Grayson R. Gimblet

Purpose: Cell tracking with zirconium-89 PET has the potential for widespread clinical and research applications, including imaging infection and inflammation and tracking cell-based therapies. This prospective first-in-human clinical trial assessed the dosimetry and safety profile of [ ⁸⁹ Zr]Zr-oxine-labeled autologous leukocytes in healthy female participants. Methods: Four healthy adult female participants (ages 37–53) received 10.9 ± 2.9 MBq of [ ⁸⁹ Zr]Zr-oxine-labeled autologous leukocytes and underwent whole-body PET/CT imaging at five time points (0, 4, 24, 48, and 72 h). Regions of interest were automatically segmented on CT using a machine learning-based approach and manually refined. Time-integrated activity coefficients were calculated using Simpson’s rule, with physical decay assumed beyond the final time point. Mean absorbed-dose and effective-dose coefficients were estimated using OLINDA 2.1. Results: Administration was well-tolerated among all participants. The highest mean absorbed-dose coefficients (mGy/MBq) with standard deviation were observed in the spleen (3.52 ± 1.38), liver (2.1 ± 0.45), adrenals (1.62 ± 0.24), uterus (1.48 ± 0.98), and kidneys (1.36 ± 0.12). The mean effective-dose coefficient was 0.92 ± 0.06 mSv/MBq, numerically lower than the predicted value of 1.14 mSv/MBq based on the distribution of [ ¹¹¹ In]In-oxine-labeled leukocytes in adult females ( P = 0.006, one-sample t-test). The use of [ ⁸⁹ Zr]Zr-oxine-labeled leukocytes enabled the visualization of leukocyte distribution and temporal dynamics. Conclusion: This study demonstrates the safety and favorable dosimetry of [ ⁸⁹ Zr]Zr-oxine-labeled leukocytes in healthy humans. These results support the further use of this approach for imaging autologous leukocytes using PET in a range of clinical and research settings. Trial registration: ClinicalTrials.gov NCT03807973. Registered January 16, 2019.

The theranostic approach, which employs diagnostic radiopharmaceuticals to select patients who would benefit from targeted radiotherapy agents, has become an invaluable strategy for effective medical care. Scandium radionuclides offer the advantage of forming elementally matched and chemically identical diagnostic and therapeutic compounds, making them ideal candidates for this strategy. PSMA-617 is an established prostate-specific membrane antigen targeting agent and can be used as a proof of concept to investigate ⁴³Sc, the diagnostic nuclide, and ⁴⁷Sc, the therapeutic nuclide, as a theranostic pair. Cellular uptake, competitive binding assays, and internalization studies were carried out using LNCaP or PC-3 cell lines. [⁴³Sc]Sc-PSMA-617 was used in PET imaging studies in LNCaP or PC-3 tumor models, with time points ranging from 1-9 h. LNCaP tumor-bearing mice injected with [⁴⁷Sc]Sc-PSMA-617 were imaged using SPECT up to 48 h. A longitudinal study was carried out using LNCaP tumor-bearing mice imaged with [⁴³Sc]Sc-PSMA-617 prior to receiving a therapeutic dose of [⁴⁷Sc]Sc-PSMA-617. ⁴³Sc and ⁴⁷Sc were incorporated into PSMA-617 at radiochemical yields of >99%. Cellular uptake studies demonstrated high uptake and specificity to PSMA receptors for [⁴⁷Sc]Sc-PSMA-617. In vivo PET studies showed specificity of [⁴³Sc]Sc-PSMA-617 while SPECT studies demonstrated tumor retention of [⁴⁷Sc]Sc-PSMA-617 up to 48 h. [⁴⁷Sc]Sc-PSMA-617 demonstrated therapeutic efficacy by delaying tumor growth and increasing survival rates from a single administered dose in xenograft models. More importantly, the PET results from [⁴³Sc]Sc-PSMA-617 PET were highly correlated with the therapeutic response from [⁴⁷Sc]Sc-PSMA-617, showing that ⁴³Sc PET data can predict therapeutic outcomes in individual animals from ⁴⁷Sc agents, even in animals sharing a genetic background and implanted with tumors from the same cell line. Two chemically identical, PSMA-targeting radioscandium pharmaceuticals demonstrated in vivo stability, specificity and retention in PSMA+ tumor models. A theranostic study showed that a higher ⁴³Sc PET SUV_mean was strongly correlated to therapeutic response from the ⁴⁷Sc agent, demonstrating that ⁴³Sc and ⁴⁷Sc can be used as an elementally matched theranostic pair.

Thyroid cancer is the most common endocrine cancer, with differentiated thyroid cancers (DTCs) accounting for 95% of diagnoses. While most DTC patients are diagnosed and treated with radioiodine (RAI), up to 20% of DTC patients become RAI refractory (RAI-R). RAI-R patients have significantly reduced survival rates compared to patients who remain RAI-avid. This study explores [⁸⁹Zr]Zr-TR1402 as a thyroid-stimulating hormone receptor (TSHR)-targeted PET radiopharmaceutical for DTC. [⁸⁹Zr]Zr-TR1402 was synthesized with a molar activity of 25.9 MBq/nmol by conjugating recombinant human TSH (rhTSH) analogue TR1402 to chelator p-SCN-Bn-deferoxamine (DFO) in a molar ratio of 3:1 (DFO/TR1402) and radiolabeling with ⁸⁹Zr (t_1/2 = 78.4 h, β⁺ = 22.7%). As TSHR is absent in commonly available DTC-derived cell lines, TSHR was reintroduced via stable transduction by delivering a lentivirus containing the full-length coding region of the human TSHR gene. Receptor-mediated uptake of [⁸⁹Zr]Zr-TR1402 was evaluated in vitro in stably transduced TSHR+ and wild-type TSHR- DTC cell lines. In vivo PET imaging was performed on Days 1-3 postinjection in male and female athymic nude mice bearing TSHR+ and TSHR- xenografts, along with ex vivo biodistribution on Day 3 postinjection. In vitro uptake of 1 nM [⁸⁹Zr]Zr-TR1402 was significantly higher in TSHR+ THJ529T (P < 0.0001) and FTC133 (P < 0.01) cells than in TSHR- THJ529T and FTC133 cells. This uptake was shown to be specific in both TSHR+ THJ529T (P < 0.0001) and TSHR+ FTC133 (P < 0.0001) cells by blocking uptake with 250 nm DFO-TR1402. In vivo PET imaging showed accumulation of [⁸⁹Zr]Zr-TR1402 in TSHR+ tumors, which was the highest on Day 1. In the male FTC133 xenograft model, ex vivo biodistribution confirmed a significant difference (P < 0.001) in uptake between FTC133+ (1.3 ± 0.1%ID/g) and FTC133- (0.8 ± 0.1%ID/g) tumors. A significant difference (P < 0.05) in uptake was also seen in the male THJ529T xenograft model between THJ529T+ (1.8 ± 0.6%ID/g) and THJ529T- (0.8 ± 0.4%ID/g) tumors. The in vitro and in vivo accumulation of [⁸⁹Zr]Zr-TR1402 in TSHR-expressing DTC cell lines support the continued preclinical optimization of this approach.