Basic Research And Clinical Translation Of Novel Radionuclide Labeled Probes

Project I Synthesis and in vivo evaluation of 68Ga-DOTA-TATE in miceObjective To synthesize 68Ga-1,4,7,10-tetraazacyclododecane-N,N,N,N-tetraacetic acid-D-Phe1-Tyr3-Thr8-octreotide (68Ga-DOTA-TATE) manually and automatically, validate its qualities in vitro, and evaluate its biodistributions in ICR mice and the microPET imaging in nude mice bearing pancreatic AR42J tumor model.Methods 68Ga-DOTA-TATE was automatically synthesized using commercial metal isotope multifunctional module with strong cation exchange (SCX) column method and manual method. The quality controls of both the product injection were proceeded. The biodistribution in ICR mice was evaluated using 5 groups of mice which were executed 10,30,60,120 and 240 min after injection respectively. The organs were weighted, and %ID/g was calculated. Nude mice models bearing pancreatic AR42J tumor were intravenously injected with 3.7 MBq 68Ga-DOTA-TATE. MicroPET imaging was acquired at 10,30,60,120,18 and 240 min to investigate the uptakes of tumor.Results 68Ga-DOTA-TATE could be successfully synthesized with the automatic and manual method. Both the product injections were colorless and clear, pH value were both 6.5, the radiochemical purities were over 99% and stable for 4 h at room temperature.68Ga-DOTA-TATE was synthesized with radiochemical yield of (51.8±3.2)%(time decay corrected) in about 30 min with the automatic method, and over 99% yield within 20 min with manual method. Three batches of samples were detected aseptic and pyrogen-free. In ICR mice,68Ga-DOTA-TATE was excreted by the kidney, relatively high in the liver, spleen, pancreas and adrenal glands while low in bone and soft tissue. The clearance from blood was fast with (4.41±0.81)%ID/g at 10 min post-injection and (0.78±0.32)%ID/g at 1 h. MicroPET imaging showed increased uptake of 68Ga-DOTA-TATE in tumor tissues in nude mice models bearing AR42J tumor and T/NT were 2.01±0.29 (10min),6.74±2.90 (30 min) and 4.46±2.05 (60min)Conclusions 68Ga-DOTA-TATE could be sucessfully synthesized manually and automatically. The product injection was up to the specification of radioactive drugs and could be a very attractive positron emitting radiotracer for detection of somatostatin receptor-positive tumors.Project II Finding out the cloak-and-dagger tumor in state of the art----68Ga-DOTATATE PET/CT versus 18F-FDG PET/CT and 99mTc-HYNIC-TOC SPECT in detection of the causative tumor in osteomalacia patientsObjective Purpose Tumor-induced osteomalacia (TIO) is a rare disease characterized by hypophosphatemia and osteomalacia. TIO patients suffer from gradually worsening bone pain and muscle weakness and live in a poor quality of life when most of them are still very young. The disease is usually driven by an occult, slow-growing tumor. The only way to cure is to find out the cloak-and-dagger tumor and remove it completely. However, localization of the causative tumor in TIO patients is usually a challenge because most of the lesions are small, stealthy and can occur on any part of the body. A novel diagnostic approach,68Ga-DOTATATE PET/CT, was evaluated for detection of the tumor-induced osteomalacia (TIO) lesions prospectively, and also compared with 99mTc-HYNIC-TOC SPECT, which has been considered superior diagnostic method, and 18F-FDG PET/CT case by case.Methods A total of 111 consecutive patients (M 59, F 52, aged 42.2±12.3 years) suffering from osteomalacia underwent PET/CT scans from head to toe 30-45 min after intravenous injection of 111-148 MBq (3-4 mCi) 68Ga-DOTATATE. All the 111 patients underwent 99mTc-HYNIC-TOC scintigraphy and accepted 18F-FDG PET/CT within 2 weeks for comparison.Results 68Ga-DOTATATE PET/CT showed positive findings in 92 (82.9%) of the 111 osteomalacia patients, while only 28 (25.2%) were positive on 18F-FDG PET/CT and 31 (27.9%) were detected by 99mTc-HYNIC-TOC scintigraphy. The tumors sized from 0.7 to 6.7 (2.2±1.1) cm were found in the mandible, base of pelvic cavity, caudal vertebrae, and other sites. The SUVmax of 68Ga-DOTA-TATE (11.4±8.6) were significantly higher than those of 18F-FDG (5.8±5.2, P<0.05). To date,89 of the 92 positive tumors were surgically removed. Among them,87 were found to be phosphaturic mesenchymal tumors,1 was diagnosed as odontogenic fibrous tumors and 1 was diagnosed as smashed osseous tissue. So far, all the 19 negative patients in 68Ga-DOTATATE PET/CT have been confirmed as true-negative, including Fanconi syndrome, responded well to conservative therapy, or confirmed diagnosis of other causes of hypophosphatemia.Conclusions 68Ga-DOTATATE PET/CT is a state-of-the-art approach for detection of the causative tumors in patients with osteomalacia.Project ⅢCharacterizing IgG4-related disease with 18F-FDG PET/CT: a prospective cohort studyObjectives IgG4-related disease (IgG4-RD) is an increasingly recognized clinicopathological disorder with immune-mediated inflammatory lesions mimicking malignancies. A cohort study was prospectively designed to investigate the value of 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) in characterizing IgG4-RD.Methods Thirty-five patients diagnosed with IgG4-RD according to the consensus criteria were enrolled with informed consent. All patients underwent baseline 18F-FDG PET/CT evaluation. Among them,29 patients underwent a second 18F-FDG PET/CT scan after 2 to 4 weeks of steroid-based therapy.Results All 35 patients were found with 18F-FDG-avid hypermetabolic lesion(s); 97.1%(34/35) of these patients showed multi-organ involvement. Among the 35 patients,71.4%(25/35) patients were found with more organ involvement on 18F-FDG PET/CT than conventional evaluations including physical examination, ultrasonography, and computed tomography (CT).18F-FDG PET/CT demonstrated specific image characteristics and pattern of IgG4-RD, including diffusely elevated 18F-FDG uptake in the pancreas and salivary glands, patchy lesions in the retroperitoneal region and vascular wall, and multi-organ involvement that cannot be interpreted as metastasis. Comprehensive understanding of all involvement aided the biopsy-site selection in seven patients and the recanalization of ureteral obstruction in five patients. After 2 to 4 weeks of steroid-based therapy at 40 mg to 50 mg prednisone per day,72.4%(21/29) of the patients showed complete remission, whereas the others exhibited> 81.8% decrease in 18F-FDG uptake.Conclusions 18F-FDG PET/CT is a useful tool for assessing organ involvement, monitoring therapeutic response, and guiding interventional treatment of IgG4-RD. The image pattern is suggested to be updated into the consensus diagnostic criteria for IgG4-RD.Project IVClinical Translation of a Novel Albumin-Binding PET Radiotracer 68Ga-NEBObjectives To synthesize a novel albumin-binding PET radiotracer 68Ga-NEB, validate its pharmacokinetics, safety, dosimetry, and document the first-in-human application.Methods A cyclic chelator, 1,4,7-triazacyclononane-N,N’,N"-triacetic acid (NOTA) conjugated truncated form of Evans blue (NEB) was synthesized and labeled with 68Ga. Sixty-minute dynamic PET imaging and biodistribution in normal mice were performed to evaluate the in vivo pharmacokinetics. After a clinical trial was approved by the institute review board, three healthy volunteers were enrolled to validate the safety of 68Ga-NEB and a total of 19 patients with written informed consent were recruited. The diagnosis was based on pathological result of surgical removal or biopsy.Results The whole labeling process of 68Ga-NEB took about 30 min with a radiochemical purity of greater than 95%. After intravenous injection,68Ga-NEB forms complex with serum albumin and majority of the radioactivity was retained in the blood circulation. With an injected dose of 3-4 mCi (121-148 MBq), a patient would be exposed to a radiation dose of 2.65 mSv, which is much lower than the dose limit as set by the FDA. The tracer was demonstrated to be safe in both healthy volunteers and patients without side effects or allergies. The small scale clinical study substantiated the role of NEB as a blood pool imaging agent in differentiating hepatic hemangioma from other benign or malignant focal hepatic lesions, delineating vascular anomalies including abdominal aortic aneurysm (AAA) and arteriovenous malformation (AVM), mapping of sentinel lymph nodes (SNLs) and evaluation of blood supply to brain tumors.Conclusions Easy labeling with different positron emitters of various half-lives, excellent pharmacokinetics, and imaging quality warrant further clinical applications of NEB based PET tracers.