A novel synthesis of 6''-[18 F]-fluoromaltotriose as a PET tracer for imaging bacterial infection.

The aim of this study was to develop a positron emission tomography (PET) tracer to visualize and monitor therapeutic response to bacterial infections. In our continued efforts to find maltose based PET tracers that can image bacterial infections, we have designed and prepared 6''-[18 F]fluoromaltotriose as a second generation PET imaging tracer targeting the maltodextrin transporter of bacteria. We have developed methods to synthesize 6''-deoxy-6''-[18 F]fluoro-α-D-glucopyranosyl-(1-4)-O-α-D-glucopyranosyl-(1-4)-O-D-glucopyranose (6''-[18 F]-fluoromaltotriose) as a bacterial infection PET imaging agent. 6''-[18 F]fluoromaltotriose was prepared from precursor, 2'',3'',4''-tri-O-acetyl-6''-O-nosyl-α-D-glucopyranosyl-(1-4)-O-2',3',6'-tri-O-acetyl-α-D-glucopyranosyl-(1-4)-1,2,3,6-tetra-O-acetyl-D-glucopyranose (per-O-acetyl-6''-O-nosyl-maltotriose 4). This method utilizes the reaction between precursor 4 and anhydrous [18 F]KF/Kryptofix 2.2.2 in dimethylformamide (DMF) at 85°C for 10 minutes to yield per-O-acetyl-6''-deoxy-6-'' [18 F]-fluoromaltotriose (7). Successive acidic and basic hydrolysis of the acetyl protecting groups in 7 produced 6''-[18 F]fluoromaltotriose (8). Also, cold 6''- [19 F]fluoromaltotriose was prepared from per-O-acetyl-6''-hydroxymaltotriose via a diethylaminosulfur trifluoride reaction followed by a basic hydrolysis. A successful synthesis of 6''-[18 F]-fluoromaltotriose has been accomplished in 8 ± 1.2% radiochemical yield (decay corrected). Total synthesis time was 120 minutes. Serum stability of 6''-[18 F]fluoromaltotriose at 37°C indicated that 6''-[18 F]-fluoromaltotriose remained intact up to 2 hours. In conclusion, we have successfully synthesized 6''-[18 F]-fluoromaltotriose via direct fluorination of an appropriate precursor of a protected maltotriose.

Evaluation of integrin αvß6 cystine knot PET tracers to detect cancer and idiopathic pulmonary fibrosis.

Advances in precision molecular imaging promise to transform our ability to detect, diagnose and treat disease. Here, we describe the engineering and validation of a new cystine knot peptide (knottin) that selectively recognizes human integrin αvß6 with single-digit nanomolar affinity. We solve its 3D structure by NMR and x-ray crystallography and validate leads with 3 different radiolabels in pre-clinical models of cancer. We evaluate the lead tracer's safety, biodistribution and pharmacokinetics in healthy human volunteers, and show its ability to detect multiple cancers (pancreatic, cervical and lung) in patients at two study locations. Additionally, we demonstrate that the knottin PET tracers can also detect fibrotic lung disease in idiopathic pulmonary fibrosis patients. Our results indicate that these cystine knot PET tracers may have potential utility in multiple disease states that are associated with upregulation of integrin αvß6.

Use of Medicare and DOD data for improving VA race data quality.

We evaluated the improvement in Department of Veterans Affairs (VA) race data completeness that could be achieved by linking VA data with data from Medicare and the Department of Defense (DOD) and examined agreement in values across the data sources. After linking VA with Medicare and DOD records for a 10% sample of VA patients, we calculated the percentage for which race could be identified in those sources. To evaluate race agreement, we calculated sensitivities, specificities, positive predictive values (PPVs), negative predictive values, and kappa statistics. Adding Medicare (and DOD) data improved race data completeness from 48% to 76%. Among older patients (≥65 years), adding Medicare data improved data completeness to nearly 100%. Among younger patients (<65 years), combining Medicare and DOD data improved completeness to 75%, 18 percentage points beyond that achieved with Medicare data alone. PPVs for white and African-American categories were 98.6 and 94.7, respectively, in Medicare and 97.0 and 96.5, respectively, in DOD data using VA self-reported race as the gold standard. PPVs for the non-African-American minority groups were lower, ranging from 30.5 to 48.2. Kappa statistics reflected these patterns. Supplementing VA with Medicare and DOD data improves VA race data completeness substantially. More study is needed to understand poor rates of agreement between VA and external sources in identifying non-African-American minority individuals.