Irradiation of salivary glands remains the main dose-limiting side effect of therapeutic PSMA-inhibitors, especially when using alpha emitters. Thus, further advances in radiopharmaceutical design and therapy strategies are needed to reduce salivary gland uptake, thereby allowing the administration of higher doses and potentially resulting in improved response rates and better tumor control. As the uptake mechanism remains unknown, this work investigates the salivary gland uptake of [177Lu]Lu-PSMA-617 by autoradiography studies on pig salivary gland tissue and on PSMA-overexpressing LNCaP cell membrane pellets. Displacement studies were performed with non-labeled PSMA-617 and 2-PMPA, respectively. The uptake of [177Lu]Lu-PSMA-617 in glandular areas was determined to be partly PSMA-specific, with a high non-specific uptake fraction. The study emphasizes that [177Lu]Lu-PSMA-617 accumulation in pig salivary glands can be attributed to a combination of both specific and non-specific uptake mechanisms. The observation is of high impact for future design of novel radiopharmaceuticals addressing the dose-limiting salivary gland irradiation of current alpha endoradiotherapy in prostate cancer.

The glucagon-like peptide-1 (GLP-1) receptors are important biomarkers for imaging pancreatic β-cell mass and detection of benign insulinomas. Using GLP-1 receptor antagonists, we aimed to eliminate the insulin-related side effects reported for all GLP-1 receptor agonists. Additionally, using a nonresidualizing tracer, 125 I-BoltonHunter-Exendin(9-39)NH 2 ( 125 I-BH-Ex(9-39)NH 2 ), we aimed to reduce the high kidney uptake, enabling a better detection of insulinomas in the tail and head of the pancreas. Methods: The affinity and biodistribution of Ex (9- ) uptake in Ins-1E tumor, 12.5 ± 2.2 %IA/g in the pancreas, and 235.8 ± 17.0 %IA/g in the kidney, with tumor-to-blood and tumor-to-kidney ratios of 100.52 and 0.17, respectively. Biodistribution of [Lys 40 (NODAGA-68 Ga)NH 2 ]Ex(9-39) showed only 2.2 ± 0.2 %IA/g uptake in Ins-1E tumor, 1.0 ± 0.1 %IA/g in the pancreas, and 78.4 ± 8.5 %IA/g in the kidney at 1 h after injection, with tumor-to-blood and tumor-to-kidney ratios of 7.33 and 0.03, respectively. In contrast, 125 I-BH-Ex(9-39)NH 2 showed tumor uptake (42.5 ± 8.1 %IA/g) comparable to the agonist and 28.8 ± 5.1 %IA/g in the pancreas at 1 h after injection. As we hypothesized, the kidney uptake of 125 I-BH-Ex(9-39)NH 2 was low, only 12.1 ± 1.4 %IA/g at 1 h after injection. The tumor-to-kidney ratio of 125 I-BH-Ex(9-39)NH 2 was improved 20-fold. Conclusion: Our results suggest that iodinated Ex(9-39)NH 2 may be a promising tracer for imaging GLP-1 receptor expression in vivo. Because of the 20-fold improved tumorto-kidney ratio 125 I-BH-Ex(9-39)NH 2 may offer higher sensitivity in the detection of insulinomas and imaging of β-cell mass in diabetic patients. Further studies with 124 I-BH-Ex(9-39)NH 2 are warranted.Key Words: GLP-1 receptor; insulinoma; β-cell mass; antagonist The glucagon-like peptide (GLP-1) receptors are important targets because they are overexpressed on more than 90% of benign insulinomas, some malignant insulinomas, most gastrinomas, and most phaeochromocytomas (1). Physiologically they are also expressed in the endocrine pancreas. Preoperative imaging of insulinomas is critical, because it helps to precisely localize these often very small lesions in the pancreas. Therefore, imaging probes for optical (2), bimodal (3), SPECT (4-7), and PET (8-13) imaging as well as MRI (14) were developed to localize GLP-1 receptors preoperatively and in addition to determine b-cell mass in diabetic animal models and potentially in patients. In particular, SPECT (4,5,7) and PET (8,13,15) agents were successfully translated into the clinic, and several promising clinical studies were reported. Still, there are a few shortcomings with the available tracers. The tracers accumulate highly in the kidneys when residualizing radiometals are used for labeling, possibly leading to not only unnecessary high radiation doses but also problems in localizing tumors in the tail and head of the pancreas (5,8,13). The usually low specific activity of the imaging tracers, exclusively agonists, and the concomitant relative...

The CD30-specific antibody-drug conjugate, brentuximab vedotin, is approved for the treatment of relapsed, refractory Hodgkin lymphomas and systemic anaplastic large T-cell lymphomas. Multiple ongoing clinical trials are investigating brentuximab vedotin efficacy in other CD30-positive hematologic malignancies. Because CD30 expression varies among different types of lymphoma and can also change during the course of treatment, companion diagnostic imaging of CD30 could be a valuable tool in optimizing patient-specific brentuximab vedotin treatment regimens. Methods: The mouse antihuman CD30 antibody AC-10 was radiolabeled with the positron-emitting radionuclide 89 Zr. The stability and specificity of 89 Zr-desferrioxamine (DFO)-labeled CD30-specific AC-10 antibody ( 89 Zr-DFO-AC-10) was evaluated in vitro. The pharmacokinetics of 89 Zr-DFO-AC-10 was studied in BALB/c nude mice bearing subcutaneous human Karpas 299 tumors (CD30-positive model) or A-431 tumors (CD30-negative model) using PET/CT imaging, biodistribution studies, and autoradiography. Results: AC-10 was conjugated with a DFO B chelator and radiolabeled with 89 Zr to give formulated 89 Zr-DFO-AC-10 with a radiochemical yield of 80%, radiochemical purity greater than 99%, and specific activity of 111-148 MBq/mg. 89 Zr-DFO-AC-10 was stable in mouse and human sera and preserved the immunoreactivity toward CD30. Biodistribution data showed the highest tissue accumulation of 89 Zr-DFO-AC-10 in CD30-positive tumors, with 37.9% ± 8.2% injected activity per gram of tissue at 72 h after injection, whereas uptake in CD30-negative tumors was 11.0% ± 0.4%. The specificity of 89 Zr-DFO-AC-10 binding to CD30 in vivo was confirmed by blocking studies. Time-activity curves showed that between 24 and 144 h after injection, tumor-to-muscle ratios increased from 18.9 to 51.8 in the CD30-positive model and from 4.8 to 8.7 in the CD30-negative model. Tumor-to-blood ratios also increased, from 3.2 to 13.6 and from 1 to 2 in the CD30-positive and -negative models, respectively. Conclusion: Our results demonstrate that for measuring CD30 expression, 89 Zr-DFO-AC-10 is a sensitive PET agent with high tumor-to-normal-tissue contrast. 89 Zr-DFO-AC-10 is a promising CD30-imaging radiotracer for clinical translation in patients with various lymphomas and other diseases. CD30,amemberoft he tumor necrosis factor receptor superfamily, is expressed by Reed-Sternberg cells and used as a primary diagnostic marker for Hodgkin lymphoma (1). CD30 is also highly expressed on the surface of some T-cell lymphomas, especially on anaplastic large cell lymphoma, and at variable levels on a subset of other non-Hodgkin lymphomas, including diffuse large B-cell lymphoma (2-4). Expression of CD30 in healthy tissues is restricted to activated T and B cells, and the receptor cannot be found outside the immune system (2,5). High expression levels on specific cancers and limited presentation in healthy tissues make CD30 an ideal target for antibody-based molecular therapies.Brentuximab vedotin (Adcentri...