Background: Targeted alpha therapy with Ac-225 has demonstrated success in patients with metastatic castration resistant prostate cancer who have progressed on all other available treatment strategies.^a Presently, standardized doses are administered, in part because the low therapeutic activities and the complex decay chain of Ac-225 complicate the calculation of a personalized patient dose.^b [¹³⁴Ce]Ce³⁺ has chemical and physical properties that match well with [²²⁵Ac]Ac³⁺ and decays by electron capture to positron-emitting La-134 (t_1/2 = 6.5 min).^c On this basis, we hypothesize that ¹³⁴Ce-labeled compounds could be used to predict Ac-225 dose by PET imaging. The aim of this study is to assess the suitability of Ce-134 as an imaging surrogate for Ac-225 in a preclinical prostate cancer model.

Methods: RPS-088^d was labeled with Ce-134 or Ac-225 in 20min in 0.1M NaOAc, pH 6 at 95 °C. Comparative biodistribution studies (n=4) of 3.1-3.7 MBq [¹³⁴Ce]Ce-RPS-088 (1.6-2.5 MBq/nmol) and 50 kBq [²²⁵Ac]Ac-RPS-088 (0.17-0.32 MBq/nmol) were carried out in LNCaP xenograft mice (n=4) 6h, 23h, and 72h post-injection (p.i.). Prior to euthanasia, 30 min static PET images were acquired. Two additional mice were co-administered 1.6 MBq [¹³⁴Ce]Ce-RPS-088 and 50 kBq [²²⁵Ac]Ac-RPS-088. Tumors, kidneys, livers, and spleens were excised 6h p.i. and sectioned for analysis by digital autoradiography. Four non-tumor bearing nude mice were imaged 2h pre- and post-euthanasia. HPLC-based radiometabolite analysis (n=3) of blood, kidney, and liver homogenates from nude mice was carried out following administration of 3.3 MBq [¹³⁴Ce]Ce-RPS-088 or 150 kBq [²²⁵Ac]Ac-RPS-088. In vitro internalization ratios of 10 nM [¹³⁴Ce]Ce- or [²²⁵Ac]Ac-RPS-088 were studied in LNCaP cells after 2h, 6h and 22h of incubation. Finally, the release of Ce-134 and Ac-225 from [¹³⁴Ce]Ce- and [²²⁵Ac]Ac-RPS-088 incubated in human serum at 37 °C was monitored by radio-TLC (50 mM citrate, pH 5.0) for up to 72h.

Results: The tissue distribution of [¹³⁴Ce]Ce-RPS-088 and [²²⁵Ac]Ac-RPS-088 was comparable in most organs, with the exception of the kidneys, for which uptake and retention of [¹³⁴Ce]Ce-RPS-088 was lower at all analyzed time points (Figure 1). Differences in tumor accumulation at earlier time points ­– 21.8 ± 2.5 %ID/g (6h) and 29.3 ± 10.7 %ID/g (23h) for [¹³⁴Ce]Ce-RPS-088; 36.1 ± 8.0 %ID/g (6h) and 36.4 ± 6.3 %ID/g (23h) for [²²⁵Ac]Ac-RPS-088 – possibly reflect the heterogeneity of the LNCaP model, but clearance of [¹³⁴Ce]Ce-RPS-088 from tumors at 72h p.i. was pronounced compared to [²²⁵Ac]Ac-RPS-088 (7.0 ± 1.4 %ID/g versus 88.3 ± 19.6 %ID/g, respectively).  Digital autoradiography confirmed equivalent distributions of the two radiopharmaceuticals in tumors, livers, and spleens, but highlighted regional differences within kidneys. Pre- and post-mortem imaging revealed that the liver activity decreased in the 2h delay time between images, suggesting that released and redistributed La-134 may contribute to the uptake. Both compounds were stable for a minimum of 6h in the blood of injected mice, while continuous degradation was observed in the kidneys. Ce-134 was released from [¹³⁴Ce]Ce-RPS-088 in human serum (1.2 ± 0.7% at 2h, 21.5 ± 4.7% at 24h and 52.4 ± 3.7% at 72h, n=2) more readily than Ac-225 from [²²⁵Ac]Ac-RPS-088 (3.3 ± 1.1% at 2h, 9.5 ± 0.4% at 24h and 11.3 ± 0.5% at 72h, n=2). Both compounds showed in vitro internalization ratios between 65% and 80% with a steady increase over time.

Conclusion: With the exception of the kidneys, the in vivo distribution profile of [¹³⁴Ce]Ce-RPS-088 matches that of [²²⁵Ac]Ac-RPS-088 at early time points. Increased release of Ce-134 from [¹³⁴Ce]Ce-RPS-088 may, however, affect the accuracy of image-based dosimetry calculations at later times. The influence on the calculated tumor and organ doses will be assessed in a next step.

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Fig 1: Biodistribution study of 3.1-3.7 MBq [¹³⁴Ce]Ce-RPS-088 and 50 kBq [²²⁵Ac]Ac-RPS-088 in selected organs at 6h, 23h, and 72h post-injection using an LNCaP xenograft mouse model. Top, representative PET images of mice injected with [¹³⁴Ce]Ce-RPS-088 acquired prior to start of the biodistribution study.

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