Targeting cancer-associated fibroblasts (CAFs) has become an attractive goal for diagnostic imaging and therapy because they can constitute as much as 90% of a tumor mass. The serine protease fibroblast activation protein (FAP) is overexpressed selectively in CAFs, drawing interest in FAP as a stromal target. The quinolinebased FAP inhibitor (FAPI) PET tracer 68 Ga-FAPI-04 has been previously shown to yield high tumor-to-background ratios (TBRs) in patients with various cancers. Recent developments toward an improved compound for therapeutic application have identified FAPI-46 as a promising agent because of an increased tumor retention time in comparison with FAPI-04. Here, we present a PET biodistribution and radiation dosimetry study of 68 Ga-FAPI-46 in cancer patients. Methods: Six patients with different cancers underwent serial 68 Ga-FAPI-46 PET/CT scans at 3 time points after radiotracer injection: 10 min, 1 h, and 3 h. The source organs consisted of the kidneys, bladder, liver, heart, spleen, bone marrow, uterus, and remainder of body. OLINDA/EXM software, version 1.1, was used to fit and integrate the kinetic organ activity data to yield total-body and organ time-integrated activity coefficients and residence times and, finally, organ-absorbed doses. SUVs and TBR were generated from the contoured tumor and source-organ volumes. Spheric volumes in muscle and blood pool were also obtained for TBR (tumor SUV max /organ SUV mean ). Results: At all time points, average SUV max was highest in the liver. Tumor and organ SUV mean decreased over time, whereas TBRs in all organs but the uterus increased. The organs with the highest effective doses were bladder wall (2.41E−03 mSv/MBq), followed by ovaries (1.15E−03 mSv/MBq) and red marrow (8.49E−04 mSv/MBq). The average effective total-body dose was 7.80E−03 mSv/MBq. Conclusion: 68 Ga-FAPI-46 PET/CT has a favorable dosimetry profile, with an estimated whole-body dose of 5.3 mSv for an administration of 200 MBq (5.4 mCi) of 68 Ga-FAPI-46 (1.56 ± 0.26 mSv from the PET tracer and 3.7 mSv from 1 low-dose CT scan). The biodistribution study showed high TBRs increasing over time, suggesting high diagnostic performance and favorable tracer kinetics for potential therapeutic applications.

Prostate-specific membrane antigen (PSMA) targeting radioligands deliver radiation to PSMA-expressing cells. However, the relationship between PSMA levels and intralesion heterogeneity of PSMA expression, and cytotoxic radiation by radioligand therapy (RLT) is unknown. Here we investigate RLT efficacy as function of PSMA levels/cell, and the fraction of PSMA þ cells in a tumor.Experimental Design: RM1 cells expressing different levels of PSMA (PSMA À , PSMA þ , PSMA þþ , PSMA þþþ ; study 1) or a mix of PSMA þ and PSMA À RM1 (study 2, 4) or PC-3/PC-3-PIP (study 3) cells at various ratios were injected into mice. Mice received 177 Lu-(studies 1-3) or 225 Ac-(study 4) PSMA617. Tumor growth was monitored. Two days post-RLT, tumors were resected in a subset of mice. Radioligand uptake and DNA damage were quantified.Results: 177 Lu-PSMA617 efficacy increased with increasing PSMA levels (study 1) and fractions of PSMA positive cells (studies 2 , 3 ) in both, the RM1 and PC-3-PIP models. In tumors resected 2 days post-RLT, PSMA expression correlated with 177 Lu-PSMA617 uptake and the degree of DNA damage. Compared with 177 Lu-PSMA617, 225 Ac-PSMA617 improved overall antitumor effectiveness and tended to enhance the differences in therapeutic efficacy between experimental groups.Conclusions: In the current models, both the degree of PSMA expression and the fraction of PSMA þ cells correlate with 177 Lu-/ 225 Ac-PSMA617 tumor uptake and DNA damage, and thus, RLT efficacy. Low or heterogeneous PSMA expression represents a resistance mechanism to RLT.

Scandium-44g (half-life 3.97h [1]) shows promise for positron emission tomography (PET) imaging of longer biological processes than that of the current gold standard, F, due to its favorable decay parameters. One source ofSc is the long-lived parent nuclide Ti (half-life 60.0 a). ATi/Sc generator would have the ability to provide radionuclidically pure Sc on a daily basis. The production ofTi via the Sc(p,2n) reaction requires high proton beam currents and long irradiation times. Recovery and purification of no-carrier added (nca)Ti from scandium metal targets involves complex separation chemistry. In this study, separation systems based on solid phase extraction chromatography were investigated, including branched diglycolamide (BDGA) resin and hydroxamate based ZR resin. Results indicate that ZR resin in HCl media represents an effective Ti/Sc separation system.

Prostate-specific membrane antigen-targeted radioligand therapy (PSMA-RLT) is effective against prostate cancer (PCa), but all patients relapse eventually. Poor understanding of the underlying resistance mechanisms represents a key barrier to development of more effective RLT. We investigate the proteome and phosphoproteome in a mouse model of PCa to identify signaling adaptations triggered by PSMA-RLT.Experimental Design: Therapeutic efficacy of PSMA-RLT was assessed by tumor volume measurements, time to progression, and survival in C4-2 or C4-2 TP53-knockout tumor-bearing Nod scid gamma mice. Two days post-RLT, the (phospho)proteome was analyzed by mass spectrometry.Results: PSMA-RLT significantly improved disease control in a dose-dependent manner.(Phospho)proteomic datasets revealed activation of genotoxic stress response pathways, including deregulation of DNA damage/replication stress response, TP53, androgen receptor, PI3K/AKT, and MYC signaling. C4-2 TP53-knockout tumors were less sensitive to PSMA-RLT than parental counterparts, supporting a role for TP53 in mediating RLT responsiveness. Conclusions:We identified signaling alterations that may mediate resistance to PSMA-RLT in a PCa mouse model. Our data enable the development of rational synergistic RLT-combination therapies to improve outcomes for PCa patients.