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Rationale: Alpha particle emitting radiopharmaceuticals are generating considerable interest for the treatment of disseminated metastatic disease. Molecular imaging of the distribution of these agents is critical to safely and effectively maximize the clinical potential of this emerging drug class. The present studies aim to investigate the feasibility and limitations of quantitative SPECT for 223Ra, 225Ac and 227Th. Methods: Three state-of-the-art SPECT/CT systems were investigated: the GE Discovery NM/CT 670, the GE Optima NM/CT 640, and the Siemens Symbia T6. A series of phantoms, including the NEMA IEC Body phantom, were used to compare and calibrate each camera. Additionally, anthropomorphic physical tumor and vertebrae phantoms were developed and imaged to evaluate the quantitative imaging protocol. Results: This work describes and validates a methodology to calibrate each clinical system. The efficiency of each gamma camera was analyzed and compared. Using the calibration factors obtained with the NEMA phantom, we were able to quantify the activity in 3D-printed tissue phantoms with an error of 2.1%, 3.5% and 11.8% for 223Ra, 225Ac, and 227Th, respectively. Conclusion: The present study validates that quantitative SPECT/CT imaging of 223Ra, 225Ac, and 227Th is achievable but that careful considerations for camera configuration are required. These results will aid in future implementation of SPECT-based patient studies and will help to identify the limiting factors for accurate image-based quantification with alpha particle emitting radionuclides.

Herein we report a new series of divalent 2-(4-hydroxyphenyl)benzothiazole bifunctional chelators (BFCs) with high affinity for amyloid β aggregates and favorable lipophilicity for blood-brain barrier (BBB) penetration. The addition of an alkyl carboxylate ester pendant arm offers high binding affinity towards Cu(II). The novel BFCs form stable 64Cu-radiolabeled complexes and exhibit promising partition coefficient (log D) values of 1.05-1.85. Among the five compounds tested, the 64Cu-YW-15 complex exhibits significant staining of amyloid β plaques in ex vivo autoradiography studies. In addition, biodistribution studies show that 64Cu-YW-15-Me exhibits elevated brain uptake (0.89 ± 0.25 %ID/g) in transgenic AD versus wild type mice.

Purpose PARP inhibitor (PARPi) therapy is approved for patients with metastatic castration-resistant prostate cancer (mCRPC) and homologous recombination repair (HRR) genomic aberrations. However, only a fraction of patients with BRCA1/2 mutations respond to PARPi therapy. In this pilot study, we assess PARP-1 expression in prostate cancer patients with and without HRR genomic alternations using a novel PARP-based imaging agent. Procedures Nine advanced prostate cancer patients were studied with PET/CT and [18F]FluorThanatrace (FTT), an analogue of the PARPi rucaparib. Images were analyzed using maximum standardized uptake values (SUVmax). PARP expression was assessed by immunohistochemistry (IHC) when feasible (n = 4). Results We found great variability in FTT uptake (SUVmax range: 2.3–15.4). Patients with HRR mutations had a significantly higher SUVmax (p = 0.0379) than patients with non-HRR mutations although there was an overlap in FTT uptake between groups. Three patients without HRR and one with HRR mutations had similarly high PARP1 IHC expression. Conclusions FTT-PET/CT may serve as an alternate biomarker for PARP1 expression and a potential method for PARPi treatment selection.

Lung cancer is the leading cause of cancer death worldwide. There is an unmet need for therapies to improve lung cancer outcomes without causing additional toxicities. Tax-interacting protein 1 (TIP1) is a radiation-inducible antigen that plays a role in lung cancer progression and resistance to therapy. TIP1 is a targetable cell surface protein. We developed human antibodies (Ab) that bind specifically to lung cancer. This study aimed to evaluate our lead anti-TIP1 human antibody targeting lung cancer in vitro and in vivo. Anti-TIP1 IgG1 Ab was developed by biopanning phage display human antibody library. The purified Ab was characterized by size-exclusion chromatography-HPLC (SEC-HPLC), mass spectrometry, ELISA, BIAcore and flow cytometry. Ab was labeled with 89Zr using desferrioxamine chelator. The surface binding of 89Zr-Ab was evaluated in the A549 and H460 lung cancer cells. Stability of the 89Zr-Ab was assessed in human serum. Mice bearing 3 patient-derived xenografts (PDX) lung tumors or A549 tumors were injected with 50 µCi of 89Zr-Ab. Small animal PET imaging and biodistribution were conducted over 7 days. Specific tumor uptake was evaluated in biodistribution studies on day 5 by injecting cold Ab before 89Zr-Ab. We obtained 95% pure anti-TIP1 Ab by SEC-HPLC. Mass spectrometry confirmed the intact mass and glycosylation pattern of the anti-TIP1 IgG1. The Ab is bound to recombinant TIP1 protein and cancer cell surface with high affinity. The radiochemical purity of the 89Zr-Ab was 99.9%, and the molar activity was 11.54 MBq/nmol with a radiolabeling yield of 91.4%. Both A549 and H460 cell lines demonstrated specific binding as >70% inhibition was observed when the cold Ab was added. The ratio of SUV tumor to SUV muscle increased from 5.8 at 2 days to 6.3 at 7 days in PDX. In biodistribution studies, we found significantly higher (p Citation Format: Abhay Kumar Singh, Calvin D. Lewis, Cristian AWV Boas, Philipp Diebolder, Prashant N. Jethva, Aaron Rhee, Jong Hee Song, Young Ah Goo, Shunqiang Li, Yongjian Liu, Buck Rogers, Vaishali Kapoor, Dennis E. Hallahan. Preclinical development of a 89Zr-labeled human antibody as a novel immuno-PET agent for noninvasive cancer detection and monitoring response to treatment. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5035.

The greatest challenge in radiotherapy is to maximize radiation doses to tumors while sparing the normal tissues. Ionizing radiation has been shown to induce expression of proteins on surface of tumor cells. Using this strategy, drug delivery can be targeted specifically to cancer and guided by use of a beam of radiation. We used phage-displayed peptide libraries to discover radiation-inducible antigens in different cancer models. One such inducible-antigen is Tax interacting protein-1 (Tip-1) which was shown to bind the hexapeptide HVGGSSV. TIP-1 is an atypical PDZ protein consisting of only a single PDZ domain that is predominantly cytosolic protein and expressed in all types of cells. Overall TIP-1 expression levels in tumor cells and non-tumor cells are similar; however it is over-expressed on the tumor cell surface following irradiation. In this study, we evaluated the affinity of binding of HVGGSSV and a scrambled peptide to TIP-1 using surface plasmon resonance (SPR) technology. A KD (dissociation constant) of 3.3e-8M for HVGGSSV and 1.37e-3M for the scrambled peptide was obtained. We next determined the specificity of HVGGSSV to bind tumors in vivo using nano SPECT technology. HVGGSSV was conjugated to a 40KDa PEG (for longer circulation time) and radiolabelled with 111Indium (111In) using diethylene triamine pentaacetic acid (DTPA) as the chelator. The A549 tumor bearing nude mice were irradiated (3Gy x 3 times) or sham irradiated prior to tail vein injections of 111In labeled HVGGSSV. The mice were imaged 48h and 96h post injection using nano CT-SPECT imager. The SPECT images revealed that HVGGSSV specifically bound to the irradiated A549 tumors while little or no binding was seen in the sham irradiated tumors. The post-SPECT imaging bio-distrubution also revealed maximum uptake in irradiated tumors. We further evaluated tumor binding of HVGGSSV in Glioma (D54), esophageal cancer (OE33), cervical cancer (HT3), and pancreatic cancer (BxPC3). The nano-SPECT imaging showed that HVGGSSV specifically bound to all the irradiated tumors tested. Phosphor images of the tumor sections showed that HVGGSSV specifically bound to the tumors and not to normal tissues. In conclusion, HVGGSSV peptide has high affinity to TIP-1 in vitro and in vivo. Radiolabeled HVGGSSV is a novel tool for imaging tumors and may be developed further as a therapeutic agent to deliver cancer specific drugs or therapeutic radioisotopes. Citation Format: Vaishali Kapoor, David Dadey, Kim Nguyen, Hua Li, Buck Rogers, Dinesh Thotala, Dennis Hallahan. Targeting radiation-inducible cell surface TIP-1 using HVGGSSV peptide as a novel imaging and therapeutic strategy for tumors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1491. doi:10.1158/1538-7445.AM2015-1491