Potential of ¹⁸⁸Re as an Alternative to ¹⁷⁷Lu and Dosimetric Consequences

TO THE EDITOR: We read with interest the article “PSMA-GCK01: A Generator-Based ^99mTc/¹⁸⁸Re Theranostic Ligand for the Prostate-Specific Membrane Antigen” in The Journal of Nuclear Medicine (1). It is noteworthy that kidney accumulation of ¹⁸⁸Re-PSMA-GCK01 in LNCaP tumor–bearing mice was found to be 14 times higher than tumor uptake 1 h after injection and 9 times higher 2 h after injection (1).

It is worthwhile to investigate ¹⁸⁸Re as an alternative to ¹⁷⁷Lu, because accredited ¹⁷⁷Lu radiopharmaceuticals are available and the amount of ¹⁷⁷Lu is limited. Further alternatives such as ¹⁶¹Tb (2) or ⁶⁷Cu (3) are moving into the focus of clinical research and could have even better therapeutic properties because of the coemission of Auger–Meitner electrons.

However, the kidney geometry in small animals is not representative for humans regarding geometry and pathlengths of the β-emission. Recently, Vargas et al. presented a method to understand the heterogeneity of absorbed doses in the kidneys of mice (4). In humans, the heterogeneity of absorbed doses in, for example, kidneys is crucial for the application of therapeutic radiopharmaceuticals (5). Hence, studies in pigs (single kidney weight, 125 g for pig vs. 150 g for human) may be required. Further, most patients currently receive radionuclide therapy as the last line of treatment after previous hormone and chemotherapy, so that bone marrow and kidney function may already be predamaged. This effect, too, can neither be simulated nor reproduced in animal experiments but requires clinical testing.

In our own efforts on ¹⁸⁸Re-PSMA derivatives, we found that biokinetics must be considered in terms of the physical half-life of the applied isotopes: at 17 h (¹⁸⁸Re) versus 6.6 d (¹⁷⁷Lu), the initial phase is more significant for ¹⁸⁸Re, and this is the phase with the greatest renal accumulation or excretion. Dosimetric calculations for ¹⁷⁷Lu-PSMA by Kurth et al. revealed kidney doses between 2.9 and 3.7 Gy, depending on the therapeutic cycle (6). On the basis of the effective half-lives for the kidneys that were reported, we calculated the biologic half-life for PSMA in the kidneys. We identified the expected effective half-life for ¹⁸⁸Re-PSMA by assuming a biodistribution identical to that for ¹⁷⁷Lu-PSMA and using the physical half-life for ¹⁸⁸Re. The calculated number of ¹⁸⁸Re decay in the kidneys was found to be approximately 66% lower than that of ¹⁷⁷Lu-PSMA decay. Nevertheless, the S value, S(kidney←kidney), for ¹⁸⁸Re is 5 times higher than that for ¹⁷⁷Lu. This means that the dose to the kidney is expected to be 1.7 times higher when using the same activity for ¹⁸⁸Re-PSMA as for ¹⁷⁷Lu-PSMA. The dose would be even higher when the initial kidney biokinetic is considered more accurately by assuming a linear accumulation within the first 2 h (6).

Furthermore, radiation biology must be considered, as higher activity levels must be used to achieve the same dose because of the shorter half-life of ¹⁸⁸Re. The authors used the same activity of ¹⁸⁸Re-PSMA and ¹⁷⁷Lu-PSMA (3.7 GBq) (1). Assuming an identical tumor uptake in a lesion with a mass of 10 g, the absorbed dose of ¹⁸⁸Re will be only 51% of the absorbed dose of ¹⁷⁷Lu. Hence, in therapeutic applications, the activity of ¹⁸⁸Re must be twice the activity of ¹⁷⁷Lu to achieve the same tumor dose. Furthermore, the various effective half-lives must be considered with respect to cellular repair mechanisms. The biologically effective dose is expected to be about 25% higher from ¹⁸⁸Re than from ¹⁷⁷Lu for equal absorbed doses. In conclusion, it is necessary to consider the dosimetric consequences carefully when replacing ¹⁷⁷Lu with ¹⁸⁸Re as mentioned above.

• © 2023 by the Society of Nuclear Medicine and Molecular Imaging.

• Received for publication May 17, 2023.
• Revision received June 14, 2023.