Description: Targeting cancer cells with vitamin B12 (cobalamin) is hampered by unwanted physiologic tissue uptake mediated by transcobalamin. Adhering to good manufacturing practice, we have developed a new 99m Tc-cobalamin derivative ( 99m Tc(CO) 3 -[(4-amido-butyl)-pyridin-2-yl-methyl-amino-acetato] cobalamin, 99m Tc-PAMA-cobalamin). The derivative shows no binding to transcobalamin but is recognized by haptocorrin, a protein present in the circulation and notably expressed in many tumor cells. In this prospective study, we investigated cancer-specific uptake of 99m Tc-PAMA-cobalamin in 10 patients with various metastatic tumors. Methods: Ten patients with biopsy-proven metastatic cancer were included. Dynamic imaging was started immediately after injection of 300–500 MBq of 99m Tc-PAMA-cobalamin, and whole-body scintigrams were obtained at 10, 30, 60, 120, and 240 min and after 24 h. The relative tumor activity using SPECT/CT over the tumor region after 4 h was measured in comparison to disease-free lung parenchyma. Patients 3–10 received between 20 and 1,000 μg of cobalamin intravenously before injection of 99m Tc-PAMA-cobalamin. The study population comprised 4 patients with adenocarcinomas of the lung, 3 with squamous cell carcinomas of the hypopharyngeal region, 1 with prostate adenocarcinoma, 1 with breast, and 1 with colon adenocarcinoma. Results: The median age of the study group was 61 ± 11 y. Six of 10 patients showed positive tumor uptake on 99m Tc-PAMA-cobalamin whole-body scintigraphy. The scan was positive in 1 patient with colon adenocarcinoma, in 3 of 4 lung adenocarcinomas, in 1 of 3 hypopharyngeal squamous cell carcinomas, and in 1 breast adenocarcinoma. Renal uptake was between 1% and 3% for the left kidney. Predosing with cobalamin increased the tumor uptake and improved blood-pool clearance. The best image quality was achieved with a predose of 20–100 ug of cold cobalamin. The mean patient dose was 2.7 ± 0.9 mSv/patient. Conclusion: To our knowledge, we report for the first time on 99m Tc-PAMA-cobalamin imaging in patients with metastatic cancer disease and show that tumor targeting is feasible.

Description: The tumor proliferation marker, Ki-67 index, is a well-established prognostic marker in gastroenteropancreatic neuroendocrine neoplasms (NENs). Noninvasive molecular imaging allows whole-body metabolic characterization of metastatic disease. We investigated the prognostic impact of 18 F-FDG PET in inoperable multifocal disease. Methods: Retrospective, dual-center analysis was performed on 89 patients with histologically confirmed, inoperable metastatic gastroenteropancreatic NENs undergoing 18 F-FDG PET/CT within the staging routine. Metabolic (PET-based) grading was in accordance with the most prominent 18 F-FDG uptake (reference tumor lesion): mG1, tumor-to-liver ratio of maximum standardized uptake value ≤ 1.0; mG2, 1.0–2.3; mG3, 〉2.3. Other potential variables influencing overall survival, including age, tumor origin, performance status, tumor burden, plasma chromogranin A (≥600 μg/L), neuron-specific enolase (≥25 μg/L), and classic grading (Ki-67–based) underwent univariate (log-rank test) and multivariate analysis (Cox proportional hazards model), with a P value of less than 0.05 considered significant. Results: The median follow-up period was 38 mo (95% confidence interval [CI], 27–49 mo); median overall survival of the 89 patients left for multivariate analysis was 29 mo (95% CI, 21–37 mo). According to metabolic grading, 9 patients (10.2%) had mG1 tumors, 22 (25.0%) mG2, and 57 (64.8%) mG3. On multivariate analysis, markedly elevated plasma neuron-specific enolase ( P = 0.016; hazard ratio, 2.9; 95% CI, 1.2–7.0) and high metabolic grade ( P = 0.015; hazard ratio, 4.7; 95% CI, 1.2–7.0) were independent predictors of survival. Conclusion: This study demonstrated the feasibility of prognostic 3-grade stratification of metastatic gastroenteropancreatic NENs by whole-body molecular imaging using 18 F-FDG PET.

Description: Chemical Reviews DOI: 10.1021/cr2001146

Description: Chemical Reviews DOI: 10.1021/cr200167v

Description: This study provides the first comprehensive quantification of translocator protein (TSPO) binding using SPECT and 6-chloro-2-(4'- 123 I-iodophenyl)-3-( N,N- diethyl)-imidazo[1,2-a]pyridine-3-acetamide ( 123 I-CLINDE) in neurologic patients. 123 I-CLINDE is structurally related to well-known PET ligands such as 18 F-PBR111 and 18 F-DPA-714. Methods: Six patients with cerebral stroke and 4 patients with glioblastoma multiforme (GBM) underwent 150-min dynamic SPECT scans with arterial blood sampling. Four of the patients were rescanned. All patients were genotyped for the rs6971 polymorphism. Volumes of interest were delineated on the individual SPECT scans and the coregistered MR images. Compartmental and graphical models using arterial input or the cerebellum as a reference region were used to quantify 123 I-CLINDE binding. Results: Among the 6 models investigated, the 2-tissue-compartment model with arterial input described the time–activity data best. Time–stability analyses suggested that acquisition time should be at least 90 min. Intersubject variation in the cerebellar distribution volume ( V T ) was clearly related to the TSPO genotype. In the stroke patients the V T in the periinfarction zone, compared with V T in the ipsilateral cerebellum, ranged from 1.4 to 3.4, and in the GBM patients the V T in the tumor, compared with the V T in the cerebellum, ranged from 1.8 to 3.4. In areas of gadolinium extravasation, 123 I-CLINDE binding parameters were not significantly changed. Thus, 123 I-CLINDE binding does not appear to be importantly affected by blood–brain barrier disruption. Conclusion: As demonstrated within a group of stroke and GBM patients, 123 I-CLINDE SPECT can be used for quantitative assessment of TSPO expression in vivo. Because of the absence of a region devoid of TSPO, reference tissue models should be used with caution. The 2-tissue-compartment kinetic analysis of a 90-min dynamic scan with arterial blood sampling is recommended for the quantification of 123 I-CLINDE binding with SPECT.