[134Ce]Ce-RPS-088 as a PET Imaging Surrogate for [225Ac]Ac-RPS-088 in a Model of Prostate Cancer: Early Preclinical Evaluation

Introduction: Only small activities of Ac-225, in the range of 100 kBq/kg per cycle, are required in targeted alpha therapy (TAT) to achieve a decline in prostate-specific antigen (PSA) values in patients with metastatic castration-resistant prostate cancer (mCRPC).^a Although the short tissue range of α-particles largely spares the surrounding healthy tissue, accumulation in off-target and/or excreting organs can cause severe side effects. In fact, xerostomia is the dose limiting factor in the treatment of mCRPC patients with ²²⁵Ac-labeled PSMA-targeting radiotherapeutics.^a Actinium-225 cannot be detected directly using non-invasive imaging techniques, meaning that imaging surrogates that closely mimic the pharmacokinetics of ²²⁵Ac-labeled therapeutics and allow for accurate dosimetry calculations are required. Widely available radioisotopes for this task are limited by a poor half-life match with Ac-225 or poor complexation by macrocylic chelators that bind [²²⁵Ac]Ac³⁺. This is particularly true for radiopharmaceuticals containing macropa, which selectively complexes [²²⁵Ac]Ac³⁺ at room temperature in exceptionally high molar activity.^b Our aim was to evaluate the Ce-134/La-134 pair as an imaging surrogate for macropa-containing ²²⁵Ac-radiopharmaceuticals.

Methods: [¹³⁴Ce]Ce³⁺ (t_1/2 = 3.16 d) decays to lanthanum-134 (t_1/2 = 6.5 min), which in turn emits positrons that are suitable for positron emission tomography (PET) imaging. [¹³⁴Ce]Ce-RPS-088 was synthesized and administered to LNCaP-bearing athymic nude mice. Labeling was performed at room temperature in 0.1 M Tris-HCl buffer (pH 8.5), and labeling yield determined by radio-TLC in 50 mM citrate, pH 5.0. The mice were imaged by µPET/CT at 2 h, 24 h, 48 h and 72 h post-injection. A comparative biodistribution study of [²²⁵Ac]Ac-RPS-088 and [¹³⁴Ce]Ce-RPS-088 was carried out in LNCaP xenografts (n = 4). In a pilot intrasubject study with 2 mice, both compounds were co-injected into each animal to determine whether the activities in each organ can be calculated as a function of A_total = A_Ac-225 + A_Ce-134 after repeated measurements in a γ-counter. Finally, the stability of [¹³⁴Ce]Ce-RPS-088 in human and mouse serum as well as in the presence of an excess of DTPA was analyzed and compared to [²²⁵Ac]Ac-RPS-088.

Results: In accordance with earlier studies,^c the radiochemical conversion (RCC) of the complexation of [¹³⁴Ce]Ce³⁺ by macropa-conjugated RPS-088 was fast (>90 % after 5 min). Tumor accumulation of [¹³⁴Ce]Ce-RPS-088 in the LNCaP xenografts was clearly visible in the PET scans up to 72 h p.i., excretion of the compound was mainly renal. At 23 h p.i., the biodistribution and tumor accumulation of [¹³⁴Ce]Ce-RPS-088 (29.3 ± 10.7 % ID/g) was comparable to [²²⁵Ac]Ac-RPS-088 (36.4 ± 6.3 % ID/g) in both the intra- and intersubject analyses with the exception of the kidneys, where the uptake of the [¹³⁴Ce]Ce-labeled compound was substantially lower (19.4 ± 8.3 %ID/g and 73.0 ± 16.2 %ID/g, respectively). Calculation and separation of activities corresponding to [¹³⁴Ce]Ce-RPS-088 and [²²⁵Ac]Ac-RPS-088, respectively, in the 2 co-injected mice showed a similar biodistribution pattern as was observed for the mice that had been injected separately with either compound. Slow release of small amounts of [¹³⁴Ce]Ce³⁺ from [¹³⁴Ce]Ce-RPS-088 was observed over 3 days in human and mouse serum as well as in a 1,000 fold excess of DTPA.

Conclusions: The rapid complexation of [¹³⁴Ce]Ce³⁺ by macropa, acceptable in vitro and in vivo stability of the [¹³⁴Ce]Ce³⁺-macropa complex and ability to image La-134 with PET, make Ce-134 a suitable candidate for the dosimetry calculations of macropa-containing ²²⁵Ac-labeled therapeutics. The impact of the reduced renal uptake needs to be confirmed and analyzed in future studies.

References:

^aJ Nucl Med 2017;58:1624, J Nucl Med 2018;59:795. ^bAngew Chem Int Ed 2017;56:14712. ^cJ Nucl Med. 2023;64:1076.