Abstract
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Introduction: Intrathecal (IT) administration is experiencing renewed interest as a potential delivery method for large molecules, such as antisense oligonucleotides, in the treatment of a broad range of neurodegenerative disorders. Imaging is a useful tool for assessing the biodistribution of such intrathecally administered molecules, particularly given the complex physiology and fluid flow associated with the CSF and the leptomeningeal space. The relatively slow CSF flow coupled with the long biological half-life of large molecules make longer-lived isotopes especially attractive for many intrathecal imaging applications. However, longer-lived isotopes are often associated with higher radiation absorbed dose and computation of absorbed dose from intrathecal administration requires special consideration compared to systemically administered tracers. Previously, a custom intrathecal dosimetry model was developed and applied to intrathecally administered 99mTc-DTPA planar imaging data, using two different volumes of injected activity (5mL, 15mL) [1]. In this work, this dosimetry model was extended to evaluate radiation absorbed dose in several other tracers, including 18F, 68Ga, 89Zr, 111In, 123I, and 131I.
Methods: Previously acquired 99mTc-DTPA time-activity curves (TACs) were modified based on isotope-specific half-life to simulate expected TACs from each of these tracers, including source regions of brain, brain ventricles, liver, bladder, lumbar CSF, lower/upper thoracic CSF, and cervical CSF regions. Example brain TACs for each isotope are shown in Figure 1. Additionally, a failed administration worst-case scenario was simulated by assuming all administered activity remained in the lumbar CSF compartment, clearing only as a result of radioactive decay. Trapezoidal integration was utilized for mean residence time (MRT) calculation of measured timepoints with tail uptake being estimated using a bi-exponential fit to each individual TAC. Application of isotope- and source-specific voxel-level absorbed dose per unit cumulated activity maps were used to generate absorbed dose estimates in all source regions as well as several additional target regions such as vertebral bone and marrow sub-regions.
Results: Self-dose to CSF+cord source/target regions is highest in all cases. Exclusive of these regions, the dose-limiting region depends upon the injected volume with lumbar vertebral marrow being the dose-limiting organ in the 5mL administration (~1200 MBq lumbar vertebral marrow vs ~1500 MBq brain) and “failed” administration (~300 MBq vs ~7.5e6 MBq) scenarios but brain being the dose-limiting organ in the 15mL administration (~2600 MBq vs ~1100 MBq). In all cases, the allowed injected activity of 99mTc is high, with a safe level of ~8 mCi (~300 MBq) even in the “failed” administration situation. Absorbed dose values per isotope relative to 99mTc for high uptake and peripheral organs is shown in Table 2.
Conclusions: The unique distribution properties inherent to intrathecal administration have ramifications in the selection of imaging isotope and administration methodology (e.g., injected volume). Use of 99mTc is safe, even in situations of a failed tracer administration. Use of longer-lived isotopes, especially 89Zr and 131I, requires additional consideration and careful planning. [1] Hesterman, Jacob Y., et al. "Three-dimensional dosimetry for radiation safety estimates from intrathecal administration." Journal of Nuclear Medicine 58.10 (2017): 1672-1678. Figure 1: Brain time-activity curves generated from the average (N = 3) of 15mL injected volume 99mTc-DTPA, administered intrathecally. The reference line (black) indicates the TAC from the original 99mTc-DTPA with decay removed.