⁶⁴Cu-DOTA Enables Late PET Imaging and Leak Detection in the Cerebrospinal Fluid Space

TO THE EDITOR: Recently, PET of the cerebrospinal fluid (CSF) space with [⁶⁸Ga]Ga-DOTA has been proposed as a fast and convenient approach for verification of spinal CSF leaks (1). PET-based radiocisternography with [⁶⁸Ga]Ga-ethylenediaminetetraacetic acid, [⁵⁵Co]Co-diethylenetriaminepentaacetic acid (DTPA), and [⁶⁴Cu]Cu-DTPA was reported as early as 1982 (2,3). We would like to highlight the existence of another tracer, [⁶⁴Cu]Cu-DOTA, for CSF space imaging.

The advantage of ⁶⁸Ga-based radiotracers is the wide availability of ⁶⁸Ga and a generally convenient and fast production via metal chelation. The disadvantage is the short half-life of 68 min, impairing imaging of slow or intermittent processes. Therefore, the radiopharmaceutical production of [⁶⁴Cu]Cu-DOTA, with a half-life of 12.7 h, has been established in our clinic in compliance with standards of good manufacturing practice (4,5).

Since 2018, 5 patients with intracranial hypotension, in whom CT or MRI as well as radionuclide cisternography with [¹¹¹In]In-DTPA were inconclusive, underwent PET/CT of the CSF space in the Clinic of Nuclear Medicine, Jena University Hospital, Germany. No immediate or late complications occurred after lumbar intrathecal [⁶⁴Cu]Cu-DOTA injection. In 3 cases, a spinal CSF leak was identified.

Because of the shorter positron range of ⁶⁴Cu than of ⁶⁸Ga, the PET image quality of [⁶⁴Cu]Cu-DOTA can be expected to be superior to that of [⁶⁸Ga]Ga-DOTA, enabling location and identification of small CSF leaks (6). This high image quality is maintained during delayed imaging performed 20 h after injection and may be particularly helpful to locate craniocervical CSF leaks after surgical procedures (case example available in (7)).

Intrathecal injection of CT or MRI contrast agents has been associated with a high probability of adverse events (8,9). Also, [¹¹¹In]In-DTPA injections have caused neurologic reactions due to ion sequestration in the CSF caused by excess chelator (10,11). The CSF is a sensible system, exhibiting few proteins and limited buffering capability. Formulations administered into the CSF space should contain ingredients in the smallest possible quantities. The amount of precursor in [⁶⁴Cu]Cu-DOTA is lower by a factor of 1,000 than that in CT or MRI contrasts agent, which makes [⁶⁴Cu]Cu-DOTA safer for intrathecal injections (5). pH, osmolality, and a low-salt concentration of [⁶⁴Cu]Cu-DOTA are optimally adjusted to the CSF fluid. In contrast, the [⁶⁸Ga]Ga-DOTA preparation as reported by Evangelou et al. (1) may contain elevated concentrations of NaCl and sodium acetate due to the acidic labeling conditions of ⁶⁸Ga (3). Furthermore, [⁶⁴Cu]Cu-DOTA production can be performed up to 24 h before administrations, thus granting a longer time frame for application than is possible with [⁶⁸Ga]Ga-DOTA.

With regard to the cost and yet limited availability of ⁶⁴Cu, PET cisternography with [⁶⁴Cu]Cu-DOTA is seen as a reserve, but important, method in difficult cases with intracranial hypertension. Because of the long half-life of the tracer and the high-resolution capabilities of PET/CT, and ⁶⁴Cu PET/CT in particular, localization of slow-flow CSF leaks in patients with intracranial hypotension can be enabled. The next research step will be dosimetric evaluation of the new tracer.

• © 2024 by the Society of Nuclear Medicine and Molecular Imaging.

• Received for publication January 30, 2024.
• Revision received February 13, 2024.