The poly(ADP-ribose) polymerase (PARP) family plays important roles in DNA repair, chromatin organization, genome integrity, apoptosis, and inflammation. PARP1 and PARP2 are validated therapeutic targets that have attracted considerable interests, with multitude of PARP1/2 inhibitors emerged for treatment of cancers, metabolic, inflammatory, and neurological disorders. PARP1/2 are activated by DNA damage caused by inflammatory responses, and are involved in the etiology of various neurological disorders. PARP1/2-targeted noninvasive PET imaging has shown potential in cancer diagnosis and prognosis. However, quantitative PARP1/2 PET imaging in the central nervous system has been challenging, due to the lack of blood-brain barrier (BBB) penetrable PARP1/2 radioligands. This work proposes the use of Pamiparib (BGB-290), a potent PARP-1 and PARP-2 inhibitor, as a lead for potential BBB penetrant PARP1/2 PET tracer. We synthetized [18F]Pamiparib and evaluated its binding specificity using Olaparib, Veliparib, and Saruparib, both in vitro and ex vivo. [18F]Pamiparib PET imaging was performed in nonhuman primate (NHP), with arterial blood sampling and radiometabolite analysis. The in vitro autoradiography results showed higher binding affinity in tumors than in rodent and NHP brain tissues. [18F]Pamiparib possess a higher parent fraction in NHP than in rodents, with similar uptake across brain regions (SUV ~ 0.2). The volume of distribution (VT) values derived from the 1-tissue compartment (1TC) model for [18F]Pamiparib and [11C]PyBic in the same NHP correlated well. In conclusion, [18F]Pamiparib showed relatively low brain penetration and stable regional uptake in NHP, positioning it as a quantitative imaging tool for target engagement of Pamiparib at individual levels and a potential tool for non-invasive quantitative imaging of PARP1/2.
Inflammatory arthritis (IA) is characterized by early T cell activation in synovial tissue, yet noninvasive methods to detect this process are limited. This study evaluated Al[18F]F-NOTA-BCP137, a CD137-targeted bicyclic peptide PET tracer, for imaging CD137+ activated immune cells in two mouse models of IA. CD137 expression was characterized in human RA synovium and arthritic mouse joints by transcriptomics, qPCR, and immunohistochemistry. Tracer specificity was assessed in vitro using activated PBMCs, and immune safety was evaluated in human CD137 transgenic mice. PET imaging was performed in collagen antibody-induced arthritis (CAIA) and ICI-induced arthritis models. CD137 was significantly upregulated in RA synovium and arthritic mouse joints, with expression levels correlating with disease activity and preceding clinical arthritis scores. Al[18F]F-NOTA-BCP137 demonstrated specific binding to CD137-expressing activated T cells without detectable immune activation. PET imaging revealed significantly higher tracer uptake in arthritic joints compared with controls, with uptake values strongly correlating with arthritis severity and increasing prior to clinical symptom onset. These results indicate that CD137-targeted PET with Al[18F]F-NOTA-BCP137 enables specific detection of early T cell activation in inflammatory arthritis and warrants further investigation as an imaging approach for early-stage detection of joint inflammation.
135La is an Auger-electron-emitting radionuclide with promising potential for targeted endoradiotherapy. To date, 135La has been produced mainly via the 135Ba(p,n)135La reaction, with reported activities limited to the 1 GBq range. In this work, we produced 135La via the higher-cross-section 136Ba(p,2n)135La reaction using enriched targets, reaching activities of up to 4.6 GBq at end of bombardment — the highest activity amount reported to date. Two target geometries were investigated, a 90° solid target and a 30° slanted target with higher [136Ba]BaCO3 mass. Their saturation yields were compared to theoretical predictions based on TENDL-2025 cross sections. Radiochemical purification, performed via one-step chromatography, allowed recovery of over 85% of the 135La activity in 1 mL of 0.01 M HCl with a radionuclidic purity above 99.99% and molar activities of 1200–3000 GBq/μmol at end of purification. Test radiolabeling with the macropa chelator gave apparent molar activities of 200–300 GBq/μmol, comparable to previously reported values for 133La. Moreover, the [135La]La-macropa complex showed high in vitro stability tested in human serum being over 99% intact after 48 h. Finally, to the best of our knowledge, we present the first experimental assessment of 135La-induced DNA strand breaks in a cell-free plasmid model, providing initial experimental support for its potential as an Auger-electron therapeutic radionuclide. These results support the 136Ba(p,2n)135La route as a scalable and reliable production method to produce 135La for future (pre)clinical radiopharmacological applications.
Background Most preclinical studies of fibroblast activation protein (FAP)-targeted radionuclide therapy (FAP-RNT) use immunodeficient xenografts, limiting evaluation within an intact immune microenvironment. This study aimed to characterized FAP-associated stromal and FAP inhibitor (FAPI) imaging phenotypes across immunocompetent syngeneic tumors and explored FAP-RNT effects in a representative model. Methods Four syngeneic models (MC38, PAN02, LLC1, and 4 T1) were assessed using [68Ga]Ga-FAPI-7ND PET/CT, Western blotting, immunohistochemistry, and multiplex immunofluorescence for tracer uptake, FAP and α-SMA expression, and co-expression. Based on these findings, 4 T1-bearing mice underwent an exploratory therapeutic evaluation with saline or a single intravenous injection of [177Lu]Lu-FAPI-7ND. Tumor volume and body weight were measured every 2 days, and tumors were harvested on day 7 for histological and molecular analyses. Results All models showed higher tumor uptake than contralateral muscle (all P < 0.05), with significant inter-model differences (P = 0.005) but comparable tumor-to-background ratios (P = 0.369). PAN02 had the highest uptake and enriched FAP+α-SMA+ stroma, whereas 4 T1 combined relatively high uptake with pronounced α-SMA-associated stromal activation. Because FAP-RNT response may reflect both tracer accumulation and stromal state, 4 T1 was selected for exploratory treatment. [177Lu]Lu-FAPI-7ND inhibited tumor growth (P < 0.0001) without significant body-weight loss. Treatment reduced CD8+ T-cell (P < 0.0001) and FOXP3+ regulatory T-cell densities (P = 0.012), did not alter their ratio (P = 0.537), and increased CD206-associated macrophage features (P < 0.05). Conclusion Syngeneic models exhibit distinct FAP-associated stromal and imaging phenotypes. In 4 T1 tumors, [177Lu]Lu-FAPI-7ND showed antitumor activity accompanied by immune microenvironmental alterations, supporting integrated model selection for immunocompetent FAP-RNT studies.
