhPSMA-7(20.0±20.2,n=89个病灶)。
结论:辐射剂量学对两种药物都有利。辐射暴露,假设排尿间隔为1小时,注入370MBq后小于5mSv。18F-rhPSMA-7.3显示膀胱摄取显著降低,与18F-rhPSMA-7相比,肿瘤的摄取趋势更高。
BACKGROUND: Radiohybrid prostate-specific membrane antigen (
rhPSMA) ligands such as 18F-
rhPSMA-7 are a new class of theranostic agents in clinical development for prostate cancer. We compared preclinical dosimetry and human biodistribution of 18F-rhPSMA-7 with that of single diastereoisomer form, 18F-
rhPSMA-7.3.
METHODS: Preclinical dosimetry was performed with SCID-mice sacrificed at multiple timepoints (10-300 min) post-injection of 25.6 ± 3.6 MBq 18F-rhPSMA-7 or 28.5 ± 4.8 MBq 18F-rhPSMA-7.3 (n = 3-6 mice per timepoint). Heart, lung, liver, spleen, pancreas, fat, stomach, small intestine, large intestine, kidney, muscle, bone, bladder, testicles, tail, and brain tissue were harvested, and urine and blood samples collected. Percentage of injected dose per gram was calculated. Absorbed doses were estimated with OLINDA/EXM 1.0. 18F-
rhPSMA-7 (n = 47) and 18F-
rhPSMA-7.3 (n = 33) PET/CT exams were used to estimate human biodistribution. Mean (range) injected activities were 324 (236-424) MBq versus 345 (235-420) MBq, and acquisition times were 84 (42-166) versus 76 (59-122) minutes for 18F-rhPSMA-7 versus 18F-
rhPSMA-7.3, respectively. SUVmean was determined for background (gluteal muscle), normal organs (salivary glands, blood pool, lung, liver, spleen, pancreas, duodenum, kidney, bladder, bone) and up to three representative tumour lesions. Qualitative analyses assessed image quality, non-specific blood pool activity, and background uptake in bone/marrow using 3/4-point scales.
RESULTS: Preclinical dosimetry revealed that at 3.5 h and 1 h bladder voiding intervals, the extrapolated total effective doses were 26.6 and 12.2 µSv/MBq for 18F-rhPSMA-7 and 21.7 and 12.8 µSv/MBq for 18F-rhPSMA-7.3 respectively. Human biodistribution of both agents was typical of other PSMA-ligands and broadly similar to each other; SUVmean were 16.9 versus 16.2 (parotid gland), 19.6 versus 19.9 (submandibular gland), 2.0 versus 1.9 (blood pool, p < 0.005), 0.7 versus 0.7 (lungs), 7.0 versus 7.3 (liver), 9.1 versus 8.4 (spleen), 32.4 versus 35.7 (kidney), 2.5 versus 2.8 (pancreas), 10.9 versus 11.0 (duodenum), 1.1 versus 1.3 (bone) and 4.6 versus 2.0 (bladder; p < 0.001) for 18F-rhPSMA-7 versus 18F-
rhPSMA-7.3, respectively. Tumour SUVmean was higher for 18F-
rhPSMA-7.3 (32.5 ± 42.7, n = 63 lesions) than for 18F-
rhPSMA-7 (20.0 ± 20.2, n = 89 lesions).
CONCLUSIONS: Radiation dosimetry is favourable for both agents. Radiation exposure, assuming a 1 h voiding interval, is less than 5 mSv after injection of 370 MBq. 18F-rhPSMA-7.3 showed significantly lower bladder uptake, and a higher uptake trend in tumours compared with 18F-rhPSMA-7.