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1.  18F-FDG PET/CT: timing for evaluation of response to therapy remains a clinical challenge 
Utilizing novel imaging modalities for defining response and predicting long-term outcome after treatment may have a significant impact on cancer patient management. 18F-FDG PET/CT has great potential for use in early assessment of response to cancer therapy. However, the lack of a general consensus on a specific set of response criteria makes adoption of PET difficult for the oncology community. The optimal time after initiating therapy for assessing response to treatment also has yet to be clearly determined.
PMCID: PMC3477715  PMID: 23133796
18F-FDG; PET/CT; Therapeutic response; Cancer
2.  Combined SPECT and multidetector CT for prostate cancer evaluations 
111In-capromab pendetide is an imaging probe for noninvasive detection of prostate cancer dissemination, and can be difficult to interpret because of low photon statistics resulting in noisy images with limited anatomical precision. We examined if a 16-slice multidetector computed tomography (MDCT) combined with single photon emission computed tomography (SPECT) could increase the impact on the clinical management and improve confidence in SPECT image interpretations in comparison to a relatively low-mA (limited resolution) CT. 17 scans were reviewed from a SPECT combined with low-mA CT scanner; 21 scans were reviewed from a SPECT combined with 16-slice MDCT scanner. Reports of the clinical interpretations from the imaging studies, additional examinations performed by referring physicians as a follow-up to the imaging results, and long-term clinical and laboratory follow-ups were used to define confidence of the SPECT/CT readings and impact of the readings on the patient management. The impact was defined as: the occurrence of the 111In-capromab pendetide interpretation resulted in additional imaging studies or biopsies. MDCT improved the quality and confidence in the characterization of small lymph nodes with or without uptake of 111In-capromab pendetide. The increased confidence with MDCT in SPECT/CT readings was evident in all cases reviewed in this study, and the impact on the clinical management was higher (8 out of 21) using SPECT/MDCT than the impact using SPECT combined with low-mA CT (2 out of 17). The dual-modality SPECT/CT provides a quantifiable benefit when MDCT is used instead of low-mA CT, particularly for prostate cancer evaluations using 111In-capromab pendetide.
PMCID: PMC3260786  PMID: 22267999
Prostate cancer; capromab pendetide; SPECT/CT; MDCT; prostate specific membrane antigen (PSMA)
3.  Design of “smart” probes for optical imaging of apoptosis 
Apoptosis is a mode of programmed cell death in multicellular organisms and plays a central role in controlling embryonic development, growth and differentiation and monitoring the induction of tumor cell death through anticancer therapy. Since the most effective chemotherapeutics rely on apoptosis, imaging apoptotic processes can be an invaluable tool to monitor therapeutic intervention and discover new drugs modulating apoptosis. The most attractive target for developing specific apoptosis imaging probes is caspases, crucial mediators of apoptosis. Up to now, various optical imaging strategies for apoptosis have been developed as an easy and economical modality. However, current optical applications are limited by poor sensitivity and specificity. A subset of molecular imaging contrast agents known as “activatable” or “smart” molecular probes allow for very high signal-to-background ratios compared to conventional targeted contrast agents and open up the possibility of imaging intracellular targets. In this review, we will discuss the unique design strategies and applications of activatable probes recently developed for fluorescence and bioluminescence imaging of caspase activity.
PMCID: PMC3327302  PMID: 22514789
Activatable probes; apoptosis; bioluminescence; caspases; optical imaging
4.  Positron emission tomography and near-infrared fluorescence imaging of vascular endothelial growth factor with dual-labeled bevacizumab 
The pivotal role of vascular endothelial growth factor (VEGF) in cancer is underscored by the approval of bevacizumab (Bev, a humanized anti-VEGF monoclonal antibody) for first line treatment of cancer patients. The aim of this study was to develop a dual-labeled Bev for both positron emission tomography (PET) and near-infrared fluorescence (NIRF) imaging of VEGF. Bev was conjugated to a NIRF dye (i.e. 800CW) and 2-S-(4-isothiocyanatobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid (p-SCN-Bn-NOTA) before 64Cu-labeling. Flow cytometry analysis of U87MG human glioblastoma cells revealed no difference in VEGF binding affinity/specificity between Bev and NOTA-Bev-800CW. 64Cu-labeling of NOTA-Bev-800CW was achieved with high yield. Serial PET imaging of U87MG tumor-bearing female nude mice revealed that tumor uptake of 64Cu-NOTA-Bev-800CW was 4.6 ± 0.7, 16.3 ± 1.6, 18.1 ± 1.4 and 20.7 ± 3.7 %ID/g at 4, 24, 48 and 72 h post-injection respectively (n = 4), corroborated by in vivo/ex vivo NIRF imaging and biodistribution studies. Tumor uptake as measured by ex vivo NIRF imaging had a good linear correlation with the % ID/g values obtained from PET (R2 = 0.93). Blocking experiments and histology both confirmed the VEGF specificity of 64Cu-NOTA-Bev-800CW. The persistent, prominent, and VEGF-specific uptake of 64Cu-NOTA-Bev-800CW in the tumor, observed by both PET and NIRF imaging, warrants further investigation and future clinical translation of such Bev-based imaging agents.
PMCID: PMC3249831  PMID: 22229128
Positron emission tomography (PET); Near-infrared fluorescence (NIRF) Imaging; Vascular endothelial growth factor (VEGF); 64Cu; Tumor angiogenesis; Cancer
5.  Non-invasive longitudinal imaging of tumor progression using an 111indium labeled CXCR4 peptide antagonist 
The chemokine receptor 4 (CXCR4) is a biomarker that is over-expressed in ductal carcinoma in situ (DCIS). Hence, CXCR4-targeted (molecular) imaging approaches may have diagnostic value in such a challenging, premalignant lesion. The indium labeled CXCR4 peptide-antagonist, 111In-DTPA-Ac-TZ14011, was used to visualize CXCR4-expression in a mammary intraepithelial neoplastic outgrowth (MIN-O) mouse tumor model resembling human DCIS. MIN-O lesion development was longitudinally monitored using SPET/CT and tracer uptake was compared to uptake in control lesions. Expression of CXCR4 was validated using immunohistochemistry and flow cytometric analysis. The uptake of 111In-DTPA-Ac-TZ14011 was related to tumor angiogenesis using 111In-cDTPA-[RGDfK]. Twenty-four hours after tracer injection, MIN-O lesions could be discriminated from low CXCR4-expressing control tumors, while the degree of angiogenesis based on the αvβ3 integrin expression in both tumor types was similar. The uptake of 111In-DTPA-Ac-TZ14011 in early MIN-O lesions was significantly lower than in larger intermediate and late-stage lesions, two-and-a-half-times (p=0.03) and seven-times (p=0.002), respectively. Intermediate and late stage lesions show a higher degree of membranous CXCR4-staining at immunohistochemistry and flow cytometric analysis. From this study we can conclude that 111In-DTPA-Ac-TZ14011 can be used to visualize the CXCR4-expression in MIN-O lesions longitudinally.
PMCID: PMC3478110  PMID: 23133805
Chemokine receptor 4 (CXCR4); ductal carcinoma in situ (DCIS); single photon emission computed tomography (SPECT); mouse model; tumor progression; longitudinal imaging
6.  Positron emission tomography (PET) imaging with 18F-based radiotracers 
Positron Emission Tomography (PET) is a nuclear medicine imaging technique that is widely used in early detection and treatment follow up of many diseases, including cancer. This modality requires positron-emitting isotope labeled biomolecules, which are synthesized prior to perform imaging studies. Fluorine-18 is one of the several isotopes of fluorine that is routinely used in radiolabeling of biomolecules for PET; because of its positron emitting property and favorable half-life of 109.8 min. The biologically active molecule most commonly used for PET is 2-deoxy-2-18F-fluoro-β-D-glucose (18F-FDG), an analogue of glucose, for early detection of tumors. The concentrations of tracer accumulation (PET image) demonstrate the metabolic activity of tissues in terms of regional glucose metabolism and accumulation. Other tracers are also used in PET to image the tissue concentration. In this review, information on fluorination and radiofluorination reactions, radiofluorinating agents, and radiolabeling of various compounds and their application in PET imaging is presented.
PMCID: PMC3478111  PMID: 23133802
Fluorine-18; positron emission tomography (PET); PET radiopharmaceuticals
7.  Molecular imaging of therapy response with 18F-FLT and 18F-FDG following cyclophosphamide and mTOR inhibition 
Purpose
Evaluation and comparison of 3’-[18F]-fluoro-3’-deoxy-L-thymidine (FLT) and 2-[18F]-fluoro-2-deoxyglucose (FDG)-PET to monitor early response following both cyclophosphamide and temsirolimus treatment in a mouse model of Burkitt lymphoma.
Methods
Daudi xenograft mice were treated with either cyclophosphamide or temsirolimus and imaged with FLT-PET and FDG-PET on appropriate days post therapy inititiation. Immunohistochemical (IHC) studies (H&E, TUNEL, CD20, PCNA and ki-67) and DNA flow cytometry studies were performed.
Results
FDG tumor uptake decreased immediately after cyclophosphamide treatment while FLT-PET showed only a late and less pronounced decrease. A fast induction of apoptosis was observed together with an early accumulation of cells in the S-phase of the cell cycle, suggesting DNA repair. Temsirolimus treatment reduced both FDG and FLT tumor uptake immediately after therapy and resulted in a fast induction of apoptosis and G0-G1 phase accumulation.
Conclusion
FLT response was less distinct than FDG response and may be controlled by DNA repair early after cyclophosphamide. Nevertheless, FLT-PET was able to reflect decreased proliferation following temsirolimus.
PMCID: PMC3478112  PMID: 23133806
FDG-PET; FLT-PET; Burkitt lymphoma; cyclophosphamide; mTOR inhibition; therapy response
8.  Preoperative 123I-iomazenil SPECT imaging predicts cerebral hyperperfusion following endarterectomy for unilateral cervical internal carotid artery stenosis 
Purpose
Cerebral hyperperfusion following carotid endarterectomy (CEA) occurs in patients with preoperative impairments in cerebral hemodynamics. The aim of the present study was to determine whether late images/early images on preoperative brain 123I-iomazenil (IMZ) single-photon emission computed tomography (SPECT), which correlate with oxygen extraction fraction images on positron emission tomography, could identify patients at risk for cerebral hyperperfusion following endarterectomy for unilateral cervical internal carotid artery (ICA) stenosis.
Methods
In 80 patients, preoperative brain SPECT scans were initiated immediately after (early images) and 180 min after (late images) administration of 123I-IMZ. A region of interest (ROI) was automatically placed in the middle cerebral artery territory in both the cerebral hemispheres using a three-dimensional stereotaxic ROI template. Transcranial regional cerebral oxygen saturation (rSO2) was monitored using near-infrared spectroscope throughout carotid endarterectomy, and a patient was defined as having cerebral hyperperfusion when a ratio of rSO2 at the end of the surgery to rSO2 before ICA clamping was ≥ 1.1.
Results
Cerebral hyperperfusion was observed on intraoperative rSO2 monitoring in eight patients (10%). Preoperative increase in affected side-to-contralateral side asymmetry on late/early 123I-IMZ value was the only significant independent predictor of cerebral hyperperfusion (95% confidence interval [CI], 1.606 to 8.710; P = 0.0010). The preoperative late/early 123I-IMZ asymmetry corresponded to an 88% sensitivity and 89% specificity, with 47% positive- and 98% negative-predictive values for the development of cerebral hyperperfusion.
Conclusions
Preoperative late/early 123I-IMZ images can identify patients at risk for cerebral hyperperfusion following endarterectomy for unilateral cervical ICA stenosis.
PMCID: PMC3478115  PMID: 23133803
123I-iomazenil; brain SPECT; hyperperfusion; carotid endarterectomy
9.  Comparative functional evaluation of immunocompetent mouse breast cancer models established from PyMT-tumors using small animal PET with [18F]FDG and [18F]FLT 
Positron emission tomography (PET) allows detection of functional changes in malignant tissue. Establishment of an immortalized immunocompetent breast cancer mouse model would provide a useful platform for the analysis of novel cancer treatment strategies. This study describes a comparative functional evaluation of murine breast cancer models established from polyoma virus middle T antigen (PyMT)-derived tumors using small animal PET imaging with [18F]FDG and [18F]FLT. Primary PyMT tumor-derived cells and a cell line derived from these tumors (MTHJ) were injected subcutaneously into immunocompetent FVB mice to generate breast cancer xenografts. Tumor growth rates were comparable in both models and tumors were analyzed after 4-5 weeks post-injection. [18F]FDG uptake in vitro followed a comparable trend in both models but reached higher uptake levels in primary PyMT cells vs. MTHJ cells after 120 min. At all time points, [18F]FLT uptake was significantly higher in MTHJ compared to primary PyMT cells. Dynamic small animal PET imaging with [18F]FDG revealed standardized uptake values (SUVs) of 2.5±0.1 (n=8) in tumors from primary cells and 2.8±0.4 (n=6) in MTHJ tumors after 60 min p.i.. The corresponding tumor-muscle-ratios were 9.3±1.5 and 10.4±0.9, respectively. Uptake of [18F]FLT resulted in slightly higher SUV60min in MTHJ tumors (1.1±0.1, n=6) compared to tumors from primary cells (SUV60min=0.9±0.05, n=8, p=0.07). The tumor-muscle-ratio was comparable in both tumors (2.1±0.2 and 1.8±0.1, respectively). The PET imaging data demonstrates that the functional profile of immunocompetent murine breast tumor model MTHJ remains the same as in primary-derived PyMT tumors in vivo. Metabolic and proliferative rates as assessed with [18F]FDG and [18F]FLT are comparable in both tumor models. The observed high SUV60min of 2.8±0.4 with [18F]FDG in MTHJ tumors allows one to monitor efficacy of therapeutic interventions connected with changes in metabolic response of the tumor by means of small animal PET.
PMCID: PMC3478116  PMID: 23133804
Polyoma virus middle T antigen (PyMT); breast cancer; PET; [18F]FDG; [18F]FLT; mouse model
10.  The clinical use of PET with 11C-acetate 
The aim of this review is to evaluate clinical applications of 11C-acetate positron emission tomography (PET). Acetate is quickly metabolized into acetyl-CoA in human cells. In this form it can either enter into the tricarboxylic acid cycle, thus producing energy, as happens in the myocardium, or participate in cell membrane lipid synthesis, as happens in tumor cells. 11C-acetate PET was originally employed in cardiology, to study myocardial oxygen metabolism. More recently it has also been used to evaluate myocardial perfusion, as well as in oncology. The first studies of 11C-acetate focused on its use in prostate cancer. Subsequently, 11C-acetate was studied in other urological malignancies, as well as renal cell carcinoma and bladder cancer. Well differentiated hepatocellular carcinoma represents an 18F-fluoro-deoxyglucose (18F-FDG) PET pitfall, so many authors have proposed to use 11C-acetate in addition to 18F-FDG in studying this tumor. 11C-acetate PET has also been used in other malignancies, such as brain tumors and lung carcinoma. Some authors reported a few cases in which 11C-acetate PET incidentally found multiple myeloma or rare tumors, such as thymoma, multicentric angiomyolipoma of the kidney and cerebellopontine angle schwannoma. Lastly, 11C-acetate PET was also employed in a differential diagnosis case between glioma and encephalitis. The numerous studies on 11C-acetate have demonstrated that it can be used in cardiology and oncology with no contraindications apart from pregnancy and the necessity of a rapid scan. Despite its limited availability, this tracer can surely be considered to be a promising one, because of its versatility and capacity to even detect non 18F-FDG-avid neoplasm, such as differentiated lung cancer or hepatocellular carcinoma.
PMCID: PMC3478117  PMID: 23133801
Positron emission tomography (PET); 11C-acetate; cancer; cardiology; prostate cancer; liver cancer; brain tumor
11.  PET imaging of metabotropic glutamate receptor subtype 5 (mGluR5) 
Metabotropic glutamate receptors (mGluRs) belong to a family of G-protein coupled receptors involved in the modulation of fast excitatory transmission. In particular, the subtype-5 receptor (mGluR5) was found to be an attractive target for the treatment and diagnosis of variety of psychiatric and neurological disease including anxiety, depression, epilepsy, drug addiction, and Parkinson's disease. Positron emission tomography (PET) is a highly sensitive imaging technique that holds great potential for the diagnosis of a brain disorder. In the study published in the American Journal of Nuclear Medicine and Molecular Imaging, a 18F labelled PET probe was developed targeting mGluR5. This paper represents the efforts and challenges on the design and development of novel PET tracers for mGluR5 imaging.
PMCID: PMC3478119  PMID: 23133800
mGluR5; positron emission tomography (PET); 18F; 11C; molecular imaging
12.  Synthesis, radiolabelling and in vitro and in vivo evaluation of a novel fluorinated ABP688 derivative for the PET imaging of metabotropic glutamate receptor subtype 5 
(E)-3-(Pyridin-2-ylethynyl)cyclohex-2-enone O-(2-(3-18F-fluoropropoxy)ethyl) oxime ([18F]-PSS223) was evaluated in vitro and in vivo to establish its potential as a PET tracer for imaging metabotropic glutamate receptor subtype 5 (mGluR5). [18F]-PSS223 was obtained in 20% decay corrected radiochemical yield whereas the non-radioactive PSS223 was accomplished in 70% chemical yield in a SN2 reaction of common intermediate mesylate 8 with potassium fluoride. The in vitro binding affinity of [18F]-PSS223 was measured directly in a Scatchard assay to give Kd = 3.34 ± 2.05 nM. [18F]-PSS223 was stable in PBS and rat plasma but was significantly metabolized by rat liver microsomal enzymes, but to a lesser extent by human liver microsomes. Within 60 min, 90% and 20% of [18F]-PSS223 was metabolized by rat and human microsome enzymes, respectively. In vitro autoradiography on horizontal rat brain slices showed heterogeneous distribution of [18F]-PSS223 with the highest accumulation in brain regions where mGluR5 is highly expressed (hippocampus, striatum and cortex). Autoradiography in vitro under blockade conditions with ABP688 confirmed the high specificity of [18F]-PSS223 for mGluR5. Under the same blocking conditions but using the mGluR1 antagonist, JNJ16259685, no blockade was observed demonstrating the selectivity of [18F]-PSS223 for mGluR5 over mGluR1. Despite favourable in vitro properties of [18F]-PSS223, a clear-cut visualization of mGluR5-rich brain regions in vivo in rats was not possible mainly due to a fast clearance from the brain and low metabolic stability of [18F]-PSS223.
PMCID: PMC3478118  PMID: 23133799
mGluR5; PET imaging; [18F]-PSS223; [11C]-ABP688; [18F]-FDEGPECO; autoradiography; microsome enzymes
13.  Peptoid and positron emission tomography: an appealing combination 
Non-invasive and quantitative imaging of tumor angiogenesis is essential for lesion detection, patient stratification, drug development, and personalized anti-cancer therapies. In particular, the right timing is critical for antiangiogenic cancer therapy and non-invasive imaging can help determine whether to start and when to start such treatment. In this inaugural issue of the American Journal of Nuclear Medicine and Molecular Imaging, a peptoid-based positron emission tomography (PET) tracer was reported for imaging of VEGFR expression in a prostate cancer model. This important proof-of-principle study opened the door to a fertile area of research, which holds tremendous potential for various applications in future personalized medicine.
PMCID: PMC3183479  PMID: 22022661
Peptoid; cancer; tumor angiogenesis; positron emission tomography (PET); molecular imaging; 64Cu
16.  Peptoid-based PET imaging of vascular endothelial growth factor receptor (VEGFR) expression 
Non-invasive detection of vascular endothelial growth factor receptor 2 (VEGFR2) by positron emission tomography (PET) would allow the evaluation of tumor vascular activity in vivo. Recently, a dimeric peptoid, GU40C4, was reported as a highly potent antagonist of VEGFR2 activation inhibiting angiogenesis and tumor growth in vivo. The purpose of this work was to evaluate the potential of this peptoid for PET imaging of VEGFR2 expression. To label GU40C4 and a control peptoid with a positron emitter, 64Cu (t1/2 = 12.7 h; β+: 0.653 MeV, 17.4%), a cysteine was introduced to the C-terminus of the peptoids and then conjugated to a bifunctional chelator (DOTA: 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) through the maleimide-thiol coupling chemistry. The in vitro binding assay showed a negligible effect of the DOTA conjugation on the VEGFR2 binding affinity of GU40C4. Both peptoid conjugates were efficiently labeled with 64Cu in high radiochemical yields (> 90%); the specific activity was in the range of 10 – 80 GBq/μmol. PET imaging evaluation using a prostate cancer xenograft (PC3) mouse model showed that 64Cu-DOTA-GU40C4 had a prominent and steady accumulation in the VEGFR2 positive PC3 tumors (2.25 ± 0.24, 2.15 ± 0.34, and 1.90 ± 0.18 %ID/g at 1, 4, and 20 h p.i., respectively; n = 3), which is significantly higher than the control peptoid conjugate (0.3 – 0.5 %ID/g; p < 0.001 at 1, 4, and 20 h p.i.). Interestingly, the mouse salivary glands were also clearly visualized by 64Cu-DOTA-GU40C4 (3.17 ± 0.25, 3.00 ± 0.36, and 1.83 ± 0.21 %ID/g at 1, 4, and 20 h p.i., respectively; n = 3) rather than its control peptoid conjugate. VEGFR2 expression in the salivary glands was shown by polymerase chain reaction (PCR) assay. Our results demonstrate that 64Cu-DOTA-GU40C4 can be used to image the expression of VEGFR2 in vivo.
PMCID: PMC3477717  PMID: 23133797
VEGFR2; peptoid; PET; 64Cu; prostate cancer; tumor angiogenesis
17.  How to study optimal timing of PET/CT for monitoring of cancer treatment 
Purpose
The use of PET/CT for monitoring treatment response in cancer patients after chemo- or radiotherapy is a very promising approach to optimize cancer treatment. However, the timing of the PET/CT-based evaluation of reduction in viable tumor tissue is a crucial question. We investigated how to plan and analyze studies to optimize this timing.
Methods
General considerations about studying the optimal timing are given and four fundamental steps are illustrated using data from a published study.
Results
The optimal timing should be examined by optimizing the schedule with respect to predicting the overall individual time course we can observe in the case of dense measurements. The optimal timing needs not to and should not be studied by optimizing the association with the prognosis of the patient.
Conclusions
The optimal timing should be examined in specific ‘schedule optimizing studies’. These should be clearly distinguished from studies evaluating the prognostic value of a reduction in viable tumor tissue.
PMCID: PMC3477720  PMID: 23133795
cancer; response evaluation; prognostic value; optimal schedule
18.  Development of NGR peptide-based agents for tumor imaging 
Molecular imaging allows direct visualization of targets and characterization of cellular pathways, as long as a high signal/background ratio can be achieved, which requires a sufficient amount of probes to accumulate in the imaging region. The Asn-Gly-Arg (NGR) tripeptide selected by phage display can specifically target tumor vasculature. Recognizing the aminopeptidase N (APN or CD13) receptor on the membrane of tumor cells, the peptide can be further internalized into cytoplasma by the endosomal pathway. Hence NGR can serve as an ideal candidate for tumor imaging, once it is conjugated with fluorescent or radiolabeled imaging probes. Herein, we highlight some recent developments of NGR peptide based imaging of tumors. Although still in the preliminary stage, some NGR probes have shown potential as promising agents in future clinical applications.
PMCID: PMC3477716  PMID: 23133793
Asparagine-glycine-arginine (NGR); arginine-glycine-aspartic acid (RGD); isoaspartate-glycine-arginine (isoDGR); cancer; imaging; tumor angiogenesis; vasculature; aminopeptidase N (APN/CD13)
19.  18F-FDG PET in sarcoma treatment response imaging 
Sarcomas are a biologically complex group of diseases that exhibit variable responses to single or combination therapy. 18F-FDG PET imaging contributes to sarcoma treatment response assessment as an objective semiquantitative biomarker of response. In this review, background and experience in 18F-FDG PET as a biomarker that successfully identifies tumor response is assessed.
PMCID: PMC3477719  PMID: 23133794
18F-FDG PET; sarcoma; imaging treatment response
20.  Design of “smart” probes for optical imaging of apoptosis 
Apoptosis is a mode of programmed cell death in multicellular organisms and plays a central role in controlling embryonic development, growth and differentiation and monitoring the induction of tumor cell death through anticancer therapy. Since the most effective chemotherapeutics rely on apoptosis, imaging apoptotic processes can be an invaluable tool to monitor therapeutic intervention and discover new drugs modulating apoptosis. The most attractive target for developing specific apoptosis imaging probes is caspases, crucial mediators of apoptosis. Up to now, various optical imaging strategies for apoptosis have been developed as an easy and economical modality. However, current optical applications are limited by poor sensitivity and specificity. A subset of molecular imaging contrast agents known as “activatable” or “smart” molecular probes allow for very high signal-to-background ratios compared to conventional targeted contrast agents and open up the possibility of imaging intracellular targets. In this review, we will discuss the unique design strategies and applications of activatable probes recently developed for fluorescence and bioluminescence imaging of caspase activity.
PMCID: PMC3327302  PMID: 22514789
Activatable probes; apoptosis; bioluminescence; caspases; optical imaging
21.  Imaging of induced pluripotent stem cells: from cellular reprogramming to transplantation 
Successful reprogramming of somatic cells into induced pluripotent stem cells (iPSCs) ushered in a new era of regenerative medicine. Human iPSCs provide powerful new approaches for disease modeling, drug testing, developmental studies, and therapeutic applications. Investigating iPSC behavior in vivo and the ultimate feasibility of cell transplantation therapy necessitates the development of novel imaging techniques to longitudinally monitor iPSC localization, proliferation, integration, and differentiation in living subjects. At this five year mark of initial iPSC discovery, we review the current status of imaging iPSCs which ranges from in vitro studies, where imaging was used to study the processes/mechanisms of cellular reprogramming, to in vivo imaging of the survival of transplanted cells. To date, most imaging studies of iPSCs have been based on optical techniques, which include fluorescence and bioluminescence imaging. Since each imaging technique has its advantages and limitations, a combination of multiple imaging modalities may provide complementary information. The ideal imaging approach for tracking iPSCs or their derivatives in patients requires the imaging tag to be non-toxic, biocompatible, and highly specific to reduce perturbation of these cells. In few other scenarios can “personalized medicine” be better illustrated than the use of individual patient-specific iPSCs. Much future effort will be required before this can become a reality and clinical routine, where imaging will play an indispensible role in many facets of iPSC-based research and therapies.
PMCID: PMC3155258  PMID: 21841970
Induced pluripotent stem cells (iPSCs); molecular imaging; regenerative medicine; cell tracking; bioluminescence imaging (BLI); fluorescence imaging; positron emission tomography (PET); teratoma
22.  Intravenous administration of diazepam significantly reduces brown fat activity on 18F-FDG PET/CT 
Background
Brown adipose tissue (BAT) activity on 18F-fluorodeoxyglucose (FDG) PET/CT can introduce an undesirable element of complexity when attempting to discern physiologic activity from more ominous entities. Recent studies have demonstrated several methods to reduce BAT FDG uptake. Benzodiazepines, however, have yet to been proven effective against BAT.
Methods
Twenty-five patients with increased BAT FDG uptake were selected retrospectively from our PET/CT database between November 2004 and January 2011. These patients had been asked to return on a different day for repeat scanning with 5mg of intravenous diazepam, administered ten minutes prior to FDG. Two patients underwent this procedure on a second occasion (for a follow-up scan at a later date), thus resulting in a total of twenty-seven scans from twenty five patients. FDG uptake in BAT was recorded using the maximum standardized uptake value (SUVmax).
Results
The mean basal BAT SUVmax was 10.1 ± 4.6 compared to a mean SUVmax of 2.8 ± 3.3 post IV diazepam (p < 0.0001). Approximately 89% (24 of 27) of scans had no significant residual BAT activity. The three remaining scans had a reduction in SUVmax ranging from 23-64% following diazepam administration. No adverse effects were noted.
Conclusion
We observed a significant reduction in brown fat activity in para-spinal, cervical, mediastinal, para-adrenal, and supra- and infra-clavicular regions on PET/CT following premedication with intravenous diazepam. We feel that IV benzodiazepines should be considered a pharmacologic option for reducing BAT FDG uptake, which in turn, will aid in distinguishing physiologic metabolic activity from pathology.
PMCID: PMC3477718  PMID: 23133792
Brown adipose tissue; diazepam; 18F-FDG PET
23.  Peptoid and Positron Emission Tomography: an Appealing Combination 
Non-invasive and quantitative imaging of tumor angiogenesis is essential for lesion detection, patient stratification, drug development, and personalized anti-cancer therapies. In particular, the right timing is critical for anti-angiogenic cancer therapy and non-invasive imaging can help determine whether to start and when to start such treatment. In this inaugural issue of the American Journal of Nuclear Medicine and Molecular Imaging, a peptoid-based positron emission tomography (PET) tracer was reported for imaging of VEGFR expression in a prostate cancer model. This important proof-of-principle study opened the door to a fertile area of research, which holds tremendous potential for various applications in future personalized medicine.
PMCID: PMC3183479  PMID: 22022661
Peptoid; cancer; tumor angiogenesis; positron emission tomography (PET); molecular imaging; 64Cu
24.  Imaging of Induced Pluripotent Stem Cells: From Cellular Reprogramming to Transplantation 
Successful reprogramming of somatic cells into induced pluripotent stem cells (iPSCs) ushered in a new era of regenerative medicine. Human iPSCs provide powerful new approaches for disease modeling, drug testing, developmental studies, and therapeutic applications. Investigating iPSC behavior in vivo and the ultimate feasibility of cell transplantation therapy necessitates the development of novel imaging techniques to longitudinally monitor iPSC localization, proliferation, integration, and differentiation in living subjects. At this five year mark of initial iPSC discovery, we review the current status of imaging iPSCs which ranges from in vitro studies, where imaging was used to study the processes/mechanisms of cellular reprogramming, to in vivo imaging of the survival of transplanted cells. To date, most imaging studies of iPSCs have been based on optical techniques, which include fluorescence and bioluminescence imaging. Since each imaging technique has its advantages and limitations, a combination of multiple imaging modalities may provide complementary information. The ideal imaging approach for tracking iPSCs or their derivatives in patients requires the imaging tag to be non-toxic, biocompatible, and highly specific to reduce perturbation of these cells. In few other scenarios can “personalized medicine” be better illustrated than the use of individual patient-specific iPSCs. Much future effort will be required before this can become a reality and clinical routine, where imaging will play an indispensible role in many facets of iPSC-based research and therapies.
PMCID: PMC3155258  PMID: 21841970
Induced pluripotent stem cells (iPSCs); molecular imaging; regenerative medicine; cell tracking; bioluminescence imaging (BLI); fluorescence imaging; positron emission tomography (PET); teratoma

Results 1-24 (24)