Establishing Radiolanthanum Chemistry for Targeted Nuclear Medicine Applications

Abstract

We report the first targeted nuclear medicine application of the lanthanum radionuclides 132/135La. These isotopes represent a matched pair for diagnosis via the positron emissions of 132La and therapy mediated by the Auger electron emissions of 135La. We identify two effective chelators, known as DO3Apic and macropa, for these radionuclides. The 18‐membered macrocycle, macropa, bound 132/135La with better molar activity than DO3Apic under similar conditions. These chelators were conjugated to the prostate‐specific membrane antigen (PSMA)‐targeting agent DUPA to assess the use of radiolanthanum for in vivo imaging. The 132/135La‐labeled targeted constructs showed high uptake in tumor xenografts expressing PSMA. This study validates the use of these radioactive lanthanum isotopes for imaging applications and motivates future work to assess the therapeutic effects of the Auger electron emissions of 135La.

Towards the stable chelation of radium for biomedical applications with an 18-membered macrocyclic ligand

“…To probe the potential of TAT using 223 Ra, macropa-NCS was conjugated to a glutamate–urea–glutamate (DUPA) targeting vector. 54 This DUPA targeting vector binds with high affinity to the PSMA, which is overexpressed on prostate cancer adenocarcinoma cells. Macropa-DUPA was found to chelate Ba 2+ effectively (Fig.…”

High yield cyclotron production of a novel 133/135La theranostic pair for nuclear medicine

“…High LET Auger electron emissions have achieved encouraging clinical results, with 111 In-DTPA-octreotide and 125 I-IUdR causing tumor remissions in patients with lower normal tissue toxicity, and improvements in the survival of glioblastoma patients using 125 I-mAb 425 with minimal normal tissue toxicity 4 . A recently developed theranostic pair is 132/135 La, where positron emissions from 132 La are used for PET imaging while the Auger electrons from 135 La have the potential for use in Auger electron therapy (AET) [5][6][7] . Theranostic La pairs are not only inherently useful but also can serve as surrogates for potential future study relating to 225 Ac alpha-particle therapy.…”

Cyclotron produced 132La as a PET imaging surrogate of therapeutic 225Ac

“…Chemical similarities between these two ions have been exploited to unravel the chemistry of actinium and stable lanthanum has been instrumental to the design of novel chelators that stably retain 225 Ac in vivo (13). Although the potential of different radiolanthanums as PET imaging surrogate of 225 Ac has been proposed (7)(8)(9), to date, no direct comparison between the in vivo distribution of a radioactive compound labeled to Ac or La has been performed. Thanks to a half-life of several hours, higher positron branching ratio and simpler, scalable production on low energy cyclotrons, we chose 132 La from the unstable lanthanum radioisotopes with positron emissions.…”

“…Irradiations of nat Ba also produce the low-energy electron-emitting radionuclide 135 La (t1/2 = 19.93h, 100%EC). Under these irradiation conditions (11.9MeV, 20µA, 3h), typical 132 La and 135 La decay corrected physical yields were 0.26 and 5.6 MBq µA -1 , respectively (7,8). Radiochemical isolation of 132/135 La 3+ ( 13x La 3+ ) was performed by precipitation and single-column extraction chromatography as previously described (7).…”

“…Other radionuclides (e.g., 68 Ga) with significant chemical dissimilarity to actinium are currently employed for this purpose, despite reports that the choice of radionuclide can affect the pharmacokinetics of radiopharmaceuticals (6). We and others hypothesize that lanthanum-labeled agents' biodistribution mirrors actinium agents' in vivo (7)(8)(9), but this hypothesis is yet to be tested. Our goal is to evaluate the potential of positron-emitting 132 La (T1/2=4.59h, 42% ß + ) as PET imaging surrogate of 225 Ac with a well-characterized, tumor-targeting alkylphosphocholine (NM600) developed by our group and used for TRT applications with 90 Y, 177 Lu, and 225 Ac (10)(11)(12).…”