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Elly L. van der Veen, Frans V. Suurs, Frederik Cleeren, Guy Bormans, Philip H. Elsinga, Geke A.P. Hospers, Marjolijn N. Lub-de Hooge, Elisabeth G.E. de Vries, Erik F.J. de Vries and Inês F. Antunes

Journal of Nuclear Medicine Sept. 2020, 6(9) 1355-1360; DOI:10.2967/jnumed.119.238782

Abstract

Recently, N-(4-¹⁸F-fluorobenzoyl)-interleukin-2 (¹⁸F-FB-IL2) was introduced as a PET tracer for T cell imaging. However, production is complex and time-consuming. Therefore, we developed 2 radiolabeled IL2 variants, namely aluminum ¹⁸F-fluoride-(restrained complexing agent)-IL2 (¹⁸F-AlF-RESCA-IL2) and ⁶⁸Ga-gallium-(1,4,7-triazacyclononane-4,7-diacetic acid-1-glutaric acid)-IL2 (⁶⁸Ga-Ga-NODAGA-IL2), and compared their in vitro and in vivo characteristics with ¹⁸F-FB-IL2. 

Methods: Radiolabeling of ¹⁸F-AlF-RESCA-IL2 and ⁶⁸Ga-Ga-NODAGA-IL2 was optimized, and stability was evaluated in human serum. Receptor binding was studied with activated human peripheral blood mononuclear cells (hPBMCs). Ex vivo tracer biodistribution in immunocompetent BALB/cOlaHsd (BALB/c) mice was performed at 15, 60, and 90 min after tracer injection. In vivo binding characteristics were studied in severe combined immunodeficient (SCID) mice inoculated with activated hPBMCs in Matrigel. Tracer was injected 15 min after hPBMC inoculation, and a 60-min dynamic PET scan was acquired, followed by ex vivo biodistribution studies. Specific uptake was determined by coinjection of tracer with unlabeled IL2 and by evaluating uptake in a control group inoculated with Matrigel only. 

Results: ⁶⁸Ga-Ga-NODAGA-IL2 and ¹⁸F-AlF-RESCA-IL2 were produced with radiochemical purity of more than 95% and radiochemical yield of 13.1% ± 4.7% and 2.4% ± 1.6% within 60 and 90 min, respectively. Both tracers were stable in serum, with more than 90% being intact tracer after 1 h. In vitro, both tracers displayed preferential binding to activated hPBMCs. Ex vivo biodistribution studies on BALB/c mice showed higher uptake of ¹⁸F-AlF-RESCA-IL2 than of ¹⁸F-FB-IL2 in liver, kidney, spleen, bone, and bone marrow. ⁶⁸Ga-Ga-NODAGA-IL2 uptake in liver and kidney was higher than ¹⁸F-FB-IL2 uptake. In vivo, all tracers revealed uptake in activated hPBMCs in SCID mice. Low uptake was seen after a blocking dose of IL2 and in the Matrigel control group. In addition, ¹⁸F-AlF-RESCA-IL2 yielded the highest-contrast PET images of target lymph nodes. 

Conclusion: Production of ¹⁸F-AlF-RESCA-IL2 and ⁶⁸Ga-Ga-NODAGA-IL2 is simpler and faster than that of ¹⁸F-FB-IL2. Both tracers showed good in vitro and in vivo characteristics, with high uptake in lymphoid tissue and hPBMC xenografts.