PET imaging of prostate tumors with 18F‐Al‐NOTA‐MATBBN

Overexpression of the gastrin‐releasing peptide receptor (GRPR) in prostate cancer provides a promising target for detection the disease. MATBBN is a new bombesin analog originating from the GRPR antagonists with a hydrophilic linker. In this study NOTA‐conjugated MATBBN was labeled by the Al¹⁸F method and the potential of ¹⁸F‐Al‐NOTA‐MATBBN for prostate tumor PET imaging was also evaluated. NOTA‐MATBBN was radiolabeled with ¹⁸F using Al¹⁸F complexes. Partition coefficient, in vitro stability and GRPR binding affinity were also determined. PET studies were performed with ¹⁸F‐Al‐NOTA‐MATBBN in PC‐3 tumor‐bearing mice. ¹⁸F‐Al‐NOTA‐MATBBN can be produced within 30 min with a decay‐corrected yield of 62.5 ± 2.1% and a radiochemical purity of >98%. The logP octanol–water value for the Al¹⁸F‐labeled BBN analog was ?2.40 ± 0.07 and the radiotracer was stable in phosphate‐buffered saline and human serum for 2 h. The IC₅₀ values of displacement for the ¹⁸F‐Al‐NOTA‐MATBBN with MATBBN was 126.9 ± 2.75 nm . The PC‐3 tumors were clearly visible with high contrast after injection of the labeled peptide. At 60 min post‐injection, the tumor uptakes for ¹⁸F‐Al‐NOTA‐MATBBN and ¹⁸F‐FDG were 4.59 ± 0.43 and 1.98 ± 0.35% injected dose/g, and tumor to muscle uptake radios for two tracers were 6.77 ± 1.10 and 1.78 ± 0.32, respectively. Dynamic PET revealed that ¹⁸F‐Al‐NOTA‐MATBBN was excreted mainly through the kidneys. GRPR‐binding specificity was also demonstrated by reduced tumor uptake of ¹⁸F‐Al‐NOTA‐MATBBN after coinjection with excess unlabeled MATBBN peptide at 1 h post‐injection. NOTA‐ MATBBN could be labeled rapidly with ¹⁸F using one step method. ¹⁸F‐Al‐NOTA‐MATBBN may be a promising PET imaging agent for prostate cancer. Copyright © 2014 John Wiley & Sons, Ltd.     

Prostate cancer imaging of FSHR antagonist modified with a hydrophilic linker

Follicle‐stimulating hormone receptor (FSHR) is selectively expressed in endothelial cells of prostate cancer (PCa) and becomes a potential target for tumor diagnosis and therapy. ¹⁸F‐Al‐NOTA‐MAL‐FSH1 is a promising PET imaging probe for targeting FSHR; however, the unfavorable abdominal backgrounds may hamper clinical translation. GGGRDN is a new hydrophilic linker, which can improve the imaging quality of radiolabeled peptides. In this study, GGGRDN‐FSH1 (denoted as FSH2) was designed and conjugated with NOTA‐MAL for ¹⁸F‐Al radiolabeling. NOTA‐MAL‐FSH2 was obtained with about 50% yield and labeled using ¹⁸F‐Al in a one‐step method within 20 min with a yield of 41.46 ± 10.36% (non‐decay‐corrected). The radiochemical purity was more than 95% and the specific activity was more than 50 GBq/µmol. The in vitro stability studies were determined in PBS and human serum. ¹⁸F‐Al‐NOTA‐MAL‐FSH2 remained stable in PBS and human serum. Balb/c nude mice bearing PC‐3 human PCa were used for in vivo study. PC‐3 tumors were clearly visualized with good contrast to background through microPET. ROI analysis showed the tumor uptake values were 2.68 ± 0.52 and 1.97 ± 0.61%ID/g at 30 and 60 min post injection (p.i.), respectively. Biodistribution studies showed that the accumulations of ¹⁸F‐Al‐NOTA‐MAL‐FSH2 in liver and intestine were 0.47 ± 0.11 and 0.12 ± 0.03%ID/g respectively at 60 min p.i. FSHR‐binding specificity was also demonstrated by reduced tumor uptake after coinjection of excessive unlabeled FSH2. In conclusion, ¹⁸F‐Al‐NOTA‐MAL‐FSH2 was successfully prepared in a one‐step method and showed better pharmacokinetics than ¹⁸F‐Al‐NOTA‐MAL‐FSH1. Favorable preclinical study revealed that ¹⁸F‐Al‐NOTA‐MAL‐FSH2 appears to be a promising candidate for FSHR‐positive tumor imaging. Copyright © 2015 John Wiley & Sons, Ltd.     

Imaging integrin alpha‐v‐beta‐3 expression in tumors with an 18F‐labeled dimeric RGD peptide

Integrin α_vβ₃ receptors are expressed on activated endothelial cells during neovascularization to maintain tumor growth. Many radiolabeled probes utilize the tight and specific association between the arginine–glycine–aspartatic acid (RGD) peptide and integrin α_vβ₃, but one main obstacle for any clinical application of these probes is the laborious multistep radiosynthesis of ¹⁸F. In this study, the dimeric RGD peptide, E‐[c(RGDfK)]₂, was conjugated with NODAGA and radiolabeled with ¹⁸F in a simple one‐pot process with a radiolabeling yield of 20%, the whole process lasting only 45 min. NODAGA‐E‐[c(RGDfK)]₂ labeled with ¹⁸F at a specific activity of 1.8 MBq nmol^?1 and a radiochemical purity of 100% could be achieved. The logP value of ¹⁸F‐labeled NODAGA‐E‐[c(RGDfK)]₂ was ?4.26 ± 0.02. In biodistribution studies, ¹⁸F‐NODAGA‐E‐[c(RGDfK)]₂ cleared rapidly from the blood with 0.03 ± 0.01 percentage injected dose per gram (%ID g^?1) in the blood at 2 h p.i., mainly via the kidneys, and showed good in vivo stability. Tumor uptake of ¹⁸F‐NODAGA‐E‐[c(RGDfK)]₂ (3.44 ± 0.20 %ID g^?1, 2 h p.i.) was significantly lower than that of reference compounds ⁶⁸Ga‐labeled NODAGA‐E‐[c(RGDfK)]₂ (6.26 ± 0.76 %ID g^?1; p <0.001) and ¹¹¹In‐labeled NODAGA‐E‐[c(RGDfK)]₂ (4.99 ± 0.64 %ID g^?1; p < 0.01). Co‐injection of an excess of unlabeled NODAGA‐E‐[c(RGDfK)]₂ along with ¹⁸F‐NODAGA‐E‐[c(RGDfK)]₂ resulted in significantly reduced radioactivity concentrations in the tumor (0.85 ± 0.13 %ID g^?1). The α_vβ₃ integrin‐expressing SK‐RC‐52 tumor could be successfully visualized by microPET with ¹⁸F‐labeled NODAGA‐E‐[c(RGDfK)]₂. In conclusion, NODAGA‐E‐[c(RGDfK)]₂ could be labeled rapidly with ¹⁸F using a direct aqueous, one‐pot method and it accumulated specifically in α_vβ₃ integrin‐expressing SK‐RC‐52 tumors, allowing for visualization by microPET. Copyright © 2013 John Wiley & Sons, Ltd.     

Gallium(III) complexes of NOTA‐bis (phosphonate) conjugates as PET radiotracers for bone imaging

Ligands with geminal bis(phosphonic acid) appended to 1,4,7‐triazacyclonone‐1,4‐diacetic acid fragment through acetamide (NOTAM^BP) or methylenephosphinate (NO2AP^BP) spacers designed for ⁶⁸Ga were prepared. Ga^III complexation is much faster for ligand with methylenephosphinate spacer than that with acetamide one, in both chemical (high reactant concentrations) and radiolabeling studies with no‐carrier‐added ⁶⁸Ga. For both ligands, formation of Ga^III complex was slower than that with NOTA owing to the strong out‐of‐cage binding of bis(phosphonate) group. Radiolabeling was efficient and fast only above 60 °C and in a narrow acidity region (pH ~3). At higher temperature, hydrolysis of amide bond of the carboxamide‐bis(phosphonate) conjugate was observed during complexation reaction leading to Ga–NOTA complex. In vitro sorption studies confirmed effective binding of the ⁶⁸Ga complexes to hydroxyapatite being comparable with that found for common bis(phosphonate) drugs such as pamindronate. Selective bone uptake was confirmed in healthy rats by biodistribution studies ex vivo and by positron emission tomography imaging in vivo. Bone uptake was very high, with SUV (standardized uptake value) of 6.19 ± 1.27 for [⁶⁸Ga]NO2AP^BP) at 60 min p.i., which is superior to uptake of ⁶⁸Ga–DOTA‐based bis(phosphonates) and [¹⁸F]NaF reported earlier (SUV of 4.63 ± 0.38 and SUV of 4.87 ± 0.32 for [⁶⁸Ga]DO3AP^BP and [¹⁸F]NaF, respectively, at 60 min p.i.). Coincidently, accumulation in soft tissue is generally low (e.g. for kidneys SUV of 0.26 ± 0.09 for [⁶⁸Ga]NO2AP^BP at 60 min p.i.), revealing the new ⁶⁸Ga complexes as ideal tracers for noninvasive, fast and quantitative imaging of calcified tissue and for metastatic lesions using PET or PET/CT. Copyright © 2014 John Wiley & Sons, Ltd.     

Semiautomated Radiosynthesis and Biological Evaluation of [<Superscript>18</Superscript>F]FEAU: A Novel PET Imaging Agent for <Emphasis Type="Italic">HSV1-tk/sr39tk</Emphasis> Reporter Gene Expression

2′-Deoxy-2′-[¹⁸F]fluoro-5-ethyl-1-β-d-arabinofuranosyluracil ([¹⁸F]FEAU) is a promising radiolabeled nucleoside designed to monitor Herpes Simplex Virus Type 1 thymidine kinase (HSV1-tk) reporter gene expression with positron emission tomography (PET). However, the challenging radiosynthesis creates problems for being able to provide [¹⁸F]FEAU routinely. We have developed a routine method using a commercial GE TRACERlab FX-FN radiosynthesis module with customized equipment to provide [¹⁸F]FEAU. All radiochemical yields are decay corrected to end-of-bombardment and reported as means ± SD. Radiofluorination (33 ± 8%; n = 4), bromination (85 ± 8%; n = 4), coupling reaction (83 ± 6%; n = 4), base hydrolysis steps, and subsequent high-performance liquid chromatography purification afforded purified [¹⁸F]FEAU β-anomer in 5 ± 1% overall yield (n = 3 runs) after ~5.5 h and a β/α-anomer ratio of 7.4. Radiochemical/chemical purities and specific activity exceeded 99% and 1.3 Ci/μmol (48 GBq/μmol), respectively. In cell culture, [¹⁸F]FEAU showed significantly (P < 0.05) higher accumulation in C6 cells expressing HSV1-tk/sr39tk as compared to wild-type C6 cells. Furthermore, [¹⁸F]FEAU showed slightly higher accumulation than 9-[4-[¹⁸F]fluoro-3-(hydroxymethyl)butylguanine ([¹⁸F]FHBG) in cells expressing HSV1-tk (P < 0.05), whereas [¹⁸F]FHBG showed significantly higher (P < 0.05) accumulation than [¹⁸F]FEAU in HSV1-sr39tk-expressing cells. micro-PET imaging of mice carrying tumor xenografts of C6 cells stably expressing HSV1-tk or HSV1-sr39tk are consistent with the cell uptake results. The [¹⁸F]FEAU mouse images also showed very low gastrointestinal signal with predominant renal clearance as compared to [¹⁸F]FHBG. The routine radiosynthesis of [¹⁸F]FEAU was successfully semiautomated using a commercial module along with customized equipment to provide the β-anomer in modest yields. Although further studies are needed, early results also suggest [¹⁸F]FEAU is a promising PET radiotracer for monitoring HSV1-tk reporter gene expression.     

Al[<Superscript>18</Superscript>F]NOTA-T140 Peptide for Noninvasive Visualization of CXCR4 Expression

Purpose

Chemokine receptor CXCR4 plays an important role in tumor aggressiveness, invasiveness, and metastasis formation. Quantification of CXCR4 expression by tumors may have an impact on prediction and evaluation of tumor response to therapies. In this study, we developed a robust and straightforward F-18 labeling route of T140, a CXCR4 peptide-based antagonist.

Procedures

T140 derivative was conjugated to 1,4,7-triazacyclononane-triacetic acid (NOTA) and labeled with Al[¹⁸F]. Al[¹⁸F]NOTA-T140 was evaluated in vitro in cell-based assay and stability in mouse serum and in vivo using CXCR4 positive and negative tumor xenograft models.

Results

Labeling of Al[¹⁸F]NOTA-T140 was completed within 30 min with a radiochemical yield of 58?±?5.3 % at the end of synthesis, based on fluoride-18 activity. Al[¹⁸F]NOTA-T140 accumulated in CHO-CXCR4 positive but not negative tumors. Al[¹⁸F]NOTA-T140 uptake in the tumors correlated with CXCR4 protein expression. Moreover, Al[¹⁸F]NOTA-T140 had high accumulation in CXCR4-positive metastatic tumors.

Conclusions

The simplicity of Al[¹⁸F]NOTA-T140 labeling along with its properties to specifically image CXCR4 expression by tumors warrant further clinical application for the diagnosis of CXCR4 clinically.

     

Multimodal imaging of tumor response to sorafenib combined with radiation therapy: comparison between diffusion‐weighted MRI,choline spectroscopy and 18F‐FLT PET imaging

The purpose of this study was to determine the value of different imaging modalities, that is, magnetic resonance imaging/spectroscopy (MRI/MRS) and positron emission tomography (PET), to assess early tumor response to sorafenib with or without radiotherapy. Diffusion‐weighted (DW)‐MRI, choline ¹H MRS at 11.7 T, and ¹⁸F‐FLT PET imaging were used to image fibrosarcoma (FSaII) tumor‐bearing mice over time. The imaging markers were compared with apoptosis cell death and cell proliferation measurements assessed by histology. Anti‐proliferative effects of sorafenib were evidenced by ¹H MRS and ¹⁸F‐FLT PET after 2 days of treatment with sorafenib, with no additional effect of the combination with radiation therapy, results that are in agreement with Ki67 staining. Apparent diffusion coefficient calculated using DW‐MRI was not modified after 2 days of treatment with sorafenib, but showed significant increase 24 h after 2 days of sorafenib treatment combined with consecutive irradiation. The three imaging markers were able to show early tumor response as soon as 24 h after treatment initiation, with choline MRS and ¹⁸F‐FLT being sensitive to sorafenib in monotherapy as well as in combined therapy with irradiation, whereas DW‐MRI was only sensitive to the combination of sorafenib with radiotherapy. Copyright © 2013 John Wiley & Sons, Ltd.     

18F‐FDG PET/CT and MRI in the follow‐up of head and neck squamous cell carcinoma

We evaluated the diagnostic performance of ¹⁸F‐FDG PET/CT and MRI for the assessment of head and neck squamous cell carcinoma (HNSCC) relapse. Since early treatment might prevent inoperable relapse, we also evaluated THE performance of early unenhanced ¹⁸F‐FDG PET/CT in residual tumor detection. The study was prospectively performed on 32 patients who underwent ¹⁸F‐FDG PET/CT and MRI before treatment and at 4 and 12 months after treatment. ¹⁸F‐FDG PET/CT was also performed 2 weeks after the end of radiotherapy. Histopathology or a minimum of 18 months follow‐up were used as gold standard. Before treatment ¹⁸F‐FDG PET/CT and MRI detected all primary tumors except for two limited vocal fold lesions (sensitivity 94%). MRI was more sensitive than ¹⁸F‐FDG PET/CT for the detection of local extension sites (sensitivity 75 vs 58%), but at the cost of a higher rate of false positive results (positive predictive value 74 vs 86%). For relapse detection at 4 months, sensitivity was significantly higher for ¹⁸F‐FDG PET/CT (92%) than for MRI (70%), but the diagnostic performances were not significantly different at 12 months. For the detection of residual malignant tissue 2 weeks post‐radiotherapy, sensitivity and specificity of ¹⁸F‐FDG PET/CT were respectively 86 and 85% (SUV cut‐off value 5.8). ¹⁸F‐FDG PET/CT is effective in the differentiation between residual tumor and radiation‐induced changes, as early as 2 weeks after treatment of a primary HNSCC. For follow‐up, performance of ¹⁸F‐FDG PET/CT and MRI are similar except for a higher sensitivity of ¹⁸F‐FDG PET/CT at 4 months. Copyright © 2011 John Wiley & Sons, Ltd.     

18F‐Fluorine‐18‐l‐dihydroxyphenylalanine (18F‐DOPA) positive isolated peritoneal carcinomatosis from a MENII‐related medullary thyroid carcinoma. About an atypical metastatic site and utility of 18F‐FDOPA

A patient, operated for a medullary thyroid carcinoma (MTC) with a positive RET mutation, showed several peritoneal nodes on a computed tomography (CT), with increased Thyrocalcitonine. A ¹⁸F‐Fluorine‐18‐l ‐dihydroxyphenylalanine (18‐F‐FDOPA) positron emission tomography (PET/CT) showed isolated tracer uptake on the nodes. A biopsy confirmed that it was from the MTC, with the same RET mutation as in blood.     

[18F]‐FBEM,a tracer targeting cell‐surface protein thiols for cell trafficking imaging

We used [¹⁸F]‐4‐fluorobenzamido‐N‐ethylamino‐maleimide ([¹⁸F]‐FBEM) to radiolabel cells ex vivo for in vivo positron emission tomography (PET) in order to assess cell trafficking in mice. In contrast to commonly used imaging agents, [¹⁸F]‐FBEM forms a covalent bond with thiol groups present on the cells surface. The stability of the probe in aqueous medium was tested at different pH values and cross‐experiment showed that thiol‐labeling efficiency was retained (at least) up to pH 9. The labeling procedure did not affect significantly the cell viability. To illustrate the procedure, PET images of living mice injected intravenously with labeled T lymphocytes were obtained. They showed the expected cell homing in the spleen that was absent in mice injected with free label. Copyright © 2013 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     

PET/CT to detect adverse reactions to metal debris in patients with metal‐on‐metal hip arthroplasty: an exploratory prospective study

Metal‐on‐metal (MoM) bearings in total hip arthroplasties and hip resurfacing arthroplasties have recently shown a new type of complication: adverse reactions to metal debris (ARMD). ARMD is characterized by local severe inflammation and tissue necrosis leading to implant failures. The gluteal muscle region is important for the patient outcome after revision surgery. This prospective positron emission tomography/computed tomography (PET/CT) study was undertaken to evaluate the characteristics of 2‐deoxy‐2‐[¹⁸F]fluoro‐d ‐glucose ([¹⁸F]FDG) and [⁶⁸Ga]Gallium citrate ([⁶⁸Ga]Citrate) PET/CT in ARMD patients. [¹⁸F]FDG and [⁶⁸Ga]Citrate PET/CT were performed in 18 hip arthroplasty patients: 12 ARMD patients (with 16 MoM hips) and six arthroplasty controls without ARMD. Tracer uptake was evaluated visually, and maximum standardized uptake (SUV_max) was measured in the gluteal muscle region. ARMD severity was graded by metal artefact reduction sequence‐magnetic resonance imaging (MARS‐MRI). Periprosthetic [¹⁸F]FDG uptake was observed in 15 of 16 hips, [⁶⁸Ga]Citrate uptake in three of 16 hips, respectively. The distribution of tracer uptake resembled infection in three hips. In the gluteal muscle region, the SUV_max of [¹⁸F]FDG was significantly greater in hips with moderate and severe ARMD compared with the controls (P = 0·009 for [¹⁸F]FDG and P = 0·217 for [⁶⁸Ga]Citrate). In patients who needed revision surgery, an intraoperative finding of gluteal muscle necrosis was associated with increased local SUV_max as detected by preoperative [¹⁸F]FDG (P = 0·039), but not by [⁶⁸Ga]Citrate (P = 0·301). In conclusion, the inflammatory reaction to metal debris in hip arthroplasty patients is best visualized with [¹⁸F]FDG.     

Improved Radiosynthesis and Biological Evaluations of L- and D-1-[<Superscript>18</Superscript>F]Fluoroethyl-Tryptophan for PET Imaging of IDO-Mediated Kynurenine Pathway of Tryptophan Metabolism

Purpose

Tryptophan metabolism via indoleamine 2,3-dioxygenase (IDO)-mediated kynurenine pathway plays a role in immunomodulation and has been emerging as a plausible target for cancer immunotherapy. Imaging IDO-mediated kynurenine pathway of tryptophan metabolism with positron emission tomography (PET) could provide valuable information for noninvasive assessment of cancer immunotherapy response. In this work, radiotracer 1-(2-[¹⁸F]fluoroethyl)-L-tryptophan (1-L-[¹⁸F]FETrp) and its enantioisomer 1-D-[¹⁸F]FETrp were synthesized and evaluated for PET imaging of IDO-mediated kynurenine pathway of tryptophan metabolism.

Procedures

Enantiopure 1-L-[¹⁸F]FETrp and 1-D-[¹⁸F]FETrp were prepared by a nucleophilic reaction of N-boc-1-(2-tosylethyl) tryptophan tert-butyl ester with [¹⁸F]Fluoride, followed by acid hydrolysis in a GE Tracerlab FX-N module. In vitro cell uptake assays were performed with a breast cancer cell line MDA-MB-231. Small animal PET/computed tomography (CT) imaging was carried out in a mouse model bearing MDA-MB-231 xenografts.

Results

Automatic radiosynthesis of 1-L-[¹⁸F]FETrp and 1-D-[¹⁸F]FETrp was achieved by a one-pot two-step approach in 19.0 ± 7.0 and 9.0 ± 3.0 % (n = 3) decay-corrected yield with radiochemical purity over 99 %, respectively. In vitro cell uptake study indicated the uptake of 1-D-[¹⁸F]FETrp in MDA-MB-231 cells was 0.73 ± 0.07 %/mg of protein at 60 min, while, the corresponding uptake of 1-L-[¹⁸F]FETrp was 6.60 ± 0.77 %/mg. Further mechanistic assays revealed that amino acid transport systems L-tpye amino acid transporter (LAT) and alanine-, serine-, and cysteine-preferring (ASC), and enzyme IDO expression were involved in cell uptake of 1-L-[¹⁸F]FETrp. Small animal PET/CT imaging study showed the tumor uptake of 1-L-[¹⁸F]FETrp was 4.6 ± 0.4 % ID/g, while, the tumor uptake of 1-D-[¹⁸F]FETrp was low to 1.0 ± 0.2 % ID/g, which were confirmed by ex vivo biodistribution study.

Conclusions

We have developed a practical method for the automatic radiosynthesis of 1-L-[¹⁸F]FETrp and 1-D-[¹⁸F]FETrp. Our biological evaluation results suggest that 1-L-[¹⁸F]FETrp is a promising radiotracer for PET imaging of IDO-mediated kynurenine pathway of tryptophan metabolism in cancer.

     

In‐vivo high‐resolution X‐ray microtomography for liver and spleen tumor assessment in mice

The present study sought to validate the use of glycery1‐2‐oley‐1,3‐bis‐[7‐(3‐amino‐2,4,6‐triiodophenyl)‐ heptanoate] (DHOG) contrast agent for mouse spleen tumor and liver metastasis imaging by high‐resolution X‐ray microtomography. Three groups of female nude mice were compared: controls (n = 5), and mice injected with 2.5 × 10⁶ STC1 tumor cells in the spleen, imaged at 15 days (group G15, n = 5) and at 30 days (group G30, n = 5, of which one died before imaging). Micro‐CT scans (X‐ray voltage, 50 kVp; anode current, 200 µA; exposure time, 632 ms; 180 rotational steps resulting in 35 µm isotropic spatial resolution) were acquired at 0, 0.75, 2 and 4 h after i.v. injection of DHOG. CT number (Hounsfield units: HU) and contrast‐to‐noise ratios (CNR) were determined in three organs. Statistical analysis was performed by Mann–Whitney U‐test. Contrast enhancement in normal spleen and liver increased, respectively to 1020 ± 159 and 351 ± 27 HU over baseline at 4 h, and 482 ± 3 and 203 ± 14 HU on day 6 after a single contrast injection. Automated three‐dimensional reconstruction and modeling of the spleen provided accurate and quantifiable images. Spleen tumor and liver metastases did not take up DHOG, making them detectable in contrast to the increased signal in normal tissue. The smallest liver metastasis detected measured 0.3 mm in diameter. High‐resolution X‐ray micro‐CT in living mice using DHOG contrast agent allowed visualization and volume quantification of normal spleen and of spleen tumor and its liver metastases. Copyright © 2007 John Wiley & Sons, Ltd.     

The Synthesis of <Superscript>18</Superscript>F-FDS and Its Potential Application in Molecular Imaging

Purpose 2-Deoxy-2-[¹⁸F]fluoro-d-glucose (FDG) is the most commonly used positron emission tomography (PET) tracer for oncological and neurological imaging, but it has limitations on detecting tumor or inflammation in brain gray matter. In this study, we describe the development of 2-deoxy-2-[¹⁸F]fluorosorbitol (¹⁸F-FDS) and its possible application in lesion detection around brain area. Procedures ¹⁸F-FDS was obtained by reduction of FDG using NaBH₄ (81 ± 4% yield in 30 min). Cell uptake/efflux experiments in cell culture and small animal PET imaging on tumor and inflammation models were performed. Results Despite the low accumulation in cell culture, ¹⁸F-FDS had good tumor uptake and contrast in the subcutaneous U87MG tumor model (4.54%ID/g at 30 min post-injection). Minimal uptake in the normal mouse brain facilitated good tumor contrast in both U87MG and GL-26 orthotopic tumor models. ¹⁸F-FDS also had increased uptake in the inflamed foci of the TPA-induced acute inflammation model. Conclusions Because of the ease of synthesis and favorable in vivo kinetics, ¹⁸F-FDS may have potential applications in certain cases where FDG is inadequate (e.g., brain tumor). Zi-Bo Li and Zhanhong Wu contributed equally to this work     

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.     

Comparison of [<Superscript>11</Superscript>C]Choline ([<Superscript>11</Superscript>C]CHO) and [<Superscript>18</Superscript>F]Bombesin (BAY 86-4367) as Imaging Probes for Prostate Cancer in a PC-3 Prostate Cancer Xenograft Model

Purpose

Carbon-11- and fluorine-18-labeled choline derivatives are commonly used in prostate cancer imaging in the clinical setting for staging and re-staging of prostate cancer. Due to a limited detection rate of established positron emission tomography (PET) tracers, there is a clinical need for innovative tumor-specific PET compounds addressing new imaging targets. The aim of this study was to compare the properties of [¹⁸F]Bombesin (BAY 86-4367) as an innovative biomarker for prostate cancer imaging targeting the gastrin-releasing peptide receptor and [¹¹C]Choline ([¹¹C]CHO) in a human prostate tumor mouse xenograft model by small animal PET/X-ray computed tomography (CT).

Procedures

We carried out a dual-tracer small animal PET/CT study comparing [¹⁸F]Bombesin and [¹¹C]CHO. The androgen-independent human prostate tumor cell line PC-3 was implanted subcutaneously in the flanks of nu/nu NMRI mice (n?=?10) (PET/CT measurements of two [¹¹C]Choline mice could not be analyzed due to technical reasons). [¹⁸F]Bombesin and [¹¹C]CHO PET/CT imaging was performed about 3–4 weeks after the implantation of PC-3 cells on two separate days. After the intravenous tail vein injection of 14 MBq [¹⁸F]Bombesin and 37 MBq [¹¹C]CHO, respectively, a dynamic study over 60 min was acquired in list mode using an Inveon animal PET/CT scanner (Siemens Medical Solutions). The sequence of [¹⁸F]Bombesin and [¹¹C]CHO was randomized. Image analysis was performed using summed images as well as dynamic data. To calculate static and dynamic tumor-to-muscle (T/M), tumor-to-blood (T/B), liver-to-blood (L/B), and kidney-to-blood (K/B) ratios, 4?×?4?×?4 mm³ volumes of interest (VOIs) of tumor, muscle (thigh), liver, kidney, and blood derived from transversal slices were used.

Results

The mean T/M ratio of [¹⁸F]Bombesin and [¹¹C]CHO was 6.54?±?2.49 and 1.35?±?0.30, respectively. The mean T/B ratio was 1.83?±?0.79 for [¹⁸F]Bombesin and 0.55?±?0.10 for [¹¹C]CHO. The T/M ratio as well as the T/B ratio for [¹⁸F]Bombesin were significantly higher compared to those for [¹¹C]CHO (p?<?0.001, respectively). Kidney and liver uptake was statistically significantly lower for [¹⁸F]Bombesin (K/B 3.41?±?0.81, L/B 1.99?±?0.38) compared to [¹¹C]CHO [K/B 7.91?±?1.85 (p?<?0.001), L/B 6.27?±?1.99 (p?<?0.001)]. The magnitudes of the time course of T/M and T/B ratios (T/M and T/B_dyn ratios) were statistically significantly different (showing a higher uptake of [¹⁸F]Bombesin compared to [¹¹C]CHO); additionally, also the change of the T/M and T/B ratios over time was significantly different between both tracers in the dynamic analysis (p?<?0.001, respectively). Furthermore, there was a statistically significantly different change of the K/B and L/B ratios over time between the two tracers in the dynamic analysis (p?=?0.026 and p?<?0.001, respectively).

Conclusions

[¹⁸F]Bombesin (BAY 86-4367) visually and semi-quantitatively outperforms [¹¹C]CHO in the PC-3 prostate cancer xenograft model. [¹⁸F]Bombesin tumor uptake was significantly higher compared to [¹¹C]CHO. [¹⁸F]Bombesin showed better imaging properties compared to the clinically utilized [¹¹C]CHO due to a higher tumor uptake as well as a lower liver and kidney uptake.

     

Spectroscopic,radiochemical, and theoretical studies of the Ga3+‐N‐2‐hydroxyethyl piperazine‐N′‐2‐ethanesulfonic acid (HEPES buffer) system: evidence for the formation of Ga3+‐ HEPES complexes in 68 Ga labeling reactions

Recent reports have claimed a superior performance of HEPES buffer in comparison to alternative buffer systems for ^67/68 Ga labeling in aqueous media. In this paper we report spectroscopic (¹H and ⁷¹ Ga NMR), radiochemical, mass spectrometry and theoretical modeling studies on the Ga³⁺/HEPES system (HEPES = N‐2‐hydroxyethylpiperazine‐N′‐2‐ethanesulfonic acid) performed with the aim of elucidating a potential contribution of HEPES in the ^68/67 Ga radiolabeling process. Our results demonstrate that HEPES acts as a weakly but competitive chelator of Ga³⁺ and that this interaction depends on the relative Ga³⁺: HEPES concentration. A by‐product formed in the labeling mixture has been identified as a [⁶⁸ Ga]Ga(HEPES) complex via chromatographic comparison with the nonradioactive analog. The formation of this complex was verified to compete with [⁶⁸ Ga]Ga(NOTA) complexation at low NOTA concentration. Putative chelation of Ga³⁺ by the hydroxyl and adjacent ring nitrogen of HEPES is proposed on the basis of ¹H NMR shifts induced by Ga³⁺ and theoretical modeling studies. Copyright © 2013 John Wiley & Sons, Ltd.     

Therapy response monitoring of the early effects of a new BRAF inhibitor on melanoma xenograft in mice: evaluation of 18F‐FDG‐PET and 18F‐FLT‐PET

Inhibition of the V600E mutated BRAF kinase gene (BRAF^V600E) is an important and effective approach to treating melanomas. A new specific small molecule inhibitor of BRAF^V600E, PLX3603, showed potent melanoma growth‐inhibiting characteristics in preclinical studies and is currently under clinical investigation. In this study we investigated the feasibility of ¹⁸F‐FDG and ¹⁸F‐FLT‐PET to monitor the early effects of the BRAF^V600E inhibitor in mice with melanoma xenografts. SCID/beige mice with subcutaneous (s.c.) A375 melanoma xenografts, expressing BRAF^V600E, received the BRAF^V600E inhibitor twice daily orally (0, 25, 50 and 75 mg/kg). At 1, 3 and 7 days after start of therapy, the uptake of ¹⁸F‐FDG and ¹⁸F‐FLT in the tumor and normal tissues was determined in ex vivo tissue samples. Serial ¹⁸F‐FDG and ¹⁸F‐FLT‐PET scans were acquired of animals at 1 day before and 1, 3 and 7 days after start of treatment with 75 mg/kg BRAF^V600E inhibitor. A dose‐dependent decrease in ¹⁸F‐FDG uptake in the A375 tumors was observed by ex vivo biodistribution analysis. Administration of 75 mg/kg BRAF inhibitor for 1, 3 and 7 days resulted in a significantly decreased ¹⁸F‐FDG uptake in A375 tumors (41, 35 and 51%, respectively). ¹⁸F‐FLT uptake in the A375 tumors was low at baseline and no significant changes in ¹⁸F‐FLT uptake were observed at any of the doses administered. These effects were corroborated by serial in vivo ¹⁸F‐FDG and ¹⁸F‐FLT‐PET imaging. These data demonstrate that ¹⁸F‐FDG‐PET can be used as an imaging biomarker to noninvasively evaluate the early effects of PLX3603. Copyright © 2014 John Wiley & Sons, Ltd.     

[18F]-FDG-PET/CT and [18F]-FAZA-PET/CT Hypoxia Imaging of Metastatic Thyroid Cancer: Association with Short-Term Progression After Radioiodine Therapy

Purpose

To examine the relationships between 2-deoxy-2-[¹⁸F]fluoro-d-glucose ([¹⁸F]-FDG) and hypoxia tracer [¹⁸F]fluoro-azomycinarabinofuranoside ([¹⁸F]-FAZA) and between ¹³¹I and [¹⁸F]-FAZA uptake in patients with metastatic thyroid cancer and to evaluate imaging features associated with short-term progression after ¹³¹I therapy.

Procedures

The study population was 20 patients (17 women and 3 men; mean age, 67 years) with metastatic thyroid cancer who underwent both [¹⁸F]-FDG- and [¹⁸F]-FAZA-positron emission tomography (PET)/X-ray computed tomography (CT) examinations before ¹³¹I therapy. Short-term response to radioiodine was assessed (mean follow-up, 19 months ±?9). PET parameters including [¹⁸F]-FDG-SUVmax, [¹⁸F]-FAZA-SUVmax, and [¹⁸F]-FAZA-tumor-to-muscle [T/M] were obtained. Mann-Whitney U, Wilcoxon signed-rank, or χ² tests were used to assess differences between two quantitative variables or compare categorical data. Predictive factors for short-term progression were investigated with logistic regression analysis.

Results

Eleven lymph node metastatic lesions were identified in 9 patients and 46 distant metastatic lesions (lung, 19; bone, 17; and liver, 10) in 14 patients. A total of 24 ¹³¹I-positive and 33 ¹³¹I-negative lesions were detected. SUVmax was significantly lower with [¹⁸F]-FAZA-PET/CT (1.3?±?0.6) than with [¹⁸F]-FDG-PET/CT (6.4?±?5.9, p?<?0.001). No significant correlation was observed between [¹⁸F]-FAZA-PET/CT and ¹³¹I imaging concerning visibility (p?=?0.36). After ¹³¹I therapy, 31 of 57 metastatic lesions displayed short-term progression. Multivariate logistic regression revealed that [¹⁸F]-FDG-SUVmax (p?=?0.022) and [¹⁸F]-FAZA-T/M (p?=?0.002) showed significant associations with short-term progression.

Conclusions

Although [¹⁸F]-FAZA uptake was low in metastatic thyroid cancers, not only glucose metabolism but also hypoxic conditions may be associated with progression after ¹³¹I therapy in patients with metastatic thyroid cancer.