D‐ and L‐[123I]‐2‐I‐phenylalanine show a long tumour retention compared with D‐ and L‐[123I]‐2‐I‐tyrosine in R1M rhabdomyosarcoma tumour‐bearing Wag/Rij rats

The aim of this study was the comparison of the tumour uptake and the long‐term retention of [¹²³I]‐2‐I‐L ‐phenylalanine and [¹²³I]‐2‐I‐D ‐phenylalanine with those of [¹²³I]‐2‐I‐L ‐tyrosine and [¹²³I]‐2‐I‐D ‐tyrosine in R1M rhabdomyosarcoma tumour‐bearing rats. The biodistribution of the radioactivity as a function of time in R1M tumour‐bearing rats was measured by planar gamma camera imaging (dynamic and static). If dissection was applied, the activity in the tumours and tissues of interest was measured by gamma counting. [¹²³I]‐2‐iodo‐L ‐phenylalanine, [¹²³I]‐2‐iodo‐D ‐phenylalaine, [¹²³I]‐2‐I‐L ‐tyrosine showed a considerable tumour uptake reaching a maximum between 10 and 30 min. At 30 min p.i. the differential uptake ratio values of this uptake were, respectively, 2.1, 2.3, 2.5 and 1.7. The activity in the tumour was shown to be related to a tumour cell uptake and not to an increased blood pool activity. All the tracers showed a clearance from the blood to the bladder without renal retention. At longer times both L ‐ and D ‐ [¹²³I]‐2‐I‐tyrosine were cleared for a large part from the tumours and the body. [¹²³I]‐2‐I‐L ‐Phe and [¹²³I]‐2‐I‐D ‐Phe showed a considerable and equal retention in the tumours: as compared with 0.5 h, 91% at 24 h and 80% at 48 h. This was related to the longer retention of activity in the blood pool noticed for these compounds (81% at 24 h and 65% at 48 h). The tumour‐to‐background ratio increased with 25% at those longer times. At short times all the tracers were taken up to a considerable extent in the tumours. In the R1M‐bearing Wag/Rij rat model only [¹²³I]‐2‐I‐L ‐phenylalanine and [¹²³I]‐2‐I‐D ‐phenylalanine showed an especially high retention at long times without any significant difference between the enantiomers. Copyright © 2007 John Wiley & Sons, Ltd.     

In vivo evaluation of the dopaminergic neurotransmission system using [123I]FP‐CIT SPECT in 6‐OHDA lesioned rats

The 6‐hydroxydopamine (6‐OHDA) rodent model of Parkinson's disease (PD) has been used to evaluate the nigrostriatal pathway. The aim of this work was to explore the relationship between the degree of 6‐OHDA‐induced dopaminergic degeneration and [¹²³I]FP‐CIT binding using single photon emission computed tomography (SPECT). Fourteen rats received a 6‐OHDA injection (4 or 8 µg) into the left medial forebrain bundle. After 3 weeks, magnetic resonance imaging and scans with a small‐animal SPECT system were performed. Finally, the nigrostriatal lesion was assessed by immunohistochemical analysis. Immunohistochemical analysis confirmed two levels of dopaminergic degeneration. Lesions induced by 6‐OHDA diminished the ipsilateral [¹²³I]FP‐CIT binding by 61 and 76%, respectively. The decrease in tracer uptake between control and lesioned animals was statistically significant, as was the difference between the two 6‐OHDA lesioned groups. Results concluded that [¹²³I]FP‐CIT SPECT is a useful technique to discriminate the degree of dopaminergic degeneration in a rat model of PD. Copyright © 2014 John Wiley & Sons, Ltd.     

Simultaneous [99mTc]TRODAT-1 and [123I]ADAM Brain SPECT in Nonhuman Primates

Purpose  This study examined the feasibility of simultaneous dopamine and serotonin transporter imaging using [¹²³I]ADAM and [^99mTc]TRODAT-1 single photon emission computed tomography (SPECT). Procedures  Simultaneous [¹²³I]ADAM (185 MBq) and [^99mTc]TRODAT-1 (740 MBq) SPECT was performed in three age-matched female Formosan rock monkeys. An asymmetric energy window was used for dual, and symmetric energy windows were used for single-isotope imaging. Oral fluoxetine (20 mg) and intravenous methylphenidate HCl (1 mg/kg) were given 24 h and 10 min, respectively, before dual-isotope SPECT to test imaging specificities of [¹²³I]ADAM and [^99mTc]TRODAT-1. Results  Comparable image quality and uptake ratios between dual- and single-isotope SPECT scans were found. Dual-isotope SPECT in fluoxetine-pretreated monkeys showed decreased uptake of [¹²³I]-ADAM, but not of [^99mTc]TRODAT-1. Dual-isotope SPECT in methylphenidate-pretreated monkeys showed decreased [^99mTc]TRODAT-1 uptake without affecting [¹²³I]-ADAM uptake. Conclusion  Simultaneous [¹²³I]-ADAM and [^99mTc]TRODAT-1 SPECT appears promising in nonhuman primates and may provide a suitable preclinical model with further clinical implications.     

Spatial Inhomogeneity of Cardiac Norepinephrine Transport Protein and Meta-[123I]Iodobenzylguanidine Uptake in Swine Myocardial Tissue

Purpose

The aim of the present study was to evaluate the expression of the cardiac norepinephrine transporter (NET) in the left ventricle (LV) of healthy pigs and its relationship with regional meta-[¹²³I]iodobenzylguanidine ([¹²³I]MIBG) myocardial uptake.

Procedures

Experiments were performed on animals injected with [¹²³I]MIBG and acquired 2 h later using an ultrafast CZT gamma camera to assess the regional myocardial uptake. After image acquisition, animals were euthanized; the heart was quickly excised and underwent to an ex vivo single photon emission tomography (SPECT) imaging. Four small samples of tissue were then harvested from mid-walls and apex of the left ventricle; NET densities were evaluated and further normalized for protein loading per cardiac region.

Results

Three variants of NET protein with different molecular weights were detected. The expression of NET was not homogenous in the LV, with the highest density in the inferior wall and the lowest one in the apical area. The regional in vivo [¹²³I]MIBG uptake revealed an analogous trend, showing a good linear relationship with NET expression. Parallel results were obtained from the ex vivo study.

Conclusion

This study elucidates the expression of three different variants of NET proteins into the left ventricular myocardium of a healthy pig. NET expression into the LV was not homogeneous and paralleled by differences in regional [¹²³I]MIBG uptake. Moreover, the correlation and the agreement between measurements of regional expression of NET variants and [¹²³I]MIBG uptake represent a relevant finding for inferences about NET expression in the context of clinical imaging.

     

<Superscript>123</Superscript>I MIBG Mapping with Intraoperative Gamma Probe for Recurrent Neuroblastoma

Intraoperative gamma probe guidance has become widely utilized for sentinel lymph node dissection in patients with breast cancer and melanoma, using ^99mTc sulfur colloid. However, new indications are possible and need to continue to be investigated. We report the use during a wedge liver biopsy of a new hand-held gamma probe designed for ¹²³I intraoperative guidance. The patient studied is a 5-year-old boy with history of stage 4 high-risk neuroblastoma. Anatomic imaging (CT, MRI), ^99mTc bone scintigraphy and 2-deoxy-2-[F-18]fluoro-d-glucose—positron emission tomography/computed tomography (FDG-PET/CT) were negative, but the ¹²³I MIBG scintigraphy suggested recurrent liver disease. A decision was made to biopsy these lesions to obtain histopathological confirmation. Intraoperative gamma probe mapping of the liver identified areas with signal above the background, but these were prove to be hemosiderin deposits on histo-pathology examination.     

Syntheses and preliminary evaluation of [18F]AlF‐NOTA‐G‐TMTP1 for PET imaging of high aggressive hepatocellular carcinoma

The goal of this study is to evaluate a new ¹⁸F‐labeled imaging agent for diagnosing high metastatic (aggressive) hepatocellular carcinoma using positron emission tomography (PET). The new ¹⁸F‐labeled imaging agent [¹⁸F]AlF‐NOTA‐G‐TMTP1 was synthesized and radiolabeled with ¹⁸F using NOTA‐AlF chelation method. The tumor‐targeting characteristics of [¹⁸F]AlF‐NOTA‐G‐TMTP1 was assessed in HepG2, SMCC‐7721, HCC97L and HCCLM3 xenografts. The total synthesis time was about 20 min with radiochemical yield of 25 ± 6%. The specific activity was about 11.1–14.8 GBq/µmol at the end of synthesis based on the amount of peptide used and the amount of radioactivity trapped on the C₁₈ column. The log P value of [¹⁸F]AlF‐NOTA‐G‐TMTP1 was ‐3.166 ± 0.022. [¹⁸F]AlF‐NOTA‐G‐TMTP1 accumulated in SMCC‐7721 and HCCLM3 tumors (high metastatic potential) in vivo and result in tumor/muscle (T/M) ratios of 4.5 ± 0.3 and 4.7 ± 0.2 (n = 4) as measured by PET at 40 min post‐injection (p.i.). Meanwhile, the tumor/muscle (T/M) ratios of HepG2 and HCC97L tumors (low metastatic potential) were1.6 ± 0.3 and 1.8 ± 0.4. The tumor uptake of [¹⁸F]AlF‐NOTA‐G‐TMTP1 could be inhibited 61.9% and 57.6% by unlabeled G‐TMTP1 in SMCC‐7721 and HCCLM3 xenografts at 40 min p.i., respectively. Furthermore, [¹⁸F]AlF‐NOTA‐G‐TMTP1 showed pretty low activity in the liver and intestines in all tumor bearing mice, such in vivo distribution pattern would be advantageous for the detection of hepatic carcinoma. Overall, [¹⁸F]AlF‐NOTA‐G‐TMTP1 may specifically target high metastatic or/and aggressive hepatocellular carcinoma with low background activity and, therefore, holds the potential to be used as an imaging agent for detecting tumor lesions within the liver area. Copyright © 2016 John Wiley & Sons, Ltd.     

[68Ga]‐HP‐DO3A‐nitroimidazole: a promising agent for PET detection of tumor hypoxia

The goal of this study is to evaluate a new ⁶⁸Ga‐based imaging agent for detecting tumor hypoxia using positron emission tomography (PET). The new hypoxia targeting agent reported here, [⁶⁸Ga]‐HP‐DO3A‐nitroimidazole ([⁶⁸Ga]‐HP‐DO3A‐NI), was constructed by linking a nitroimidazole moiety with the macrocyclic ligand component of ProHance®, HP‐DO3A. The hypoxia targeting capability of this agent was evaluated in A549 lung cancer cells in vitro and in SCID mice bearing subcutaneous A549 tumor xenografts. The cellular uptake assays showed that significantly more [⁶⁸Ga]‐HP‐DO3A‐NI accumulates in hypoxic tumor cells at 30, 60 and 120 min than in the same cells exposed to 21% O₂. The agent also accumulated in hypoxic tumors in vivo to give a tumor/muscle ratio (T/M) of 5.0 ± 1.2 (n = 3) as measured by PET at 2 h post‐injection (p.i.). This was further confirmed by ex vivo biodistribution data. In addition, [⁶⁸Ga]‐HP‐DO3A‐NI displayed very favorable pharmacokinetic properties, as it was cleared largely through the kidneys with little to no accumulation in liver, heart or lung (%ID/g < 0.5%) at 2 h p.i. The specificity of the agent for hypoxic tissues was further validated in a comparative study with a control compound, [⁶⁸Ga]‐HP‐DO3A, which lacks the nitroimidazole moiety, and by PET imaging of tumor‐bearing mice breathing air versus 100% O₂. Given the commercial availability of cGMP ⁶⁸Ge/⁶⁸Ga generators and the ease of ⁶⁸Ga labeling, the new agent could potentially be widely applied for imaging tumor hypoxia prior to radiation therapy. Copyright © 2015 John Wiley & Sons, Ltd.     

Comparison of [18F]-Tracers in Various Experimental Tumor Models by PET Imaging and Identification of an Early Response Biomarker for the Novel Microtubule Stabilizer Patupilone

Purpose  The suitability of [¹⁸F]FDG, [¹⁸F]FLT, [¹⁸F]FET, and [¹⁸F]FCH as non-invasive positron emission tomography (PET) biomarkers for monitoring response to chemotherapy was analyzed in various experimental tumor models. Procedures  Tracer uptake into three syngeneic rodent tumor models and ten human xenograft models was evaluated using semiquantitative analysis of small-animal PET data. Murine RIF-1 fibrosarcomas and [¹⁸F]FLT were selected to monitor the effects of the novel cytotoxic patupilone. Results  Except [¹⁸F]FCH, all tracers provided good tumor visualization. Highest [¹⁸F]FDG uptake was identified in syngeneic tumors. Xenograft models, however, showed low [¹⁸F]FDG SUVs and were better visualized by [¹⁸F]FLT. Monitoring the effects of patupilone on [¹⁸F]FLT uptake in RIF-1 tumors revealed a significant decrease of tracer uptake after 24 h, which strongly negatively correlated with apoptosis. Conclusion  [¹⁸F]FLT PET of experimental tumors is a viable complement to [¹⁸F]FDG for preclinical drug development. [¹⁸F]FLT may be an excellent biomarker for patupilone-induced apoptosis. T. Ebenhan and M. Honer contributed equally to this work. An erratum to this article can be found at     

Real‐time cardiac metabolism assessed with hyperpolarized [1‐13C]acetate in a large‐animal model

Dissolution‐dynamic nuclear polarization (dissolution‐DNP) for magnetic resonance (MR) spectroscopic imaging has recently emerged as a novel technique for noninvasive studies of the metabolic fate of biomolecules in vivo. Since acetate is the most abundant extra‐ and intracellular short‐chain fatty acid, we focused on [1‐¹³C]acetate as a promising candidate for a chemical probe to study the myocardial metabolism of a beating heart. The dissolution‐DNP procedure of Na[1‐¹³C]acetate for in vivo cardiac applications with a 3 T MR scanner was optimized in pigs during bolus injection of doses of up to 3 mmol. The Na[1‐¹³C]acetate formulation was characterized by a liquid‐state polarization of 14.2% and a T_1Eff in vivo of 17.6 ± 1.7 s. In vivo Na[1‐¹³C]acetate kinetics displayed a bimodal shape: [1‐¹³C]acetyl carnitine (AcC) was detected in a slice covering the cardiac volume, and the signal of ¹³C‐acetate and ¹³C‐AcC was modeled using the total area under the curve (AUC) for kinetic analysis. A good correlation was found between the ratio AUC(AcC)/AUC(acetate) and the apparent kinetic constant of metabolic conversion, from [1‐¹³C]acetate to [1‐¹³C]AcC (k_AcC), divided by the AcC longitudinal relaxation rate (r₁). Our study proved the feasibility and the limitations of administration of large doses of hyperpolarized [1‐¹³C]acetate to study the myocardial conversion of [1‐¹³C]acetate in [1‐¹³C]acetyl‐carnitine generated by acetyltransferase in healthy pigs. Copyright © 2014 John Wiley & Sons, Ltd.     

The mitochondrial fluorescent dye rhodamine 123 is a high‐affinity substrate for organic cation transporters (OCTs) 1 and 2

Rhodamine 123 is a fluorescent cationic dye commonly used as a mitochondrial probe and known or suspected to be transported by certain drug membrane transporters. The present study was designed to characterize the putative interactions of rhodamine 123 with human organic cation transporter (OCT) 1 and OCT2. Intracellular uptake of the dye was demonstrated to be enhanced in both hOCT1‐ and hOCT2‐overexpressing HEK293 cells when compared with control HEK293 cells. This increase of rhodamine 123 influxes was found to be a saturable carrier‐mediated process, with low K_m values (K_m = 0.54 μm and K_m = 0.61 μm for transport of the dye in hOCT1‐ and hOCT2‐positive HEK293 cells, respectively). Known inhibitors of hOCT1 and hOCT2 activities such as verapamil, amitriptyline, prazosin, and quinine were next demonstrated to decrease rhodamine 123 accumulation in hOCT1‐ and hOCT2‐overexpressing HEK293 cells. In addition, the dye was found to inhibit hOCT1‐ and hOCT2‐mediated uptake of tetraethylammonium (TEA), a model substrate for both hOCT1 and hOCT2; rhodamine 123 appeared nevertheless to be a more potent inhibitor of hOCT1‐mediated TEA transport (IC₅₀ = 0.37 μm ) than of that mediated by hOCT2 (IC₅₀ = 61.5 μm ). Taken together, these data demonstrate that rhodamine 123 is a high‐affinity substrate for both hOCT1 and hOCT2. This dye may be therefore useful for fluorimetrically investigating cellular hOCT1 or hOCT2 activity, knowing, however, that other factors potentially contributing to cellular accumulation of rhodamine 123, including mitochondrial membrane potential or expression of the efflux transporter P‐glycoprotein, have also to be considered.     

Evaluation of [123I]IBZM pinhole SPECT for the detection of striatal dopamine D2 receptor availability in rats

Single photon emission computed tomography (SPECT) and MRI coregistration have been assessed to characterize striatal dopamine D2/D3 receptor (D2/D3R) availability in rats following injection of the D2 and D3R radioligand [123I] iodobenzamide ([123I]IBZM). High-resolution SPECT data were obtained with a pinhole collimator. In order to precisely estimate brain regions of low radioligand uptake, SPECT images were coregistered onto a MRI template with high accuracy (maximum mismatch 1.1 mm). To evaluate an adequate dose of radioligand to be administered without exceeding the radioligand-to-receptor occupancy >5% and to define an appropriate time period for image acquisition, three untreated groups of animals received 29.6, 37, and 44.4 MBq of [123I]IBZM and underwent five consecutive SPECT acquisitions lasting 64 min each. Ratio calculations between specific striatal radioligand uptake and nondisplaceable cerebellar uptake revealed a secular equilibrium between 75 and 355 min post-tracer application in all three animal groups. Consequently, since the highest regional uptake values were obtained in the animal group receiving 44.4 MBq [123I]IBZM, this injection dose was considered to be appropriate. Finally, the capacity of the imaging method to detect distinct severity levels of striatal dopamine D2/D3 receptor loss was tested in a low, medium, and high dose quinolinic acid (QA) animal model of Huntington's disease. Motor impairment indicative of striatal dysfunction was monitored using amphetamine-induced rotational behavior and locomotor activity. Loss of striatal D2/D3R bearing medium-sized spiny neurons was assessed by DARPP-32 immunohistochemistry and compared to [123I]IBZM binding. Optical density measures of DARPP-32 immunohistochemistry demonstrated QA dose-dependent mild to subtotal unilateral striatal lesions ranging from 29.4% to 96.9% when compared to the nonlesioned side. Linear regression analysis showed that measurements of striatal DARPP-32 optical density and striatal [123I]IBZM uptake of the lesioned side were highly correlated (r2=0.83; P<0.001) whereas correlation with locomotor activity was less tight (r2=0.23; P<0.05; amphetamine-induced rotational behavior was not significantly correlated). This is the first study to demonstrate that in vivo [123I]IBZM SPECT and MRI coregistration are highly sensitive and, in contrast to behavioral measures, accurately detect mild to subtotal striatal lesions by measuring loss of D2/D3R availability. SPECT-MRI-based estimation of regional [123I]IBZM uptake provides a cost effective and widely available in vivo imaging technique for assessing striatal integrity in animal studies.     

Erythrocytes labeled with [18F]SFB as an alternative to radioactive CO for quantification of blood volume with PET

Inhaled radioactive CO is currently the tracer of choice for blood volume quantification by positron emission tomography (PET). This measurement is of great interest for several clinical and research applications. However, owing to the short half‐life of the radiolabeled CO, it can only be used in centers equipped with a cyclotron. In the present work, we propose an alternative method to label the red blood cells with [¹⁸F] in order to obtain blood volume measurements by PET. The use of the radioactive synthon [¹⁸F] N‐succinimidyl 4‐[¹⁸F]fluorobenzoate ([¹⁸F]SFB) was evaluated for erythrocyte labeling and PET blood volume imaging. The images provided by [¹⁸F]SFB labeled erythrocytes were compared with those obtained with inhaled [¹¹C]CO. Blood volumes obtained with [¹⁸F]SFB labeled erythrocytes were similar to those obtained with [¹¹C]CO in all of the evaluated organs with the exception of spleen, which presented lower uptake with this method. Since the [¹⁸F]‐SFB binds irreversibly to red blood cells, in vivo stability of the radiolabel was higher compared with the [¹¹C]CO method. Additionally, owing to the longer half‐life and the shorter positron range of [¹⁸F], the image quality was also higher with the [¹⁸F]SFB radiolabeled erythrocytes. The labeling of red blood with [¹⁸F]SFB represents an advantageous alternative to radioactive CO for blood volume measurement by PET and cardiovascular isotopic imaging. Copyright © 2013 John Wiley & Sons, Ltd.     

Semiquantitative Parameters in PSMA-Targeted PET Imaging with [18F]DCFPyL: Impact of Tumor Burden on Normal Organ Uptake

Purpose

In this study, we aimed to quantitatively investigate the biodistribution of [¹⁸F]DCFPyL in patients with prostate cancer (PCa) and to determine whether uptake in normal organs correlates with an increase in tumor burden.

Procedures

Fifty patients who had been imaged with [¹⁸F]DCFPyL positron emission tomography/computed tomography (PET/CT) were retrospectively included in this study. Forty of 50 (80 %) demonstrated radiotracer uptake on [¹⁸F]DCFPyL PET/CT compatible with sites of PCa. Volumes of interests (VOIs) were set on normal organs (lacrimal glands, parotid glands, submandibular glands, liver, spleen, and kidneys) and on tumor lesions. Mean standardized uptake values corrected to lean body mass (SUL_mean) and mean standardized uptake values corrected to body weight (SUV_mean) for normal organs were assessed. For the entire tumor burden, SUL_mean/max, SUV_mean, tumor volume (TV), and the total activity in the VOI were obtained using tumor segmentation. A Spearman’s rank correlation coefficient was used to investigate correlations between normal organ uptake and tumor burden.

Results

There was no significant correlation between TV with the vast majority of the investigated organs (lacrimal glands, parotid glands, submandibular glands, spleen, and liver). Only the kidney showed significant correlation: With an isocontour threshold at 50 %, left kidney uptake parameters correlated significantly with TV (SUV_mean, ρ?=???0.214 and SUL_mean, ρ?=???0.176, p?<?0.05, respectively).

Conclusions

Only a minimal sink effect with high tumor burden in patients imaged with [¹⁸F]DCFPyL was observed. Other factors, such as a high intra-patient variability of normal organ uptake, may be a much more important consideration for personalized dosimetry with PSMA-targeted therapeutic agents structurally related to [¹⁸F]DCFPyL than the tumor burden.

     

Assessment of real‐time myocardial uptake and enzymatic conversion of hyperpolarized [1‐13C]pyruvate in pigs using slice selective magnetic resonance spectroscopy

Hyperpolarization of ¹³C‐labeled energy substrates enables the noninvasive detection and mapping of metabolic activity, in vivo, with magnetic resonance spectroscopy (MRS). Therefore, hyperpolarization and ¹³C MRS can potentially become a powerful tool to study the physiology of organs such as the heart, through the quantification of kinetic patterns under both normal and pathological conditions. In this study we assessed myocardial uptake and metabolism of hyperpolarized [1‐¹³ C]pyruvate in anesthetized pigs. Pyruvate metabolism was studied at baseline and during dobutamine‐induced stimulation. We applied a numerical approach for spectral analysis and kinetic fitting (LSFIT/KIMOfit), making a comparison with a well‐known jMRUI/AMARES analysis and γ‐variate function, and we estimated the apparent conversion rate of hyperpolarized [1‐¹³ C]pyruvate into its downstream metabolites [1‐¹³C]lactate, [1‐¹³C]alanine and [¹³C]bicarbonate in a 3 T MR scanner. We detected an increase in the apparent kinetic constants (k_PX) for bicarbonate and lactate of two‐fold during dobutamine infusion. These data correlate with the double product (rate‐pressure product), an indirect parameter of cardiac oxygen consumption: we observed an increase in value by 46 ± 11% during inotropic stress. The proposed approach might be applied to future studies in models of cardiac disease and/or for the assessment of the pharmacokinetic properties of suitable ¹³C‐enriched tracers for MRS. Copyright © 2012 John Wiley & Sons, Ltd.     

L‐Amino acid load to enhance PET differentiation between tumor and inflammation: an in vitro study on 18F‐FET uptake

Labeled amino acids (AA) are tumor tracers for use in nuclear medecine. O‐(2‐[¹⁸F]fluoroethyl)‐L ‐tyrosine (FET) is transported by the L ‐system, known to function as an exchanger. In vitro utilization of FET, after a preload or prior to an afterload of non radioactive L ‐amino acids, was evaluated in order to measure the potential effects of AA content on the distinction between tumor and inflammatory lesions. Cellular uptake of FET was studied on rat osteosarcoma cells (ROS 17/2.8) and human leukocytes, initially loaded with nonradioactive L ‐tyrosine or L ‐methionine. FET efflux was evaluated from cells loaded with nonradioactive L ‐phenylalanine after tracer uptake. ROS 17/2.8 showed a higher sensitivity to preload and afterload effects on cellular FET content as compared with the leukocytes. We conclude that preload with L ‐tyrosine, prior to the administration of FET, may be a potential procedure to improve PET differentiation between tumor and inflammatory lesions. Copyright © 2006 John Wiley & Sons, Ltd.     

Biodistribution and evaluation of 131I‐labeled neuropilin‐binding peptide for targeted tumor imaging

Neuropilin‐1 (NRP‐1) is overexpressed in several kinds of cancer cell and contributes to tumor aggressiveness. Recently, the arginine/lysine‐rich peptide with C‐terminal motifs (R/K)XX(R/K) indicated promising penetrating and transporting capability into NRP‐1 positive cancer cells. In the present study, we describe a ¹³¹I‐labeled C‐end rule motif peptide conjugate, Tyr–tLyp‐1, for NRP‐1 positive tumor targeting and imaging properties. Briefly, a truncated Lyp‐1 peptide was designed to expose its C‐end motif and conjugated to tyrosine for radiolabeling after structural modification. The peptide indicated specific binding to A549 cancer cells at 2 μM concentration, and its binding was dependent on NRP‐1 expression and could be inhibited by other NRP‐1‐binding peptides. In vivo imaging of ¹³¹I‐labeled Tyr–tLyp‐1peptide showed that a subcutaneous A549 xenograft tumor could be visualized using a SPECT/CT scanner. The tumor uptake of ¹³¹I‐Tyr–tLyp‐1 was 4.77 times higher than the uptake in muscles by SPECT/CT software quantification at 6 h post injection. Together, this study indicated that truncated Lyp‐1 peptide could specifically localize in NRP‐1 positive tumors and successfully mediate the ¹³¹I radionuclide diagnosis, indicating promising targeted imaging capability for NRP‐1 positive tumors. Copyright © 2016 John Wiley & Sons, Ltd.     

The clinical value of cardiac sympathetic imaging in heart failure

The autonomic nervous system plays an important role in the pathology of heart failure. The single‐photon emission computed tomography tracer iodine‐123‐metaiodobenzylguanidine (¹²³I‐MIBG) can be used to investigate the activity of the predominant neurotransmitter of the sympathetic nervous system, norepinephrine. Also, positron emission tomography tracers are being developed for the same purpose. With ¹²³I‐MIBG as a starting point, this brief review introduces the modalities used for cardiac sympathetic imaging.     

Transcranial Sonography and I-FP-CIT Single Photon Emission Computed Tomography in Movement Disorders

Diagnosis of Parkinson's disease (PD) can be difficult in the early stages of the disease. The aim of the study described here was to assess the correlation between transcranial sonography (TCS) and ¹²³I-FP-CIT ([¹²³I]ioflupane, N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-[¹²³I]iodophenyl)nortropane) SPECT (single photon emission computed tomography) findings and the diagnosis of PD. A total of 49 patients were enrolled in the study: 29 patients with PD, 7 patients with other parkinsonian syndromes, 11 patients with essential tremor and 2 with psychogenic movement disorder. Substantia nigra echogenicity was measured using TCS. SPECT was performed using DaTSCAN ([¹²³I]ioflupane). TCS and SPECT findings were correlated in 84% of patients, with κ = 0.62 (95% confidence interval: 0.38–0.86). TCS-measured substantia nigra echogenicity and SPECT-measured striatal binding ratio were negatively correlated (r = –0.326, p = 0.003). TCS/SPECT sensitivity, specificity and positive and negative predictive values for the diagnosis of PD were 89.7%/96.6%, 60.0%/70.0%, 76.5%/82.4% and 80.0%/93.3%, respectively. Both positive TCS and SPECT findings correlated significantly with the diagnosis of PD (κ = 0.52, 95% confidence interval: 0.27–0.76, and κ = 0.69, 95% confidence interval: 0.49–0.90, respectively).     

Nature‐inspired nanoformulations for contrast‐enhanced in vivo MR imaging of macrophages

Magnetic resonance imaging (MRI) of macrophages in atherosclerosis requires the use of contrast‐enhancing agents. Reconstituted lipoprotein particles that mimic native high‐density lipoproteins (HDL) are a versatile delivery platform for Gd‐based contrast agents (GBCA) but require targeting moieties to direct the particles to macrophages. In this study, a naturally occurring methionine oxidation in the major HDL protein, apolipoprotein (apo) A‐I, was exploited as a novel way to target HDL to macrophages. We also tested if fully functional GBCA–HDL can be generated using synthetic apo A‐I peptides. The fluorescence and MRI studies reveal that specific oxidation of apo A‐I or its peptides increases the in vitro macrophage uptake of GBCA–HDL by 2–3 times. The in vivo imaging studies using an apo E‐deficient mouse model of atherosclerosis and a 3.0 T MRI system demonstrate that this modification significantly improves atherosclerotic plaque detection using GBCA–HDL. At 24 h post‐injection of 0.05 mmol Gd kg^?1 GBCA–HDL containing oxidized apo A‐I or its peptides, the atherosclerotic wall/muscle normalized enhancement ratios were 90 and 120%, respectively, while those of GBCA–HDL containing their unmodified counterparts were 35 and 45%, respectively. Confocal fluorescence microscopy confirms the accumulation of GBCA–HDL containing oxidized apo A‐I or its peptides in intraplaque macrophages. Together, the results of this study confirm the hypothesis that specific oxidation of apo A‐I targets GBCA–HDL to macrophages in vitro and in vivo. Furthermore, our observation that synthetic peptides can functionally replace the native apo A‐I protein in HDL further encourages the development of these contrast agents for macrophage imaging. Copyright © 2014 John Wiley & Sons, Ltd.     

Preserved Extrastriatal 123I-FP-CIT Binding in Scans Without Evidence of Dopaminergic Deficit (SWEDD)

Purpose

Scans without evidence of dopaminergic deficit (SWEDD) have been initially described in a minority of subjects with suspected Parkinson’s disease (PD). Although a highly controversial entity, longitudinal studies showed that SWEDD cases mostly involve non-degenerative conditions mimicking PD or misattribution of scan images to normal status. Using the Parkinson’s Progression Markers Initiative (PPMI) cohort, we undertook a case-controlled analysis of [123I]N-ω-fluoropropyl-2β-carbomethoxy-iodophenyl nortropane ([123I]FP-CIT) single photon emission computed tomography (SPECT) images to measure extrastriatal serotonergic transporter (SERT) density in SWEDD and PD.

Procedures

We included 37 SWEDD cases (mean age 60 years, 33 % female) with available [123I]FP-CIT SPECT imaging and high-resolution T1-weighted magnetic resonance imaging (MRI) for coregistration. Sixty-one controls and 62 similarly aged PD subjects were included for group comparisons. Regional [123I]FP-CIT was extracted with PETPVE12 using geometric transfer matrix and partial volume effect correction.

Results

PD subjects showed significantly lower [123I]FP-CIT binding in both striatal (caudate nucleus and putamen) and extrastriatal regions (pallidum and insula) compared with controls and SWEDD (all between-group p?<?0.0001). PD group also showed lower binding in the thalamus relative to controls (p?=?0.007). Receiver operating characteristics (ROC) area under the curve (AUC) did not show a significant difference when using extrastriatal region in addition to striatal ROIs for the separation of SWEDD and PD (95 % ROC-AUC for both methods, p?=?0.52). In addition, striatal [123I]FP-CIT binding contralateral to the clinically more affected side was usually lower for PD (>?75 %) but not for SWEDD (<?49 %, p?<?0.002). No significant difference regarding [123I]FP-CIT binding was observed between SWEDD and controls.

Conclusion

These findings corroborate the view that SWEDD cases represent a heterogeneous group of conditions not involving dopaminergic and serotonergic terminals. Further studies are warranted to be assessed whether using extrastriatal [123I]FP-CIT evaluation can be of help in the assessment of degenerative parkinsonism.