The idea of personalized medicine has been growing in clinical research for the past decade. Molecular imaging, first introduced in 2001 as a multidisciplinary practice, is undoubtedly playing an important role in the transition of conventional medical practice. When compared to optical imaging modalities, positron emission tomography (PET) is highly sensitive and it has the ability to obtain absolute imaging quantification after corrections for photon attenuation and scattering. In addition, due to the unique feature to image 11C, 13N, or 15O labeled compounds naturally in the body, the role of PET has been well-established in the field of molecular imaging. Our aim in this article is therefore to provide an overview of the recent advances in PET radiopharmaceuticals and their clinical application in oncology.

1465 Objectives: The considerable growth of 68Ga-radiopharmaceuticals applications in molecular imaging over the past few years continue to thrive. Evident by the number of clinical studies published, facilitated by the commercial availability of the 68Ge/68Ga-generator and FDA approval of 68Ga-imaging agents. In this work, we describe the development of a cost-effective automated production method using cyclotron produced 68Ga for synthesizing 68Ga-DOTATOC and 68Ga-PSMA-11 in routine clinical practice, which could be further applied to centralized radiopharmacy services. Methods: The synthesis of68Ga-DOTATOC and 68Ga-PSMA-11 was performed by a commercially available module under a cGMP-controlled environment. 68Ga was produced via irradiation of a 68Zn solid target (enrichment: 99.26%, 20-40 mg) by a medical cyclotron for 60 min, with protons at 14.5 MeV energy and beam current of 40 μA. The irradiated target was dissolved and processed by an automation module fitted with our patented single-column purification system. The purified 68Ga with activity between 9.25-14.8 GBq (0.25-0.40 Ci), was transferred to a reactor containing the precursor, 0.5 M sodium acetate buffer, and L-ascorbic acid. Radiolabeling was performed at 95° C for 10 min, product was then purified on a C-18 cartridge and passed through a 0.22µm filter for final collection. The QC for the final radiolabeled product was performed under the USP guidelines. Results: 68Ga-DOTATOC and 68Ga-PSMA-11 were successfully produced with typical yields of 5.55-11.1 GBq (0.15-0.3 Ci) at the end of synthesis. The total synthetic time was within 46 minutes from target dissolution to the final formulation of the product. The HPLC analysis of the finished products has consistently reported a radiochemical purity of greater than 98%. Additionally, the final product was determined to be sterile, colorless, and remained radiochemically pure (≥ 97%) after 4 h of radiosynthesis at room temperature. Conclusions: While our ANDAs are currently underway, we have established a cost-effective route for preparing two recently FDA approved 68Ga-radiopharmaceuticals, 68Ga-DOTATOC and 68Ga-PSMA-11. The production method is reliable, feasible and economically desirable for routine clinical practice. More importantly, this cost-efficient procedure can be utilized by centralized radiopharmacy services to support the availability and distribution of large-scale production of 68Ga- radiopharmaceuticals to local clinics.

The concept of personalized medicine has been steadily growing for the past decades. Monoclonal antibodies (mAbs) are undoubtedly playing an important role in the transition away from conventional medical practice to a more tailored approach to deliver the best therapy with the highest safety margin to a specific patient. In certain instances, mAbs and antibody drug conjugates (ADCs) may represent the preferred therapeutic option for several types of cancers due to their high specificity and affinity to the antigen. Monoclonal antibodies can be labeled with specific radionuclides well-suited for PET (Positron Emission Tomography) or gamma camera scintigraphy. The use of radiolabeled mAbs allows the interrogation of specific biomarkers and assessment of tumor heterogeneity in vivo by a single diagnostic imaging scan that includes the whole-body in the field-of-view. Moreover, the same mAb can then be radiolabeled with an analogous radionuclide for the delivery of beta-minus radiation or alpha-particles as part of a radioimmunotherapy (RIT) approach. However, the path to develop, validate, and implement mAb-based radiopharmaceuticals from bench-to-bedside is complex due to the extensive pre-clinical experiments and toxicological studies required, and the necessity of labor-intensive clinical trials that often require multi-time-point imaging and blood draws for internal radiation dosimetry and pharmacokinetics. As more mAb-based radiopharmaceuticals have been developed and evaluated, the opportunities and limitations offered by mAbs have become better defined. Our aim with this manuscript is therefore to provide an overview of the recent advances in the development of mAb-based radiopharmaceuticals and their clinical applications in Oncology.

Prostate cancer is the most common cancer to affect men in the United States and the second most common cancer in men worldwide. Prostate-specific membrane antigen (PSMA)-based positron emission tomography (PET) imaging has become increasingly popular as a novel molecular imaging technique capable of improving the clinical management of patients with prostate cancer. To date, several 68Ga and 18F-labeled PSMA-targeted molecules have shown promising results in imaging patients with recurrent prostate cancer using PET/computed tomography (PET/CT). Studies of involving PSMA-targeted radiopharmaceuticals also suggest a higher sensitivity and specificity, along with an improved detection rate over conventional imaging (CT scan and methylene diphosphonate bone scintigraphy) and 11C/18F-choline PET/CT. In addition, PSMA-617 and PSMA I&T ligands can be labeled with α- and β-emitters (e.g., 225Ac, 90Y, and 177Lu) and serve as a theranostic tool for patients with metastatic prostate cancer. While the clinical impact of such concept remains to be verified, the preliminary results of PSMA molecular radiotherapy are very encouraging. Herein, we highlighted the current status of development and future perspectives of PSMA-targeted radiopharmaceuticals and their clinical applications.

Phase I Study of P-cadherin–targeted Radioimmunotherapy with Y-FF-21101 Monoclonal Antibody in Solid Tumors A C Vivek Subbiah, William Erwin, Osama Mawlawi, Asa McCoy, David Wages, Catherine Wheeler, Carlos Gonzalez-Lepera, Holly Liu, Homer Macapinlac, Funda Meric-Bernstam, David S. Hong, Shubham Pant, Dao Le, Elmer Santos, Jose Gonzalez, Jason Roszik, Takeaki Suzuki, Ruth Ann Subach, Timothy Madden, Mary Johansen, Fumiko Nomura, Hirokazu Satoh, Tadashi Matsuura, Masamichi Kajita, Eri Nakamura, Yuichi Funase, Satoshi Matsushima, and Gregory Ravizzini

AbstractPurpose: 90Y-FF-21101 is an Yttrium-90–conjugated, chimeric mAb that is highly specific for binding to human placental (P)-cadherin, a cell-to-cell adhesion molecule overexpressed and associated with cancer invasion and metastatic dissemination in many cancer types. We report the clinical activity of 90Y-FF-21101 in a first-in-human phase I study in patients with advanced solid tumors. Patients and Methods: The safety and efficacy of 90Y-FF-21101 were evaluated in a phase I 3+3 dose-escalation study in patients with advanced solid tumors (n = 15) over a dose range of 5–25 mCi/m2. Dosimetry using 111In-FF-21101 was performed 1 week prior to assess radiation doses to critical organs. Patients who demonstrated clinical benefit received repeated 90Y-FF-21101 administration every 4 months. Results: 111In-FF-21101 uptake was observed primarily in the spleen, kidneys, testes, lungs, and liver, with tumor uptake observed in the majority of patients. Organ dose estimates for all patients were below applicable limits. P-cadherin expression H-scores ranged from 0 to 242 with 40% of samples exhibiting scores ≥100. FF-21101 protein pharmacokinetics were linear with increasing antibody dose, and the mean half-life was 69.7 (±12.1) hours. Radioactivity clearance paralleled antibody clearance. A complete clinical response was observed in a patient with clear cell ovarian carcinoma, correlating with a high tumor P-cadherin expression. Stable disease was observed in a variety of other tumor types, without dose-limiting toxicity. Conclusions: The favorable safety profile and initial antitumor activity observed for 90Y-FF-21101 warrant further evaluation of this radioimmunotherapeutic (RIT) approach and provide initial clinical data supporting P-cadherin as a potential target for cancer treatment.

466 Objectives: The increasing demand of 68Ga during the last decade has been a challenge for suppliers of this short-lived radionuclide. Although high production volumes of the 68Ge/68Ga generators have recently been made to meet existing needs, there is a strong commercial appeal for cyclotron-produced 68Ga to overcome limited availability of 68Ga radiopharmaceuticals, particularly in densely populated regions. With these in mind, the focus of this study was to validate our cyclotron-produced 68Ga as an alternative source for compounding radiopharmaceutical kits that can be used in routine clinical practice. Methods: The entirety of 68Ga-chloride production was performed using a commercially available module under a cGMP controlled environment. The 68Ga was produced via irradiation of a 68Zn solid target (enrichment: 99.26%, 20-40 mg) by a medical cyclotron for 90 min, with protons at 14.5 MeV energy and beam current of 40 μA. The irradiated target was dissolved and processed by an automation module fitted with our patented single-column purification system. The purified 68Ga-chloride with activity between 14.8-29.6 GBq (0.4-0.8 Ci) was formulated with 26 mL of 0.1 N HCl and passed through a 0.22 µm filter as the compounding substance. To validate its feasibility to compound a radiopharmaceutical kit, 5 mL of the formulated 68Ga-chloride solution containing activity of 1.48-2.22 GBq (40-60 mCi) was added directly to GalliProst, a commercially available single-dose kit of 68Ga-THP-PSMA provided by Theragnostics Inc. The final radiolabeled product required no further purification and QC was performed under the USP guidelines. Results: The fully-automated process of 68Ga-chloride production takes less than 30 minutes after target irradiation. The radionuclidic purity was ≥ 99.8% at the end of production with 67Ga as the primary radionuclidic impurity found through gamma-ray spectroscopy. ICP-MS analysis of the decayed 68Ga-chloride samples was compared to the 68Ga eluent from both ITG and IGG-100 68Ge/68Ga generators (Table 1), in which the data indicated our cyclotron-produced 68Ga is equal, if not better in quality, compared to its generator-produced counterpart. Additionally, the formulated 68Ga-chloride solution was determined to be sterile and colorless. The TLC analysis of the compounding product (68Ga-THP-PSMA) has consistently reported a radiochemical purity of greater than 95% with the pH of 6.0-7.0, which is comparable to the 68Ga eluent from the 68Ge/68Ga generator as the compounding substance. Conclusions We have developed a reliable and fully automated method for the routine production of 68Ga-chloride that is comparable to its generator-produced counterpart and can be used as an alternative source for compounding radiopharmaceutical kits. Whereas the validation toward other commercially available kits are currently underway, our preliminary results indicate the potential for the future development of radiopharmaceutical kits in multi-dose vials compounding with large scale 68Ga activity.

635 Objectives: 68Ga-PSMA-11 is currently one of the most widely used PET agent for imaging both recurrent prostate cancer and relevant metastases. However, the production and distribution of 68Ga-PSMA-11 are limited to a few daily doses by commercially available 68Ge/68Ga generators that nominally deliver a modest activity up to 1850 MBq (50 mCi) when new but decreases over time. In response to the need for a more economically viable alternative, we present a simple and fully automated method for producing 68Ga-PSMA-11 using cyclotron-produced 68Ga.\n Methods: The entirety of the 68Ga-PSMA-11 production process was performed using a commercially available module under cGMP controlled environment. The 68Ga was initially produced via irradiation of a 68Zn solid target (enrichment ≥ 99%, 80-100 mg) by a medical cyclotron for 1.0-1.5 h, with protons at 14.5 MeV energy and beam currents of 30 μA. The irradiated target was dissolved and processed by an automation module fitted with a unique single-column purification system that was developed in-house. Purified 68Ga with activity of 25.9-55.5 GBq (0.7-1.5 Ci) was eluted from the column by low concentration HCl and transferred directly to a reactor pre-loaded with PSMA-11 precursor, sodium acetate buffer, and L-ascorbic acid. Radiolabeling was conducted at 95oC for 10 min and product was eventually passed through a 0.22µm filter prior collection. All quality control tests were performed in accordance to the USP guidelines.\n Results: The fully-automated process from target dissolution to 68Ga-PSMA-11 final formulation takes less than 45 minutes and typically yields 18.5-37.0 GBq (0.5-1.0 Ci) at the end of synthesis (EOS). The HPLC analysis of the combined diastereomers of 68Ga-PSMA-11 product has consistently reported a radiochemical purity of greater than 99%, and the specific activity was up to 740 GBq (20 Ci)/μmol. Additionally, the final product was determined to be sterile, colorless, and remained radiochemically pure (≥ 99%) after 4 h of radiosynthesis at room temperature.\n Conclusions: We have developed a reliable and fully automated method for the routine production of 68Ga-PSMA-11 at curie level quantity. Whereas the in vitro cell uptake and in vivo small animal PET imaging studies are currently underway to further demonstrate the biological sameness, our data indicate the potential for large scale production of 68Ga-PSMA-11 that in turn can meet the increasing demand and facilitate regional distribution.

68Ga-PSMA-11 is currently one of the most investigated PET agents for imaging both recurrent prostate cancer and relevant metastases; however, the production and distribution of 68Ga-PSMA-11 is limited to a supply of only a few daily doses when using a commercially available 68Ge/68Ga generator. 68Ge/68Ga generators deliver only a modest amount of activity, up to 1850 MBq (50 mCi), when new, but it decreases with time. Additionally, the production of 68Ga/68Ge generators has not been able to meet the increasing demand of 68Ga radiotracers. In response to the need for a more economically viable alternative, the focus of this study was to provide a simple and efficient method for producing 68Ga-PSMA-11, using cyclotron-produced 68Ga that is ready for routine clinical practice.

Pancreatic adenocarcinoma is one of the most lethal and therapeutically resistant malignancies.1 There is no uniform consensus regarding standard of care for treatment of unresectable, locally advanced pancreatic cancer (LAPC). Treatment options include chemotherapy alone, chemotherapy followed by chemoradiotherapy, or stereotactic body radiation therapy.2,3

F.F. Knapp and A. Dash New York, NY: Springer, 2016, 347 pages, $109 There is no denying that the next phase of growth for nuclear medicine is in radionuclide therapy. Radiopharmaceuticals for Therapy is a well-executed book, divided into 5 parts with the primary focus on the use of radioisotopes

W.C. Klingensmith III New York, NY: Springer, 2016, 274 pages, $109 Nuclear medicine relies on capturing the biodistribution of radiopharmaceuticals on images that can be interpreted by the physician. The Mathematics and Biology of the Biodistribution of Radiopharmaceuticals: A Clinical

C.N. Cole, S.M. Shaw, and R.J. Kowalsky Washington, DC: American Pharmacists Association, 2012, 150 pages, $30.95 Nuclear Pharmacy Quick Reference is a practical and informative text on radiopharmaceuticals. This book is authored by experienced and well-respected individuals in the nuclear