[en] Highlights: • A new P2X7R radioligand [¹⁸F]IUR-1602 was synthesized. • A 2-step 2-pot fully automated [¹⁸F]-radiosynthesis for [¹⁸F]IUR-1602 was developed. • A semi-preparative RP HPLC-SPE technique was employed in radiosynthesis. • K_i value of IUR-1602 was 23.6 ± 0.96 nM. - Abstract: The overexpression of P2X7R is associated with neuroinflammation and plays an important role in various neurodegenerative diseases. The [¹⁸F]fluoropropyl derivative of GSK1482160, [¹⁸F]IUR-1602, has been first prepared and examined as a new potential P2X7R radioligand. The reference standard IUR-1602 was synthesized from tert-butyl (S)-5-oxopyrrolidine-2-carboxylate, fluoropropylbromide, and 2-chloro-3-(trifluoromethyl)benzylamine with overall chemical yield 13% in three steps. The target tracer [¹⁸F]IUR-1602 was synthesized from desmethyl-GSK1482160 with 3-[¹⁸F]fluoropropyl tosylate, prepared from propane-1,3-diyl bis(4-methylbenzenesulfonate) and K[¹⁸F]F/Kryptofix2.2.2, in two steps and isolated by HPLC combined with SPE in 2–7% decay corrected radiochemical yield. The radiochemical purity was >99%, and the molar activity at end of bombardment (EOB) was 74–370 GBq/μmol. The potency of IUR-1602 in comparison with GSK1482160 was determined by a radioligand competitive binding assay using [¹¹C]GSK1482160, and the binding affinity K_i values for IUR-1602 and GSK1482160 are 23.6 and 3.07 nM, respectively. The initial in vitro evaluation results, 8-fold less potency of [¹⁸F]IUR-1602 compared to [¹¹C]GSK1482160, prevent further in vivo evaluation of [¹⁸F]IUR-1602 in animals and human.

[en] Introduction: Positron emission tomography scanning with radiolabeled phenyltropane cocaine analogs is important for quantifying the in vivo density of monoamine transporters, including the dopamine transporter (DAT). [¹¹C]β-CFT is useful for studying DAT as a marker of dopaminergic innervation in animal models of psychiatric and neurological disorders. [¹¹C]β-CFT is commonly labeled at the N-methyl position. However, labeling of [¹¹C]β-CFT at the O-methyl position is a simpler procedure and results in a shorter synthesis time [desirable in small-animal studies, where specific activity (SA) is crucial]. In this study, we sought to validate that the O-methylated form of [¹¹C]β-CFT provides equivalent quantitative results to that of the more commonly reported N-methyl form. Methods: Four female Sprague-Dawley rats were scanned twice on the IndyPET II small-animal scanner, once with [N-methyl-¹¹C]β-CFT and once with [O-methyl-¹¹C]β-CFT. DAT binding potentials (BP≡B'_avail/K_d) were estimated for right and left striata with a nonlinear least-squares algorithm, using a reference region (cerebellum) as the input function. Results: [N-Methyl-¹¹C]β-CFT and [O-methyl-¹¹C]β-CFT were synthesized with 40-50% radiochemical yields (HPLC purification). Radiochemical purity was >99%. SA at end of bombardment was 258±30 GBq/μmol. Average BP values for right and left striata with [N-methyl-¹¹C]β-CFT were 1.16±0.08 and 1.23±0.14, respectively. BP values for [O-methyl-¹¹C]β-CFT were 1.18±0.08 (right) and 1.22±0.16 (left). Paired t tests demonstrated that labeling position did not affect striatal DAT BP. Conclusions: These results suggest that [O-methyl-¹¹C]β-CFT is quantitatively equivalent to [N-methyl-¹¹C]β-CFT in the rat striatum

[en] Hepatocellular carcinoma (HCC) remains a global health problem with unique diagnostic and therapeutic challenges, including difficulties in identifying the highest risk patients. Previous work from our lab has established the murine multidrug resistance-2 mouse (MDR2) model of HCC as a reasonable preclinical model that parallels the changes seen in human inflammatory associated HCC. The purpose of this study is to evaluate modalities of PET/CT in MDR2^−/− mice in order to facilitate therapeutic translational studies from bench to bedside. ¹⁸F-FDG and ¹¹C-acetate PET/CT was performed on 12 m MDR2^−/− mice (n = 3/tracer) with HCC and 12 m MDR2^−/+ control mice (n = 3/tracer) without HCC. To compare PET/CT to biological markers of HCC and cellular function, serum alpha-fetoprotein (AFP), lysophosphatidic acid (LPA), cAMP and hepatic tumor necrosis factor α (TNFα) were quantified in 3-12 m MDR2^−/− (n = 10) mice using commercially available ELISA analysis. To translate results in mice to patients ¹¹C-acetate PET/CT was also performed in 8 patents suspected of HCC recurrence following treatment and currently on the liver transplant wait list. Hepatic¹⁸F-FDG metabolism was not significantly increased in MDR2^−/− mice. In contrast, hepatic ¹¹C-acetate metabolism was significantly elevated in MDR2^−/− mice when compared to MDR2^−/+ controls. Serum AFP and LPA levels increased in MDR2^−/− mice contemporaneous with the emergence of HCC. This was accompanied by a significant decrease in serum cAMP levels and an increase in hepatic TNFα. In patients suspected of HCC recurrence there were 5 true positives, 2 true negatives and 1 suspected false ¹¹C-acetate negative. Hepatic ¹¹C-acetate PET/CT tracks well with HCC in MDR2^−/− mice and patients with underlying liver disease. Consequently ¹¹C-acetate PET/CT is well suited to study 1) HCC emergence/progression in patients and 2) reduce animal numbers required to study new chemotherapeutics in murine models of HCC

[en] The etiology of enlarged subarachnoid spaces of infancy is unknown; however, there is radiologic similarity with normal pressure hydrocephalus. Adults with normal pressure hydrocephalus have been shown to have altered cerebrospinal (CSF) flow through the cerebral aqueduct. To explore potential similarity between enlarged subarachnoid spaces of infancy and normal pressure hydrocephalus, we compared MRI-measured CSF flow through the cerebral aqueduct in infants with enlarged subarachnoid spaces of infancy to infants with normal brain MRIs. This was an IRB approved retrospective study. Clinical brain MRI examinations including axial T2 imaging and phase contrast through the aqueduct were reviewed for infants with enlarged subarachnoid spaces of infancy and for infants with a qualitatively normal brain MRI. The brain and CSF volumes were segmented using a semi-automatic technique (Analyze 12.0) and CSF flow parameters were measured (cvi42, 5.14). All data was assessed for significant differences while controlling for age and sex using analysis of covariance (ANCOVA). Twenty-two patients with enlarged subarachnoid spaces (mean age 9.0 months, 19 males) and 15 patients with normal brain MRI (mean age 18.9 months, 8 females) were included. Volumes of the subarachnoid space (P < 0.001), lateral (P < 0.001), and third ventricles (P < 0.001) were significantly larger in infants with enlarged subarachnoid spaces of infancy. Aqueductal stroke volume significantly increased with age (P = 0.005), regardless of group. CSF volumes were significantly larger in infants with enlarged subarachnoid spaces of infancy versus infants with a normal MRI; however, there was no significant difference in CSF flow parameters between the two groups.

[en] Multi-instrument activity estimation and decay correction techniques were developed for radionuclide mixtures, motivated by the desire for accurate quantitation of Tc-94m positron emission tomography (PET) studies. Tc-94m and byproduct Tc isotopes were produced by proton irradiation of enriched Mo-94 and natural Mo targets. Mixture activities at the end of bombardment were determined with a calibrated high purity germanium detector. The activity fractions of the greatest mixture impurities relative to 100% for Tc-94m averaged 10.0% (Tc-94g) and 3.3% (Tc-93) for enriched targets and 10.1% (Tc-94g), 11.0% (Tc-95), 255.8% (Tc-96m), and 7.2% (Tc-99m) for natural targets. These radioisotopes have different half-lives (e.g., 52.5 min for Tc-94m, 293 min for Tc-94g), positron branching ratios (e.g., 0.72 for Tc-94m, 0.11 for Tc-94g) and gamma ray emissions for themselves and their short-lived, excited Mo daughters. This complicates estimation of injected activity with a dose calibrator, in vivo activity with PET and blood sample activity with a gamma counter. Decay correction using only the Tc-94m half-life overestimates activity and is inadequate. For this reason analytic formulas for activity estimation and decay correction of radionuclide mixtures were developed. Isotope-dependent sensitivity factors for a PET scanner, dose calibrator, and gamma counter were determined using theoretical sensitivity models and fits of experimental decay curves to sums of exponentials with fixed decay rates. For up to 8 h after the end of bombardment with activity from enriched and natural Mo targets, decay-corrected activities were within 3% of the mean for three PET studies of a uniform cylinder, within 3% of the mean for six dose calibrator decay studies, and within 6% of the mean for four gamma counter decay studies. Activity estimation and decay correction for Tc-94m mixtures enable routine use of Tc-94m in quantitative PET, as illustrated by application to a canine Tc-94m sestamibi study

[en] Introduction: ["1"1C]PBR28 is a high-affinity ligand for the Translocator Protein 18 kDa (TSPO), which is considered to be a marker for microglial activation. Volume of distribution (V_T) estimated with an arterial plasma input function is the gold standard for quantitation of ["1"1C]PBR28 binding. However, arterial sampling is impractical at many PET sites for multiple reasons. Reference region modeling approaches are not ideal for TSPO tracers, as the existence of a true reference region cannot be assumed. Given that it would be desirable to have a non-invasive index of ["1"1C]PBR28 binding, we elected to study the utility of the semi-quantitative metric, standardized uptake value (SUV) for use in brain ["1"1C]PBR PET studies. The primary goal of this study was to determine the relationship between SUV and V_T. Methods: We performed a retrospective analysis of data from sixteen ["1"1C]PBR28 PET scans acquired in baboons at baseline and at multiple time points after IV injection of lipopolysaccharide, an endotoxin that transiently induces neuroinflammation. For each scan, data from 14 brain regions of interest were studied. V_T was estimated with the Logan plot, using metabolite-corrected input functions. SUV was calculated with data from 30 to 60 minutes after ["1"1C]PBR28 injection. Results: Within individual PET studies, SUV tended to correlate well with V_T. Across studies, the relationship between SUV and V_T was variable. Conclusions: From study to study, there was variability in the degree of correlation between ["1"1C]PBR28 V_T and SUV. There are multiple physiological factors that may contribute to this variance. Advances in Knowledge: As currently applied, the non-invasive measurement of SUV does not appear to be a reliable outcome variable for ["1"1C]PBR28. Additional work is needed to discover the source of the discrepancy in SUV between ["1"1C]PBR28 scans. Implications for Patient Care: There is a need to develop alternatives to arterial plasma input functions for TSPO ligands in order to facilitate multi-center trials

[en] The early detection of atherosclerotic disease is vital to the effective prevention and management of life-threatening cardiovascular events such as myocardial infarctions and cerebrovascular accidents. Given the potential for positron emission tomography (PET) to visualize atherosclerosis earlier in the disease process than anatomic imaging modalities such as computed tomography (CT), this application of PET imaging has been the focus of intense scientific inquiry. Although ¹⁸F-FDG has historically been the most widely studied PET radiotracer in this domain, there is a growing body of evidence that ¹⁸F-NaF holds significant diagnostic and prognostic value as well. In this article, we review the existing literature on the application of ¹⁸F-FDG and ¹⁸F-NaF as PET probes in atherosclerosis and present the findings of original animal and human studies that have examined how well ¹⁸F-NaF uptake correlates with vascular calcification and cardiovascular risk. (orig.)

[en] Characteristic features of chronic pancreatitis (CP) may be absent on standard imaging studies. Quantitative Magnetic Resonance Imaging (MRI) techniques such as T₁ mapping, extracellular volume (ECV) fraction, diffusion-weighted imaging (DWI) with apparent diffusion coefficient map (ADC), MR elastography (MRE), and T₁-weighted signal intensity ratio (SIR) have shown promise for the diagnosis and grading severity of CP. However, radiologists still use the Cambridge classification which is based on traditional ductal imaging alone. There is an urgent need to develop new diagnostic criteria that incorporate both parenchymal and ductal features of CP seen by MRI/MRCP. Designed to fulfill this clinical need, we present the MINIMAP study, which was funded in September 2018 by the National Institutes of Health. This is a comprehensive quantitative MR imaging study which will be performed at multiple institutions in well-phenotyped CP patient cohorts. We hypothesize that quantitative MRI/MRCP features can serve as valuable non-invasive imaging biomarkers to detect and grade CP. We will evaluate the role of T₁ relaxometry, ECV, T₁-weighted gradient echo SIR, MRE, arteriovenous enhancement ratio, ADC, pancreas volume/atrophy, pancreatic fat fraction, ductal features, and pancreatic exocrine output following secretin stimulation in the assessment of CP. We will attempt to generate a multi-parametric pancreatic tissue fibrosis (PTF) scoring system. We anticipate that a quantitative scoring system may serve as a biomarker of pancreatic fibrosis; hence this imaging technique can be used in clinical practice as well as clinical trials to evaluate the efficacy of agents which may slow the progression or reverse measures of CP.