Rhenium-188 Labeled Radiopharmaceuticals: Current Clinical Applications in Oncology and Promising Perspectives

Abstract

Rhenium-188 (¹⁸⁸Re) is a high energy beta-emitting radioisotope with a short 16.9 h physical half-life, which has been shown to be a very attractive candidate for use in therapeutic nuclear medicine. The high beta emission has an average energy of 784 keV and a maximum energy of 2.12 MeV, sufficient to penetrate and destroy targeted abnormal tissues. In addition, the low-abundant gamma emission of 155 keV (15%) is efficient for imaging and for dosimetric calculations. These key characteristics identify ¹⁸⁸Re as an important therapeutic radioisotope for routine clinical use. Moreover, the highly reproducible on-demand availability of ¹⁸⁸Re from the ¹⁸⁸W/¹⁸⁸Re generator system is an important feature and permits installation in hospital-based or central radiopharmacies for cost-effective availability of no-carrier-added (NCA) ¹⁸⁸Re. Rhenium-188 and technetium-99 m exhibit similar chemical properties and represent a "theranostic pair." Thus, preparation and targeting of ¹⁸⁸Re agents for therapy is similar to imaging agents prepared with ^99mTc, the most commonly used diagnostic radionuclide. Over the last three decades, radiopharmaceuticals based on ¹⁸⁸Re-labeled small molecules, including peptides, antibodies, Lipiodol and particulates have been reported. The successful application of these ¹⁸⁸Re-labeled therapeutic radiopharmaceuticals has been reported in multiple early phase clinical trials for the management of various primary tumors, bone metastasis, rheumatoid arthritis, and endocoronary interventions. This article reviews the use of ¹⁸⁸Re-radiopharmaceuticals which have been investigated in patients for cancer treatment, demonstrating that ¹⁸⁸Re represents a cost effective alternative for routine clinical use in comparison to more expensive and/or less readily available therapeutic radioisotopes.

Keywords: Rhenium-188; bone pain palliation; oncology; peptides; radioembolization; radionuclide therapy; radiopharmaceuticals.

Figure 1

Number of publications/year on clinical use of ¹⁸⁸Re, ¹⁷⁷Lu and, ⁹⁰Y over the last 30 years. (A) data from Sci-Finder, ^©2019 American Chemical Society, (B) data from Web of Science, ^©2019 Clarivate Analytics.

Figure 2

The useful shelf-life of the ORNL alumina-based ¹⁸⁸W/¹⁸⁸Re generator shows consistently high ¹⁸⁸Re-perrhenate yields and low ¹⁸⁸W breakthrough over at least 2 months (Image property of ORNL, courtesy of Dr. Russ Knapp, Oak Ridge, TN).

Figure 3

¹⁸⁸Re-DMSA isomers.

Figure 4

Typical distribution of ¹⁸⁸Re-HEDP, 24 h post-injection [from Shinto et al. (105), available under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike License (CC BY-NC-SA)].

Figure 5

Patient from Phase Ia study with mediastinal and lung metastases: top panel—¹⁸FDG PET/CT 10 days before the study, lower panel—SPECT/CT of ¹⁸⁸Re-6D2 mAb at 2 h after injection [from Klein et al. (156), available under the terms of the Creative Commons Attribution (CC BY)].

Figure 6

Structure of ¹⁸⁸ReO-P2045.

Figure 7

Example of ¹⁸⁸Re-SSS biodistribution profile. Whole-body scintigraphy at 1 and 72 h (A) and SPECT/CT at 1 h (B) (Courtesy of Prof. Etienne Garin, Rennes, France).

Figure 8

Kaplan-Mayer surviving curves for patients (N = 13) after radioembolization of liver tumors with ¹⁸⁸Re-HSA microspheres [from Nowicki et al. (207), available under the terms of the Creative Commons Attribution Non Commercial-No Derivs 3.0 (CC BY-NC-ND 3.0)].

Figure 9

Kaplan Meier curves of mice treated with saline solution (PBS), blank LNC, immuno-LNCs (12G5-LNCs and IgG2a-LNCs) and internal radiation therapies (LNC¹⁸⁸Re, IgG2a-LNC¹⁸⁸Re, and 12G5-LNC¹⁸⁸Re) after single infusion through convection-enhanced delivery into CXCR4-positive brain tumors [from Séhédic et al. (214), available under the terms of the Creative Commons Attribution Non Commercial 4.0 (CC BY-NC 4.0)].

Figure 10

Rhenium-SCT device developed by OncoBeta^® GmbH (Garching, Germany). Applicator and dispensing carpoules filled with ¹⁸⁸Re-cream (A) and illustration of the principle (B) (Courtesy of Dr. Shannon Brown III, OncoBeta®).