Synthesis and bioevaluation of the cyclopentadienyl tricarbonyl technetium-99m 2-nitroimidazole derivatives for tumor hypoxia imaging.

Hypoxia imaging agents can play an important role in the tumor treatment by avoiding the worse effect of radiotherapy and chemotherapy due to the tumor hypoxia. Due to the small size and easy coordination, tricarbonyl technetium-99m can be used to label a wide range of imaging agents. In this work, the tricarbonyl 99mTc labeled small-sized hypoxia imaging agents containing 2-nitroimidazoles were prepared, which have different carbon chain lengths between cyclopentadienyl and 2-nitroimidazole, and which have one or two 2-nitroimidazole groups. The results of S180 cell experiment and biodistribution indicated that these molecules have different hypoxic selectivity. When contains one 2-nitroimidazole, as the carbon chain lengthens, which means the molecular volume becomes larger, hypoxia cellular uptake and selectivity decrease in S180 cell uptake experiment. In biodistribution study in mice bearing S180 tumor, Tc-2 (1-cyclopentadienyl-5-(2-nitro-1H-imidazol-1-yl)-pentan-1-one tricarbonyl 99mTc complex), which has intermediate carbon chain, is better due to the more complex factors. Its tumor/blood (T/B) ratio is 3.56 ± 0.25, tumor/muscle(T/M) ratio is 1.73 ± 0.29 and tumor uptake is 2.23 ± 0.24%ID/g at 2 h. Comparing to other tricarbonyl technetium complexes containing one 2-nitroimidazole, the complexes in this work have an advantage in tumor/blood ratio and tumor uptake. This suggests that the small-volume cyclopentadienyl may have an advantage when used as a ligand. When contains two 2-nitroimidazole groups, the complex, 1-cyclopentadienyl-5-di(2-(2-nitro-1H-imidazol-1-yl)ethyl)amino-pentan-1-one tricarbonyl 99mTc complex (Tc-4), has the better results in the cell experiment than those which contain one 2-nitroimidazole group. Thus the hypoxia imaging agent contains two 2-nitroimidazole groups is more advantageous, but further modifications of Tc-4 are needed to improve its clearance rate in the blood, because the increased lipophilicity leads to a decrease in the T/B ratio of Tc-4. In conclusion, small volume hypoxia imaging agents with two 2-nitroimidazole groups may be the trend of development.

Design, Synthesis and Preclinical Assessment of 99mTc-iFAP for In Vivo Fibroblast Activation Protein (FAP) Imaging.

Fibroblast activation protein (FAP) is expressed in the microenvironment of most human epithelial tumors. 68Ga-labeled FAP inhibitors based on the cyanopyrrolidine structure (FAPI) are currently used for the detection of the tumor microenvironment by PET imaging. This research aimed to design, synthesize and preclinically evaluate a new FAP inhibitor radiopharmaceutical based on the 99mTc-((R)-1-((6-hydrazinylnicotinoyl)-D-alanyl) pyrrolidin-2-yl) boronic acid (99mTc-iFAP) structure for SPECT imaging. Molecular docking for affinity calculations was performed using the AutoDock software. The chemical synthesis was based on a series of coupling reactions of 6-hidrazinylnicotinic acid (HYNIC) and D-alanine to a boronic acid derivative. The iFAP was prepared as a lyophilized formulation based on EDDA/SnCl2 for labeling with 99mTc. The radiochemical purity (R.P.) was verified via ITLC-SG and reversed-phase radio-HPLC. The stability in human serum was evaluated by size-exclusion HPLC. In vitro cell uptake was assessed using N30 stromal endometrial cells (FAP positive) and human fibroblasts (FAP negative). Biodistribution and tumor uptake were determined in Hep-G2 tumor-bearing nude mice, from which images were acquired using a micro-SPECT/CT. The iFAP ligand (Ki = 0.536 nm, AutoDock affinity), characterized by UV-Vis, FT-IR, 1H-NMR and UPLC-mass spectroscopies, was synthesized with a chemical purity of 92%. The 99mTc-iFAP was obtained with a R.P. >98%. In vitro and in vivo studies indicated high radiotracer stability in human serum (>95% at 24 h), specific recognition for FAP, high tumor uptake (7.05 ± 1.13% ID/g at 30 min) and fast kidney elimination. The results found in this research justify additional dosimetric and clinical studies to establish the sensitivity and specificity of the 99mTc-iFAP.

Hydroxamate-Based Selective Macrophage Elastase (MMP-12) Inhibitors and Radiotracers for Molecular Imaging.

Macrophage elastase [matrix metalloproteinase (MMP)-12] is the most upregulated MMP in abdominal aortic aneurysm (AAA) and, hence, MMP-12-targeted imaging may predict AAA progression and rupture risk. Here, we report the design, synthesis, and evaluation of three novel hydroxamate-based selective MMP-12 inhibitors (CGA, CGA-1, and AGA) and the methodology to obtain MMP-12 selectivity from hydroxamate-based panMMP inhibitors. Also, we report two 99mTc-radiotracers, 99mTc-AGA-1 and 99mTc-AGA-2, derived from AGA. 99mTc-AGA-2 displayed faster blood clearance in mice and better radiochemical stability compared to 99mTc-AGA-1. Based on this, 99mTc-AGA-2 was chosen as the lead tracer and tested in murine AAA. 99mTc-AGA-2 uptake detected by autoradiography was significantly higher in AAA compared to normal aortic regions. Specific binding of the tracer to MMP-12 was demonstrated through ex vivo competition. Accordingly, this study introduces a novel family of selective MMP-12 inhibitors and tracers, paving the way for further development of these agents as therapeutic and imaging agents.

Self-Assembled Hybrid Nanocomposites for Multimodal Imaging-Guided Photothermal Therapy of Lymph Node Metastasis.

Multimodal imaging-guided therapy holds great potential for precise theranostics of cancer metastasis. However, imaging agents enabling the convergence of complementary modalities with therapeutic functions to achieve perfect theranostics have been less exploited. This study reports the construction of a multifunctional nanoagent (FIP-99mTc) that comprises Fe3O4 for magnetic resonance imaging, radioactive 99mTc for single-photon-emission computed tomography, and IR-1061 to serve for the second near-infrared fluorescence imaging, photoacoustic imaging, and photothermal therapy treatment of cancer metastasis. The nanoagent possessed superior multimodal imaging capability with high sensitivity and resolution attributing to the complement of all the imaging modalities. Moreover, the nanoagent showed ideal photothermal conversion ability to effectively kill tumor cells at low concentration and power laser irradiation. In the in vivo study, FIP-99mTc confirmed the fast accumulation and clear delineation of metastatic lymph nodes within 1 h after administration. Attributing to the efficient uptake and photothermal conversion, FIP-99mTc could raise the temperature of metastatic lymph nodes to 54 °C within 10 min laser irradiation, so as to facilitate tumor cell ablation. More importantly, FIP-99mTc not only played an active role in suppressing cancer growth in metastatic lymph nodes with high efficiency but also could effectively prevent further lung metastasis after resection of the primary tumor. This study proposes a simple but effective theranostic approach toward lymph node metastasis.

[99mTc]Tc-DB1 Mimics with Different-Length PEG Spacers: Preclinical Comparison in GRPR-Positive Models.

Background: The frequent overexpression of gastrin-releasing peptide receptors (GRPRs) in human cancers provides the rationale for delivering clinically useful radionuclides to tumor sites using peptide carriers. Radiolabeled GRPR antagonists, besides being safer for human use, have often shown higher tumor uptake and faster background clearance than agonists. We herein compared the biological profiles of the GRPR-antagonist-based radiotracers [99mTc]Tc-[N4-PEGx-DPhe6,Leu-NHEt13]BBN(6-13) (N4: 6-(carboxy)-1,4,8,11-tetraazaundecane; PEG: polyethyleneglycol): (i) [99mTc]Tc-DB7 (x = 2), (ii) [99mTc]Tc-DB13 (x = 3), and (iii) [99mTc]Tc-DB14 (x = 4), in GRPR-positive cells and animal models. The impact of in situ neprilysin (NEP)-inhibition on in vivo stability and tumor uptake was also assessed by treatment of mice with phosphoramidon (PA). Methods: The GRPR affinity of DB7/DB13/DB14 was determined in PC-3 cell membranes, and cell binding of the respective [99mTc]Tc-radioligands was assessed in PC-3 cells. Each of [99mTc]Tc-DB7, [99mTc]Tc-DB13, and [99mTc]Tc-DB14 was injected into mice without or with PA coinjection and 5 min blood samples were analyzed by HPLC. Biodistribution was conducted at 4 h postinjection (pi) in severe combined immunodeficiency disease (SCID) mice bearing PC-3 xenografts without or with PA coinjection. Results: DB7, -13, and -14 displayed single-digit nanomolar affinities for GRPR. The uptake rates of [99mTc]Tc-DB7, [99mTc]Tc-DB13, and [99mTc]Tc-DB14 in PC-3 cells was comparable and consistent with a radioantagonist profile. The radiotracers were found to be ≈70% intact in mouse blood and >94% intact after coinjection of PA. Treatment of mice with PA enhanced tumor uptake. Conclusions: The present study showed that increase of PEG-spacer length in the [99mTc]Tc-DB7-[99mTc]Tc-DB13-[99mTc]Tc-DB14 series had little effect on GRPR affinity, specific uptake in PC-3 cells, in vivo stability, or tumor uptake. A significant change in in vivo stability and tumor uptake was observed only after treatment of mice with PA, without compromising the favorably low background radioactivity levels.

Synthesis and Antimicrobial Evaluation of Some New Organic Tellurium Compounds Based on Pyrazole Derivatives.

A novel series of organic tellurium compounds based on pyrazole derivatives with a general formula of ArTeBr3 and Ar2TeBr2 [Ar = 2-(3-(4-substituted phenyl)-5-(2-chlorophenyl)-1H-pyrazol-1-yl)-3,5-dinitrophenyl] were obtained by the refluxing of corresponding aryl mercuric chlorides with TeBr4 in two different mole ratio of 1:1 and 2:1, respectively, in free-moisture dioxane solvent under an argon atmosphere. Compounds of ArTeBr3 and Ar2TeBr2 were reduced by the action of ethanolic solution of hydrazine hydrate obtained Ar2Te2 and Ar2Te, respectively. Reaction of Ar2Te2 with excess thionyl chloride or iodine gave the corresponding trihalides ArTeCl3 and ArTeI3, respectively while the reaction of Ar2Te with thionyl chloride or iodine gave the corresponding Ar2TeCl3 and Ar2TeI3, respectively. The structures were elucidated according to their elemental analysis of carbon, hydrogen and nitrogen (CHN) and some of the spectroscopic techniques such as infrared IR and nuclear magnetic resonance for 1H and 13C. The antimicrobial activity for all the synthetic compounds were assayed against both Gram-negative and Gram-positive bacteria by using the agar diffusion method. The tellurated pyrazole derivatives showed a good degree against bacteria growth. In some cases, the antimicrobial activities of the synthetic compounds were better than amoxicillin.

Test-Retest Precision of Myocardial Blood Flow Measurements With 99mTc-Tetrofosmin and Solid-State Detector Single Photon Emission Computed Tomography.

BACKGROUND: Measurement of myocardial blood flow (MBF) with single photon emission computed tomography (SPECT) is feasible using cardiac cameras with solid-state detectors. SPECT MBF has been shown to be accurate when compared with positron emission tomography MBF measured in the same patients. However, the value of a test result applied to an individual patient depends strongly on the precision or repeatability of the test. The purpose of our study is to measure the precision of SPECT MBF measurements using 99mTc-tetrofosmin and a solid-state cardiac camera. METHODS: SPECT MBF was measured in 30 patients and repeated at a mean interval of 18 days. MBF was evaluated from images with and without attenuation correction based on a separately acquired CT scan. The dynamic images were processed independently by 2 operators using in-house kinetic analysis software that applied a 1-tissue-compartment model. The K1 rate constant was converted to MBF using previously determined extraction fraction corrections. Correction for patient body motion was applied manually. RESULTS: The average coefficient of variation (COV) in the differences between the 2 MBF measurements was between 28% and 31%. The interobserver COV was between 11% and 15%. Myocardial flow reserve is the ratio of MBF measured at stress and rest, and the COV is correspondingly higher. The COV for the difference in repeated myocardial flow reserve was 33% to 38%, whereas the interobserver COV was 13% to 22%. CONCLUSIONS: The COV for the difference in SPECT MBF measurements obtained on separate days is 28% to 31%. The corresponding COV for myocardial flow reserve is 33% to 38%.

Synthesis and characterization of novel 99mTc-DGC nano-complexes for improvement of heart diagnostic.

In this research, early diagnosis of cardiovascular diseases can reduce their mortality and burden. In our study, we developed a new nano-agent, 99mTc-Dendrimer Glyco Conjugate (99mTc-DGC), and assessed its safety and capability for myocardial viability scan. To develop 99mTc-DGC, we first synthesized the dendrimer and then, glucose has been conjugated. Afterwards, we measured toxicity of the product on normal cells by XTT and apoptosis/necrosis methods. We compared the myocardial viability scan (measured by SPECT and dynamic planar imaging) in two rabbit models, with and without infarction. We also assessed the biodistribution of 99mTc-DGC in rats with no infarction. DGC synthesis was confirmed by Fourier transform infrared (FT-IR), proton nuclear magnetic resonance (1H NMR), liquid chromatography-mass spectrometry (LC-MS), dynamic light scattering (DLS) and static light scattering techniques (SLS). Then radiochemical purity (RCP) was done to present the stability and potential of DGC to complex formation with 99mTc. In vitro cytotoxicity showed nontoxic concentration up to 8 mg/mL. Single Photon Emission Computed Tomography (SPECT) and dynamic planar imaging clearly showed the accumulation of 99mTc-DGC in myocardial. Biodistribution result showed the 2.60% accumulation of 99mTc-DGC in myocardial after 2 h. Our findings indicated 99mTc-DGC to be safe and can accurately diagnose myocardial infarctions at early stages. Human studies to further assess such effects are critical.

Preparation and evaluation of 99mTc-labeled HYNIC-palbociclib analogs for cyclin-dependent kinase 4/6-positive tumor imaging.

Overexpression and amplification of cyclin-dependent kinase 4/6 (CDK4/6) occur in many cancers and may be the cause of resistance to CDK4/6 inhibitors in preclinical models. However, there are few investigations on the assessment of CDK4/6 expression in tumors or other tissues. Palbociclib, which was approved in 2015 to treat ER+/HER2-breast cancer in combination with letrozole, is a selective CDK4/6 inhibitor. In this study, an intermediate (compound 3), which could be hydrolyzed into the ligand (compound L) consisting of palbociclib as the bioactive molecule and 6-hydrazino nicotinamide (HYNIC) as the bifunctional chelator, was synthesized. Compound L was radiolabeled with 99mTc using tricine/TPPTS or tricine/TPPMS as co-ligands. 99mTc-tricine-TPPTS-L and 99mTc-tricine-TPPMS-L were prepared with high radiochemical purity without postlabeling purification. They had great in vitro stability. Both radiotracers were hydrophilic, but 99mTc-tricine-TPPTS-L had a lower log P value. In vitro cell uptake studies in MCF-7 cells showed that cellular uptake was blocked by preincubation with palbociclib, suggesting a CDK4/6-mediated uptake mechanism. Biodistribution in mice bearing MCF-7 tumors showed that 99mTc-tricine-TPPTS-L had higher tumor uptake than 99mTc-tricine-TPPMS-L, while they had comparable tumor-to-muscle and tumor-to-blood ratios. Radioactivity accumulation in tumors was obvious in micro-SPECT/CT images with 99mTc-tricine-TPPTS-L. When mice were preinjected with palbociclib, tumor uptake of 99mTc-tricine-TPPTS-L significantly decreased and the tumor accumulation was clearly lost, confirming CDK4/6 specificity. All results in this work indicated that 99mTc-tricine-TPPTS-L is a promising tumor imaging agent that targets CDK4/6.

Synthesis, physicochemical and biological evaluation of tacrine derivative labeled with technetium-99m and gallium-68 as a prospective diagnostic tool for early diagnosis of Alzheimer's disease.

Design, physicochemical and biological studies of novel radioconjugates for the early diagnosis of Alzheimer's disease, based on the newly synthesized tacrine derivatives were performed. Novel tacrine analogues were labeled with technetium-99m and gallium-68. For all obtained radioconjugates ([99mTc]Tc-Hynic-(tricine)2NH(CH2)ntacrine and [68Ga]Ga-DOTA-NH(CH2)9tacrine, where n = 2-9 denotes the number of methylene groups CH2) the studies of physicochemical properties (lipophilicity, stability in the presence of an excess of standard amino acids cysteine or histidine, human serum and in cerebrospinal fluid) were performed. For two selected radioconjugates [99mTc]Tc-Hynic-(tricine)2NH(CH2)9Tac and [68Ga]Ga-DOTA-NH(CH2)9tacrine (characterized with the highest lipophilicity values) the biological tests (inhibition of cholinesterases action, molecular docking and biodistribution studies) have been performed. All novel radioconjugates showed high stability in biological solutions used. Both selected radioconjugates proved to be good inhibitors of cholinesterases and be able to cross the blood-brain barrier. Radioconjugates [99mTc]Tc-Hynic-(tricine)2NH(CH2)9tacrine and [68Ga]Ga-DOTA-NH(CH2)9tacrine fulfil the conditions for application in nuclear medicine. Radiopharmaceutical [68Ga]Ga-DOTA-NH(CH2)9tacrine, due to increased accuracy and improved sensitivity in PET imaging, may be better potential diagnostic tool for early diagnosis of Alzheimer's disease.

Protective effects of extracorporeal shockwave on rat chondrocytes and temporomandibular joint osteoarthritis; preclinical evaluation with in vivo99mTc-HDP SPECT and ex vivo micro-CT.

OBJECTIVE: Extracorporeal shockwave therapy (ESWT) has been shown to have chondroprotective effects on arthritic diseases. We investigated the effects of ESWT on temporomandibular joint osteoarthritis (TMJOA) using rat chondrocytes and TMJOA rat models. DESIGN: Cell viability and expression of pro-inflammatory cytokines, cartilage degradation, and apoptosis markers were measured in control, monosodium iodoacetate (MIA)-treated and ESWT plus MIA-treated chondrocytes in vitro, and intra-articular MIA injection (TMJOA) and ESWT on TMJOA rats in vivo. In vivo99mTc-hydroxymethylene diphosphonate (HDP) single-photon emission computerized tomography/computerized tomography (SPECT/CT) and ex-vivo micro-CT and histologic examinations were performed in rat models. RESULTS: ESWT plus MIA-treated chondrocytes showed increased cell viability significantly (P = 0.007), while decreased genetic expression of pro-inflammatory cytokines [tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), and interleukin-6 (IL-6); P < 0.001 for each] and cartilage degradation markers [matrix metalloproteinase-3 (MMP3), matrix metalloproteinase-13 (MMP13), and bone morphogenetic protein 7 (BMP7); P < 0.001 for each], and number of apoptotic cells (P < 0.001) compared to MIA-treated chondrocytes. Changes in cytochrome c and cleaved caspase-3 levels relative to procaspase-3 were decreased over MIA-treated chondrocytes. ESWT on TMJOA rat models was associated with a significant decrease in pro-inflammatory and cartilage degradation markers, as demonstrated by real-time PCR and immunohistochemistry stains (P < 0.001 for each). On 99mTc-HDP SPECT/CT, the ESWT group showed a significantly lower uptake ratio compared to the TMJOA group (P = 0.008). Micro-CT analysis revealed that the ESWT group showed improved structure and bone quality compared to the TMJOA control group. CONCLUSIONS: ESWT was associated with a protective effect on cartilage and subchondral bone structures of TMJOA by reducing inflammation, cartilage degradation, and chondrocyte apoptosis.

Synthesis and biological evaluation of Tc-99m-cyclopentadienyltricarbonyl-technetium-labeled A-85380: An imaging probe for single-photon emission computed tomography investigation of nicotinic acetylcholine receptors in the brain.

We have designed (S)-(5-(azetidin-2-ylmethoxy)pyridine-3-yl)methyl cyclopentadienyltricarbonyl technetium carboxylate ([99mTc]CPTT-A-E) with high affinity for nicotinic acetylcholine receptors (nAChRs) using (2(S)-azetidinylmethoxy)-pyridine (A-85380) as the lead compound to develop a Tc-99m-cyclopentadienyltricarbonyl-technetium (99mTc)-labeled nAChR imaging probe. Because technetium does not contain a stable isotope, cyclopentadienyltricarbonyl rhenium (CPTR) was synthesized by coordinating rhenium, which is a homologous element having the same coordination structure as technetium. Further, the binding affinity to nAChR was evaluated. CPTR-A-E exhibited a high binding affinity to nAChR (Ki = 0.55 nM). Through the radiosynthesis of [99mTc]CPTT-A-E, an objective compound could be obtained with a radiochemical yield of 33% and a radiochemical purity of greater than 97%. In vitro autoradiographic study of the brain exhibited that the local nAChR density strongly correlated with the amount of [99mTc]CPTT-A-E that was accumulated in each region of interest. Further, the in vivo evaluation of biodistribution revealed a higher accumulation of [99mTc]CPTT-A-E in the thalamus (characterized by the high nAChR density) when compared with that in the cerebellum (characterized by the low nAChR density). Although additional studies will be necessary to improve the uptake of [99mTc]CPTT-A-E to the brain, [99mTc]CPTT-A-E met the basic requirements for nAChR imaging.

Tc-99m HYNIC-TOC scintigraphy in dedifferentiated thyroid cancer.

There is literature evidence showing utility of somatostatin receptor (SSTR) positron emission tomography-CT (PET-CT) imaging in differentiated thyroid cancer with Thyroglobulin Elevated and Negative Iodine Scan (TENIS). These patients are less benefited with I-131 therapy and surgery remains only curable option if disease could be localised. If surgery is not feasible, other therapeutic options are not promising. However, if these patients show strongly positive SSTR imaging, then possibility of peptide receptor radionuclide therapy may be explored. As SSTR PET-CT imaging is expensive and not widely available, Technetium-99m (Tc-99m) hydrazinonicotinyl-Tyr3-octreotide (HYNIC-TOC), which is a Single photon emission computed tomography (SPECT) tracer, can be used. We are documenting a case of raised serum thyroglobulin antibody and negative I-131 whole body scan with disease recurrence localised on Tc-99m HYNIC-TOC scan.

Development of the 99mTc-Hydroxamamide Complex as a Probe Targeting Carbonic Anhydrase IX.

Carbonic anhydrase IX (CA-IX) is regarded as a favorable target for in vivo imaging because of its specific expression in hypoxic regions of tumors. Hypoxia assists tumor propagation and growth and is resistant to chemotherapy and radiotherapy. Here, we designed and synthesized [99mTc]hydroxamamide ([99mTc]Ham) and [99mTc]methyl-substituted-hydroxamamide ([99mTc]MHam) complexes including a bivalent CA-IX ligand, sulfonamide (SA), and ureidosulfonamide (UR). In a cell binding assay, [99mTc]Ham complexes with bivalent SA ([99mTc]SAB2A and [99mTc]SAB2B) and UR ([99mTc]URB2A and [99mTc]URB2B) showed significantly greater uptake into CA-IX high-expressing (HT-29) cells than that into CA-IX low-expressing cells. Since the binding affinity of [99mTc]URB2A and [99mTc]URB2B for CA-IX was significantly higher than that of [99mTc]SAB2A and [99mTc]SAB2B, we additionally synthesized [99mTc]MURB2 (a [99mTc]MHam complex with bivalent UR) and evaluated the CA-IX-specific binding affinity of [99mTc]URB2A, [99mTc]URB2B, and [99mTc]MURB2. Their uptake into HT-29 cells was reduced by the addition of a CA inhibitor, acetazolamide, suggesting their CA-IX-specific binding affinity. A biodistribution study in HT-29 tumor-bearing mice was carried out using [99mTc]URB2A and [99mTc]MURB2 with the highest specificity for HT-29 cells. [99mTc]URB2A showed moderate tumor uptake and reduction by coinjection with acetazolamide; however, the tumor/blood ratio was insufficient for in vivo imaging. These results provided key information for the design of novel Ham-based imaging probes targeting CA-IX.

Gamma Emitters in Pancreatic Endocrine Tumors Imaging in the PET Era: Is there a Clinical Space for 99mTc-peptides?

BACKGROUND: Pancreatic Neuroendocrine Tumors (PNETs) are rare neoplasms, sporadic or familial, even being part of a syndrome. Their diagnosis is based on symptoms, hormonal disorders or may be fortuitous. The role of Nuclear Medicine is important, mainly because of the possibility of a theranostic strategy. This approach is allowed by the availability of biochemical agents, which may be labeled with radionuclides suitable for diagnostic or therapeutic purposes, showing almost identical pharmacokinetics. The major role for radiopharmaceuticals is connected with radiolabeled Somatostatin Analogues (SSA), since somatostatin receptors are highly expressed on some of the neoplastic cell types. DISCUSSION: Nowadays, in the category of radiolabeled SSA, although 111In-pentetreotide, firstly commercially proposed, is still used, the best choice for diagnosis is related to the so called DOTAPET radiotracers labeled with 68-Gallium (Ga), such as 68Ga-DOTATATE, 68Ga-DOTANOC, and 68Ga-DOTATOC. More recently, labeling with 64-Copper (Cu) (64Cu-DOTATATE) has also been proposed. In this review, we discuss the clinical interest of a SAA (Tektrotyd©) radiolabeled with 99mTc, a gamma emitter with better characteristics, with respect to 111Indium, radiolabeling Octreoscan ©. By comparing both pharmacokinetics and pharmacodynamics of Octreoscan©, Tektrotyd© and PET DOTA-peptides, on the basis of literature data and of our own experience, we tried to highlight these topics to stimulate further studies, individuating actual clinical indications for all of these radiotracers. CONCLUSION: In our opinion, Tektrotyd© could already find its applicative dimension in the daily practice of NETs, either pancreatic or not, at least in centers without a PET/CT or a 68Ga generator. Because of wider availability, a lower cost, and a longer decay, compared with respect to peptides labeled with 68Ga, it could be also proposed, in a theranostic context, for a dosimetry evaluation of patients undergoing Peptide Receptor Radionuclide Therapy (PRRT), and for non-oncologic indications of radiolabelled SSA. In this direction, and for a more rigorous cost/effective evaluation, more precisely individuating its clinical role, further studies are needed.

Cardiac molecular pathways influenced by doxorubicin treatment in mice.

Doxorubicin (DOX) is a potent chemotherapeutic with distinct cardiotoxic properties. Understanding the underlying cardiotoxic mechanisms on a molecular level would enable the early detection of cardiotoxicity and implementation of prophylactic treatment. Our goal was to map the patterns of different radiopharmaceuticals as surrogate markers of specific metabolic pathways induced by chemotherapy. Therefore, cardiac distribution of 99mTc-sestamibi, 99mTc-Annexin V, 99mTc-glucaric acid and [18F]FDG and cardiac expression of Bcl-2, caspase-3 and -8, TUNEL, HIF-1α, and p53 were assessed in response to DOX exposure in mice. A total of 80 mice (64 treated, 16 controls) were evaluated. All radiopharmaceuticals showed significantly increased uptake compared to controls, with peak cardiac uptake after one (99mTc-Annexin V), two (99mTc-sestamibi), three ([18F]FDG), or four (99mTc-glucaric acid) cycles of DOX. Strong correlations (p < 0.01) were observed between 99mTc-Annexin V, caspase 3 and 8, and TUNEL, and between [18F]FDG and HIF-1α. This suggests that the cardiac DOX response starts with apoptosis at low exposure levels, as indicated by 99mTc-Annexin V and histological apoptosis markers. Late process membrane disintegration can possibly be detected by 99mTc-sestamibi and 99mTc-glucaric acid. [18F]FDG signifies an early adaptive response to DOX, which can be further exploited clinically in the near future.

Solar angle of the distal phalanx is associated with scintigraphic evidence of subchondral bone injury in the palmar/plantar aspect of the third metacarpal/tarsal condyles in Thoroughbred racehorses.

BACKGROUND: Subchondral bone injury at the palmar/plantar aspect of the condyles of the third metacarpal/metatarsal bone (MC/MT3) commonly causes lameness and poor performance in racehorses. Injury occurs due to repetitive loading, the magnitude of which may be influenced by the position of the distal phalanx relative to the ground surface, i.e. the solar angle. The association of solar angle and injury at the palmar/plantar condyles of distal MC/MT3 therefore warrants investigation. OBJECTIVES: Investigate the relationship between solar angle and radiopharmaceutical uptake at the palmar/plantar aspect of distal MC/MT3 on scintigraphic images of racehorses. STUDY DESIGN: Retrospective case-controlled study. METHODS: Scintigraphic images of Thoroughbred racehorses presented for poor performance or lameness were graded for intensity of radiopharmaceutical uptake in the palmar/plantar aspect of distal MC/MT3. Solar angle was graded (positive, neutral or negative), referring to the angle of the solar plane of the distal phalanx relative to the ground surface. Repeatability of solar angle (n = 1226 limbs) and agreement with objective radiographic evaluation (n = 52 limbs) were evaluated. Prescintigraphy performance data were collected from race records. Associations between solar angle, performance and radiopharmaceutical uptake were investigated using multivariable logistic regression. RESULTS: Repeatability of scintigraphic solar angle grading (κ = 0.89, 95% CI 0.87-0.91) and agreement of scintigraphic and radiographic solar angle (κ = 0.88, 95% CI 0.75-0.97) were excellent. Horses that performed best prior to presentation were more likely to have both greater radiopharmaceutical uptake and a neutral/negative solar angle. When controlling for prior performance, horses with neutral/negative forelimb solar angle were twice as likely to have moderate/marked radiopharmaceutical uptake than horses with positive solar angle (P<0.02). Horses with negative hindlimb solar angle were six times more likely to have moderate/marked radiopharmaceutical uptake than horses with positive/neutral solar angle (P<0.001). MAIN LIMITATIONS: Population bias due to preselected hospital population. CONCLUSIONS: Both solar angle and race performance are independently associated with increased bone activity in the palmar/plantar aspect of the third metacarpal/tarsal condyles. The Summary is available in Portuguese - see Supporting Information.

Interactions between myocardial sympathetic denervation and left ventricular mechanical dyssynchrony: A CZT analysis.

BACKGROUND: A correlation between left ventricular (LV) dyssynchrony (LVD) and impaired myocardial sympathetic tone has been hypothesized. We sought to assess the interactions between regional LV sympathetic innervation, perfusion, and mechanical dyssynchrony. METHODS: Eighty-three patients underwent evaluation of LV perfusion and sympathetic innervation on 99mTc-tetrofosmin/123I-metaiodobenzylguanidine (123I-MIBG) imaging. The summed rest score and summed 123I-MIBG score (SS-MIBG) were computed. The extent of "innervation/perfusion" mismatch was defined as the number of denervated LV segments with relatively preserved perfusion. LVD was evaluated on phase analysis and the wall with latest mechanical activation identified. RESULTS: LVD was revealed in 36 (43%) patients. Patients with LVD had more abnormal values of SRS (21 ± 9 vs 10 ± 8, P < 0.001) and SS-MIBG (29 ± 9 vs 17 ± 11, P < 0.001) than those without LVD. The presence of LVD also clustered with a higher burden of "innervation/perfusion" mismatch (P = 0.019). On per-wall analysis, LV walls with delayed mechanical activation showed a higher burden of "innervation/perfusion" mismatch (2.3 ± 1.4 segments) than normally contracting walls (1.3 ± 1.2 segments; P < 0.001). On multivariate analysis, the extent of "innervation/perfusion" mismatch was the only predictor of delayed mechanical activation (P = 0.029). CONCLUSIONS: Patients with LVD show an elevated burden of "innervation/perfusion" mismatch that is concentrated at the level of the most dyssynchronous walls.

Whole-body Imaging of Cell Death Provides a Systemic, Minimally Invasive, Dynamic, and Near-real Time Indicator for Chemotherapeutic Drug Toxicity.

PURPOSE: Response to toxicity in chemotherapies varies considerably from tissue to tissue and from patient to patient. An ability to monitor the tissue damage done by chemotherapy may have a profound impact on treatment and prognosis allowing for a proactive management in understanding and mitigating such events. For the first time, we investigated the feasibility of using whole-body imaging to map chemotherapeutic drug-induced toxicity on an individual basis. EXPERIMENTAL DESIGN: In a preclinical proof-of-concept, rats were treated with a single clinical dose of cyclophosphamide, methotrexate, or cisplatin. In vivo whole-body imaging data were acquired using 99mTc-duramycin, which identifies dead and dying cells as an unambiguous marker for tissue injury in susceptible organs. Imaging results were cross-validated using quantitative ex vivo measurements and histopathology and compared with standard blood and serum panels for toxicology. RESULTS: The in vivo whole-body imaging data detected widespread changes, where spatially heterogeneous toxic effects were identified across different tissues, within substructures of organs, as well as among different individuals. The signal changes were consistent with established toxicity profiles of these chemotherapeutic drugs. Apart from generating a map of susceptible tissues, this in vivo imaging approach was more sensitive compared with conventional blood and serum markers used in toxicology. Also, repeated imaging during the acute period after drug treatment captured different kinetics of tissue injury among susceptible organs in males and females. CONCLUSIONS: This novel and highly translational imaging approach shows promise in optimizing therapeutic decisions by detecting and managing drug toxicity on a personalized basis.Toxicity to normal tissues is a significant limitation in chemotherapies. This work demonstrated an in vivo imaging-based approach for characterizing toxicity-induced tissue injury in a systemic, dynamic, and near-real time fashion. This novel approach shows promise in optimizing therapeutic decisions by monitoring drug toxicity on a personalized basis.

Susceptibility of 99mTc-Ciprofloxacin for Common Infection Causing Bacterial Strains Isolated from Clinical Samples: an In Vitro and In Vivo Study.

99mTc-ciprofloxacin scintigraphy is useful in the detection of gram-positive and gram-negative bacterial infections and also for differentiating the infection from aseptic inflammation. However, due to growing bacterial resistance to antibiotics, the 99mTc-ciprofloxacin no longer can be effective in broad-spectrum infection imaging as it is gradually losing specificity. In this study, we are presenting our findings regarding the in vitro and in vivo susceptibility of 99mTc-ciprofloxacin for multi-drug-resistant Staphylococcus aurous, Escherichia coli, and Pseudomonas aeruginosa bacterial strains which were isolated from clinical samples. The results of radiosynthesis of 99mTc-ciprofloxacin showed more the 95% radiochemical purity and less than 5% radioactive impurities. In vitro 99mTc-ciprofloxacin susceptibility test showed that E. coli offered more resistant to 99mTc-ciprofloxacin as compared to S. aurous and P. aeruginosa. In vivo study using bacterial infection induced rabbit model also revealed lowest uptake by E. coli lesion. The T/NT values were obtained 1.96 ± 0.15 in the case of E. coli; 2.81 ± 0.51 in the case of S. aurous; and 2.32 ± 0.66 in the case of P. aeruginosa at 4 h post-injection. The SPECT infection imaging of S. aurous, E. coli, and P. aeruginosa bacterial infection induced rabbit models also indicated the clear accumulation in S. aurous and P. aeruginosa lesions while negligible uptake by E. coli lesion further verify the in vitro and in vivo susceptibility profile. On the bases of the results obtained, the 99mTc-ciprofloxacin showed selective and poor broad spectrum SPECT infection imaging.