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1.
Inorg Chem ; 61(11): 4778-4787, 2022 Mar 21.
Article in English | MEDLINE | ID: mdl-35245023

ABSTRACT

Positron emission tomography (PET), which uses positron-emitting radionuclides to visualize and measure processes in the human body, is a useful noninvasive diagnostic tool for Alzheimer's disease (AD). The development of longer-lived radiolabeled compounds is essential for further expansion of the use of PET imaging in healthcare, and diagnostic agents employing longer-lived radionuclides such as 64Cu (t1/2 = 12.7 h, ß+ = 17%, ß- = 39%, electron capture EC = 43%, and Emax = 0.656 MeV) can accomplish this task. One limitation of 64Cu PET agents for neuroimaging applications is their limited lipophilicity due to the presence of several anionic groups needed to ensure strong Cu chelation. Herein, we evaluate a series of neutral chelators containing the 1,4,7-triazacyclononane or 2,11-diaza[3.3](2,6)pyridinophane macrocycles that have pyridyl-containing arms incorporating Aß-peptide-interacting fragments. The crystal structures of the corresponding Cu complexes confirm that the pyridyl N atoms are involved in binding to Cu. Radiolabeling and autoradiography studies show that the compounds efficiently chelate 64Cu, and the resulting complexes exhibit specific binding to the amyloid plaques in the AD mouse brain sections versus wild-type controls.


Subject(s)
Alzheimer Disease , Alzheimer Disease/diagnostic imaging , Alzheimer Disease/metabolism , Animals , Chelating Agents/chemistry , Ligands , Mice , Plaque, Amyloid , Positron-Emission Tomography/methods , Radiopharmaceuticals/chemistry , Radiopharmaceuticals/pharmacology
2.
Drug Deliv ; 29(1): 186-191, 2022 Dec.
Article in English | MEDLINE | ID: mdl-35191342

ABSTRACT

The treatment of bone metastatsis as primary bone cancer itself is still a challenge. The use od radium dichloride ([223Ra] RaCl2) has emerged in the last few years as one of the best treatment choice for bone cancer, with especial focus in bone metastasis. The alpha-emitter radiopharmaceutical has showed potent and efficient results in several clinical trials. In this study we have formulated radium dichloride ([223Ra] RaCl2) nanomicelles in order to evaluate and compare with pure radium dichloride ([223Ra] RaCl2). The results showed that nanomicelles at the same dose had a superior effect (20% higher efficient) when compared with pure radium dichloride ([223Ra] RaCl2). The results corroborated the effectiveness of the nanosystem validating the application of nanotechnology in alpha-radiotherapy with radium dichloride ([223Ra] RaCl2).


Subject(s)
Bone Neoplasms/pathology , Nanoparticles/chemistry , Osteosarcoma/pathology , Radiopharmaceuticals/pharmacology , Radium/pharmacology , Cell Line, Tumor , Cell Survival/drug effects , Chemistry, Pharmaceutical , Dose-Response Relationship, Drug , Drug Carriers/chemistry , Humans , Micelles , Particle Size , Poloxamer/chemistry , Radioisotopes/administration & dosage , Radioisotopes/pharmacology , Radiopharmaceuticals/administration & dosage , Radium/administration & dosage
3.
Sci Rep ; 12(1): 3020, 2022 02 22.
Article in English | MEDLINE | ID: mdl-35194100

ABSTRACT

Radiopharmaceutical therapy (RPT) is an attractive strategy for treatment of disseminated cancers including those overexpressing the HER2 receptor including breast, ovarian and gastroesophageal carcinomas. Single-domain antibody fragments (sdAbs) exemplified by the HER2-targeted VHH_1028 evaluated herein are attractive for RPT because they rapidly accumulate in tumor and clear faster from normal tissues than intact antibodies. In this study, VHH_1028 was labeled using the residualizing prosthetic agent N-succinimidyl 3-guanidinomethyl 5-[131I]iodobenzoate (iso-[131I]SGMIB) and its tissue distribution evaluated in the HER2-expressing SKOV-3 ovarian and BT474 breast carcinoma xenograft models. In head-to-head comparisons to [131I]SGMIB-2Rs15d, a HER2-targeted radiopharmaceutical currently under clinical investigation, iso-[131I]SGMIB-VHH_1028 exhibited significantly higher tumor uptake and significantly lower kidney accumulation. The results demonstrated 2.9 and 6.3 times more favorable tumor-to-kidney radiation dose ratios in the SKOV-3 and BT474 xenograft models, respectively. Iso-[131I]SGMIB-VHH_1028 was prepared using a solid-phase extraction method for purification of the prosthetic agent intermediate Boc2-iso-[131I]SGMIB that reproducibly scaled to therapeutic-level doses and obviated the need for its HPLC purification. Single-dose (SKOV-3) and multiple-dose (BT474) treatment regimens demonstrated that iso-[131I]SGMIB-VHH_1028 was well tolerated and provided significant tumor growth delay and survival prolongation. This study suggests that iso-[131I]SGMIB-VHH_1028 is a promising candidate for RPT of HER2-expressing cancers and further development is warranted.


Subject(s)
Breast Neoplasms/drug therapy , Breast Neoplasms/genetics , Gastrointestinal Neoplasms/drug therapy , Gastrointestinal Neoplasms/genetics , Gene Expression/genetics , Immunoglobulin Fragments/therapeutic use , Iodine Radioisotopes/pharmacology , Iodine Radioisotopes/therapeutic use , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/genetics , Radiopharmaceuticals/pharmacology , Radiopharmaceuticals/therapeutic use , Receptor, ErbB-2/genetics , Receptor, ErbB-2/immunology , Single-Domain Antibodies/pharmacology , Single-Domain Antibodies/therapeutic use , Animals , Disease Models, Animal , Female , Humans , Receptor, ErbB-2/metabolism , Xenograft Model Antitumor Assays
4.
Sci Rep ; 12(1): 2955, 2022 02 22.
Article in English | MEDLINE | ID: mdl-35194089

ABSTRACT

Regenerative medicine uses the patient own stem cells to regenerate damaged tissues. Molecular imaging techniques are commonly used to image the transplanted cells, either right after surgery or at a later time. However, few techniques are fast or straightforward enough to label cells intraoperatively. Adipose tissue-derived stem cells (ADSCs) were harvested from knee joints of minipigs. The cells were labeled with PET contrast agent by flowing mechanoporation using a microfluidic device. While flowing through a series of microchannels, cells are compressed repeatedly by micro-ridges, which open transient pores in their membranes and induce convective transport, intended to facilitate the transport of 68Ga-labeled and lipid-coated mesoporous nanoparticles (MSNs) into the cells. This process enables cells to be labeled in a matter of seconds. Cells labeled with this approach were then implanted into cartilage defects, and the implant was imaged using positron emission tomography (PET) post-surgery. The microfluidic device can efficiently label millions of cells with 68Ga-labeled MSNs in as little as 15 min. The method achieved labeling efficiency greater than 5 Bq/cell on average, comparable to 30 min-long passive co-incubation with 68Ga-MSNs, but with improved biocompatibility due to the reduced exposure to ionizing radiation. Labeling time could also be accelerated by increasing throughput through more parallel channels. Finally, as a proof of concept, ADSCs were labeled with 68Ga-MSNs and quantitatively assessed using clinical PET/MR in a mock transplant operation in pig knee joints. MSN-assisted mechanoporation is a rapid, effective and straightforward approach to label cells with 68Ga. Given its high efficiency, this labeling method can be used to track small cells populations without significant effects on viability. The system is applicable to a variety of cell tracking studies for cancer therapy, regenerative therapy, and immunotherapy.


Subject(s)
Adipose Tissue/metabolism , Gallium Radioisotopes/pharmacology , Nanoparticles , Positron-Emission Tomography , Radiopharmaceuticals/pharmacology , Stem Cells/metabolism , Animals , Swine , Swine, Miniature
5.
Bioorg Med Chem Lett ; 60: 128583, 2022 03 15.
Article in English | MEDLINE | ID: mdl-35085720

ABSTRACT

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.


Subject(s)
Nitroimidazoles/pharmacology , Organotechnetium Compounds/pharmacology , Radiopharmaceuticals/pharmacology , Tumor Hypoxia/drug effects , Animals , Cell Line, Tumor , Diagnostic Imaging , Dose-Response Relationship, Drug , Mice , Molecular Structure , Neoplasms, Experimental/diagnostic imaging , Neoplasms, Experimental/drug therapy , Nitroimidazoles/chemical synthesis , Nitroimidazoles/chemistry , Organotechnetium Compounds/chemical synthesis , Organotechnetium Compounds/chemistry , Radiopharmaceuticals/chemical synthesis , Radiopharmaceuticals/chemistry , Structure-Activity Relationship , Tissue Distribution
6.
Eur Radiol ; 32(5): 3035-3044, 2022 May.
Article in English | MEDLINE | ID: mdl-35031838

ABSTRACT

OBJECTIVES: Although expert consensus recommendations suggest 2-3 h as the time interval between bone-seeking radiotracers injection and acquisition, it has been reported that images obtained early after [99mTc]Tc-HMDP administration are sufficient to diagnose cardiac amyloidosis. We evaluated the diagnostic performance of [99mTc]Tc-DPD early phase whole body scan with respect to late phase imaging. METHODS: We qualitatively and semiquantitatively reviewed [99mTc]Tc-DPD imaging of 53 patients referred for suspect cardiac amyloidosis. Findings of early and late phase images were compared with SPECT results (considered the standard-of-reference) determining sensitivity and specificity for visual analysis of each phase imaging and for each semiquantitative index. RESULTS: SPECT imaging was negative for cardiac accumulation in 25 patients and positive in 28. Visual analysis of early phase whole body scan had an extremely significant capability to predict SPECT results; nevertheless, complete agreement was not reached. Visual analysis of late phase imaging showed slightly better results. Semiquantitative analysis of early phase images, namely heart to mediastinum ratio, performed better than semiquantitative analysis of late phase images. CONCLUSION: Visual analysis of [99mTc]Tc-DPD early phase whole body scan is promising in diagnosing cardiac amyloidosis; further studies are needed to confirm our results in different clinical scenarios. KEY POINTS: • Visual analysis of early phase planar imaging using [99mTc]Tc-DPD is accurate to diagnose cardiac amyloidosis and may be satisfactory at least in frail patients with high cardiac burden of amyloid fibrils.


Subject(s)
Amyloidosis , Cardiomyopathies , Amyloid , Amyloidosis/diagnostic imaging , Cardiomyopathies/diagnostic imaging , Humans , Prealbumin , Radionuclide Imaging , Radiopharmaceuticals/pharmacology , Whole Body Imaging
7.
Int J Mol Sci ; 23(2)2022 Jan 13.
Article in English | MEDLINE | ID: mdl-35055005

ABSTRACT

The prevalence of obesity has increased dramatically in the Western population. Obesity is known to influence not only the proportion of adipose tissue but also physiological processes that could alter drug pharmacokinetics. Yet, there are no specific dosing recommendations for radiopharmaceuticals in this patient population. This could potentially lead to underdosing and thus suboptimal treatment in obese patients, while it could also lead to drug toxicity due to high levels of radioactivity. In this review, relevant literature is summarized on radiopharmaceutical dosing and pharmacokinetic properties, and we aimed to translate these data into practical guidelines for dosing of radiopharmaceuticals in obese patients. For radium-223, dosing in obese patients is well established. Furthermore, for samarium-153-ethylenediaminetetramethylene (EDTMP), dose-escalation studies show that the maximum tolerated dose will probably not be reached in obese patients when dosing on MBq/kg. On the other hand, there is insufficient evidence to support dose recommendations in obese patients for rhenium-168-hydroxyethylidene diphosphonate (HEDP), sodium iodide-131, iodide 131-metaiodobenzylguanidine (MIBG), lutetium-177-dotatate, and lutetium-177-prostate-specific membrane antigen (PSMA). From a pharmacokinetic perspective, fixed dosing may be appropriate for these drugs. More research into obese patient populations is needed, especially in the light of increasing prevalence of obesity worldwide.


Subject(s)
Radiopharmaceuticals/administration & dosage , Biomarkers , Clinical Decision-Making , Disease Management , Drug Monitoring , Humans , Molecular Targeted Therapy , Obesity/diagnosis , Obesity/drug therapy , Obesity/etiology , Organ Specificity/drug effects , Prognosis , Radiopharmaceuticals/chemistry , Radiopharmaceuticals/pharmacology , Radiopharmaceuticals/therapeutic use , Treatment Outcome
8.
PLoS One ; 17(1): e0261982, 2022.
Article in English | MEDLINE | ID: mdl-35061763

ABSTRACT

Hepatocellular carcinoma is the most common primary liver cancer and the fifth most frequently diagnosed cancer worldwide. Most patients with advanced disease are offered non-surgical palliative treatment options. This work explores the first alpha-particle emitting radioembolization for the treatment and monitoring of hepatic tumors. Furthermore, this works demonstrates the first in vivo simultaneous multiple-radionuclide SPECT-images of the complex decay chain of an [225Ac]Ac-labeled agent using a clinical SPECT system to monitor the temporal distribution. A DOTA chelator was modified with a lipophilic moiety and radiolabeled with the α-particle emitter Actinium-225. The resulting agent, [225Ac]Ac-DOTA-TDA, was emulsified in ethiodized oil and evaluated in vivo in mouse model and the VX2 rabbit technical model of liver cancer. SPECT imaging was performed to monitor distribution of the TAT agent and the free daughters. The [225Ac]Ac-DOTA-TDA emulsion was shown to retain within the HEP2G tumors and VX2 tumor, with minimal uptake within normal tissue. In the mouse model, significant improvements in overall survival were observed. SPECT-imaging was able to distinguish between the Actinium-225 agent (Francium-221) and the loss of the longer lived daughter, Bismuth-213. An α-particle emitting TARE agent is capable of targeting liver tumors with minimal accumulation in normal tissue, providing a potential therapeutic agent for the treatment of hepatocellular carcinoma as well as a variety of hepatic tumors. In addition, SPECT-imaging presented here supports the further development of imaging methodology and protocols that can be incorporated into the clinic to monitor Actinium-225-labeled agents.


Subject(s)
Alpha Particles/therapeutic use , Bismuth/pharmacology , Carcinoma, Hepatocellular/radiotherapy , Embolization, Therapeutic , Liver Neoplasms, Experimental/radiotherapy , Radioisotopes/pharmacology , Radiopharmaceuticals/pharmacology , Animals , Carcinoma, Hepatocellular/diagnostic imaging , Hep G2 Cells , Humans , Liver Neoplasms, Experimental/diagnostic imaging , Male , Mice , Rabbits , Radiopharmaceuticals/chemistry , Tomography, Emission-Computed, Single-Photon , Xenograft Model Antitumor Assays
10.
Molecules ; 27(1)2022 Jan 01.
Article in English | MEDLINE | ID: mdl-35011496

ABSTRACT

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.


Subject(s)
Endopeptidases/metabolism , Liver Neoplasms, Experimental , Membrane Proteins/metabolism , Neoplasm Proteins/metabolism , Organotechnetium Compounds , Radiopharmaceuticals , Single Photon Emission Computed Tomography Computed Tomography , Technetium , Animals , Hep G2 Cells , Humans , Liver Neoplasms, Experimental/diagnostic imaging , Liver Neoplasms, Experimental/metabolism , Male , Mice , Mice, Inbred BALB C , Organotechnetium Compounds/chemistry , Organotechnetium Compounds/pharmacokinetics , Organotechnetium Compounds/pharmacology , Radiopharmaceuticals/chemistry , Radiopharmaceuticals/pharmacokinetics , Radiopharmaceuticals/pharmacology , Technetium/chemistry , Technetium/pharmacokinetics , Technetium/pharmacology
11.
Eur J Med Chem ; 228: 114011, 2022 Jan 15.
Article in English | MEDLINE | ID: mdl-34875522

ABSTRACT

Herein, we describe the design, synthesis and deciphering of the key characteristics of the structure activity relationship (SAR) of trifluoromethyloxadiazole (TFMO) bearing class-IIa HDAC inhibitors. Our medicinal chemistry campaign of 23 compounds identified compound 1 as a highly potent inhibitor with sub nM affinity to class-IIa HDAC4 isoform. Therefore, We radiolabeled compound 1 (named thereafter as NT160) with [18F]fluoride thus producing the identical [18F]-NT160 as a diagnostic tool for positron emission tomography (PET). [18F]-NT160 was produced in high radiochemical purity (>95%), moderate radiochemical yield (2-5%) and moderate molar activity in the range of 0.30-0.85 GBq/umol (8.0-23.0 mCi/umol). We also established that [18F]-NT160 can cross the blood brain barrier and bind to class-IIa HDACs in vivo. The combination of [18F]-NT160 and 1 represent a novel theranostic pair using the same molecule to enable diagnostic PET imaging with [18F]-NT160 followed by targeted therapy with NT160.


Subject(s)
Drug Design , Histone Deacetylase Inhibitors/pharmacology , Histone Deacetylases/metabolism , Oxadiazoles/pharmacology , Radiopharmaceuticals/pharmacology , Dose-Response Relationship, Drug , Fluorine Radioisotopes , HT29 Cells , Histone Deacetylase Inhibitors/chemical synthesis , Histone Deacetylase Inhibitors/chemistry , Humans , Isoenzymes/antagonists & inhibitors , Isoenzymes/metabolism , Molecular Structure , Oxadiazoles/chemical synthesis , Oxadiazoles/chemistry , Positron-Emission Tomography , Radiopharmaceuticals/chemical synthesis , Radiopharmaceuticals/chemistry , Structure-Activity Relationship
12.
Bioorg Med Chem ; 53: 116525, 2022 01 01.
Article in English | MEDLINE | ID: mdl-34871844

ABSTRACT

Mutations in isocitrate dehydrogenase 1 (IDH1) are commonly found in various human malignancies. Inhibitors of several mutant IDH1 enzymes have entered clinical trials as target therapeutic drugs for the treatment of patients with IDH1 mutations. Herein, we report the synthesis and evaluation of two 18F-labeled tracers, [18F]AG120 and [18F]AG135 for imaging expression of mutated IDH1 in positron emission tomography (PET). [18F]AG120 and [18F]AG135 were synthesized in decay-corrected radiochemical yield of 1 % and 3 %, respectively, high molar activity (52-66 MBq/nmol and 216-339 MBq/nmol, respectively) and high radiochemical purity (>99%). Both tracers showed good in vitro stability, selective uptake into mutated IDH1-expressing cells and good pharmacokinetic profiles with low uptake in most organs/tissues. Furthermore, [18F]AG120 micro-PET/CT imaging displayed significantly greater uptake in IDH1-mutant than in wild-type tumors, Relatively, uptake of [18F]AG135 was observed neither in IDH1-mutant tumor xenografts nor in wild-type tumors. This study suggests that [18F]AG120 is a promising radiotracer for PET imaging of IDH1 mutation, However, further optimization and investigation are necessary for [18F]AG135 due to the limited uptake in mutated IDH1-expressing tumors.


Subject(s)
Enzyme Inhibitors/pharmacology , Isocitrate Dehydrogenase/antagonists & inhibitors , Positron-Emission Tomography , Radiopharmaceuticals/pharmacology , Animals , Cell Line, Tumor , Dose-Response Relationship, Drug , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/chemistry , Fluorine Radioisotopes , Humans , Injections, Subcutaneous , Isocitrate Dehydrogenase/genetics , Isocitrate Dehydrogenase/metabolism , Male , Mice , Mice, Inbred BALB C , Mice, Nude , Molecular Structure , Radiopharmaceuticals/administration & dosage , Radiopharmaceuticals/chemistry , Structure-Activity Relationship , Tissue Distribution
13.
Cancer Biother Radiopharm ; 37(1): 47-55, 2022 Feb.
Article in English | MEDLINE | ID: mdl-34762521

ABSTRACT

Background: The purpose of this study was to examine the effect of 4-p-(tolyl)butyric acid as an albumin-binding (ALB) moiety on tumor targeting and biodistribution properties of 67Ga-labeled albumin binder-conjugated alpha-melanocyte-stimulating hormone peptides. Materials and Methods: DOTA-Lys(ALB)-G/GG/GGG-Nle-CycMSHhex {1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid-Lys(ALB)-Gly/GlyGly/GlyGlyGly-Nle-c[Asp-His-DPhe-Arg-Trp-Lys]-CONH2} were synthesized with 4-p-(tolyl)butyric acid serving as an ALB moiety. The melanocortin-1 receptor (MC1R)-binding affinities of the peptides were determined on B16/F10 melanoma cells. The biodistribution of 67Ga-DOTA-Lys(ALB)-G/GG/GGG-Nle-CycMSHhex was examined on B16/F10 melanoma-bearing C57 mice at 2 h postinjection to select a lead peptide for further evaluation. The melanoma targeting and imaging properties of 67Ga-DOTA-Lys(ALB)-GGNle-CycMSHhex {67Ga-ALB-G2} were determined on B16/F10 melanoma-bearing C57 mice. Results: The IC50 value of DOTA-Lys(ALB)-G/GG/GGG-Nle-CycMSHhex {ALB-G1, ALB-G2, ALB-G3} was 0.67 ± 0.07, 0.5 ± 0.09 and 0.51 ± 0.03 nM on B16/F10 cells, respectively. 67Ga-ALB-G2 was further evaluated as a lead peptide because of its higher tumor uptake (30.25 ± 3.24%ID/g) and lower kidney uptake (7.09 ± 2.22%ID/g) than 67Ga-ALB-G1 and 67Ga-ALB-G3 at 2 h postinjection. The B16/F10 melanoma uptake of 67Ga-ALB-G2 was 15.64 ± 4.55, 30.25 ± 3.24, 26.76 ± 3.23, and 10.71 ± 1.21%ID/g at 0.5, 2, 4, and 24 h postinjection, respectively. The B16/F10 melanoma lesions were clearly visualized by SPECT/CT using 67Ga-ALB-G2 as an imaging probe at 2 h postinjection. Conclusions: The introduction of 4-p-(tolyl)butyric acid as an ALB moiety increased the blood retention, and resulted in higher tumor/kidney ratio of 67Ga-ALB-G2 as compared with its counterpart without an albumin binder. However, the resulting high uptake of 67Ga-ALB-G2 in blood and liver need to be further reduced to facilitate its therapeutic application when replacing 67Ga with therapeutic radionuclides.


Subject(s)
Melanoma, Experimental , alpha-MSH , Albumins , Animals , Cell Line, Tumor , Lactams/chemistry , Melanoma, Experimental/diagnostic imaging , Melanoma, Experimental/pathology , Mice , Mice, Inbred C57BL , Radiopharmaceuticals/chemistry , Radiopharmaceuticals/pharmacology , Tissue Distribution , alpha-MSH/chemistry
14.
Eur Radiol ; 32(5): 3085-3096, 2022 May.
Article in English | MEDLINE | ID: mdl-34842956

ABSTRACT

OBJECTIVE: To determine the optimal 2-[18F]FDG-PET/MRI imaging protocol for the initial staging of patients with suspected or confirmed multiple myeloma. METHODS: Radiologists and nuclear medicine specialists reviewed all PET/MRI exams of 104 patients with a monoclonal gammopathy (MG). The presence of focal and diffuse bone marrow involvement (BMI) was assessed using 4 different image datasets: WB-MRI, PET, WB-PET/MRI, and WB-DCE-PET/MRI. A reference standard was established by a panel review of all baseline and follow-up imaging, and biological and pathological information. The diagnostic performance for each image dataset to detect BMI was evaluated and compared (Fisher's exact test). RESULTS: Sensitivity, specificity, and accuracy for focal BMI of WB-MRI was 87%, 97%, and 92%; of PET was 78%, 97%, and 95%; of WB-PET/MRI was 93%, 97%, and 95%; and of WB-DCE-PET/MRI was 93%, 97%, and 95%, respectively. WB-PET/MRI and WB-DCE-PET/MRI were statistically superior to PET (p = 0.036) without decreasing specificity. The sensitivity, specificity, and accuracy of WB-MRI for diffuse BMI detection was 91%, 80%, and 85%; of 3DT1-PET was 53%, 89%, and 74%; of WB-PET/MRI was 98%, 66%, and 79%; and of WB-DCE-PET/MRI was 98%, 59%, and 75%, respectively. PET lacked sensitivity compared to all other dataset studies (p < 0.0001). WB-MRI had the best accuracy without reaching statistical significance when compared to the other datasets. CONCLUSION: The WB-PET/MRI dataset including T1 and T2 Dixon, WB-DWI, and PET images provides optimal diagnostic performance to detect both focal lesions and diffuse BMI, with limited added value of WB-DCE for baseline staging of patients with MG. Key Points • The combination of morphological and functional MRI sequences and metabolic (2-[18F]FDG-PET) images increases the diagnostic performance of PET/MRI to detect focal bone lesions. • The adjunction of dynamic contrast-enhanced sequences did not improve diagnostic performance.


Subject(s)
Fluorodeoxyglucose F18 , Multiple Myeloma , Diffusion Magnetic Resonance Imaging/methods , Humans , Magnetic Resonance Imaging/methods , Multiple Myeloma/diagnostic imaging , Neoplasm Staging , Positron Emission Tomography Computed Tomography/methods , Positron-Emission Tomography , Radiopharmaceuticals/pharmacology , Whole Body Imaging/methods
15.
Curr Radiopharm ; 15(1): 84-91, 2022.
Article in English | MEDLINE | ID: mdl-34053431

ABSTRACT

BACKGROUND: The choice of mice strain can significantly influence the physiological distribution and may lead to an inadequate assessment of the radiopharmaceutical properties. OBJECTIVE: This work aims to present how the legal requirements that apply to radiopharmaceuticals contained in the various guidelines determine the choice of the mouse strain for quality control and preclinical studies and affect the results of physiological distribution. METHODS: Swiss and BALB/c mice were chosen as commonly used strains in experiments for research and quality control purposes. Radiopharmaceuticals, i.e., preparations containing one or more radioactive isotopes in their composition, are subject to the same legal regulations at every stage of the research, development and routine quality control as all other medicines. Therefore, in vivo experiments are to be carried out to confirm the pharmacological properties and safety. Moreover, if a radiopharmaceutical's chemical structure is unknown or complex and impossible to be determined by physicochemical methods, an analysis of physiological distribution in a rodent animal model needs to be performed. RESULTS: In our studies, thirty-six mice (Swiss n=18, BALB/c n=18) were randomly divided into six groups and injected with the following radiopharmaceuticals: [99mTc]Tc-Colloid, [99mTc]Tc-DTPA and [99mTc]Tc-EHIDA. Measurement of physiological distribution was conducted following the requirements of European Pharmacopoeia (Ph. Eur.) monograph 0689, internal instructions and the United States Pharmacopeia (USP) monograph. Additionally, at preclinical studies, ten mice (Swiss n=5, BALB/c n=5) were injected with the new tracer [99mTc]Tc-PSMA-T4, and its physiological distribution has been compared. The p-value <0.05 proved the statistical significance of the radiopharmaceutical physiological distribution. CONCLUSION: We claim that mice strain choice can significantly influence the physiological distribution and may lead to inaccurate quality control results and incomprehensible interpretation of the results from preclinical in vivo studies of a new radiopharmaceutical.


Subject(s)
Radioisotopes , Radiopharmaceuticals , Animals , Mice , Mice, Inbred BALB C , Radiopharmaceuticals/pharmacology
16.
Curr Radiopharm ; 15(1): 32-39, 2022.
Article in English | MEDLINE | ID: mdl-33397277

ABSTRACT

BACKGROUND: Nimotuzumab is a humanized anti-epidermal growth factor receptor (EGFR) monoclonal antibody, nowadays used for tumour immunochemotherapy. This study aimed to label the conjugate DOTA-nimotuzumab with yttrium-90, in order to provide a ß- emitting radioimmunoconjugate (90Y-DOTA-nimotuzumab) potentially useful to assess the feasibility of a new radio-guided surgery approach. METHODS: The synthesis of 90Y-DOTA-nimotuzumab was performed in two days. Nimotuzumab was conjugated with a 50-fold excess of DOTA and then labelled with 90Y3+. The 90Y-DOTA-nimotuzumab preparation was optimized considering several parameters such as pH, temperature and reaction volume. Moreover, the 90Y-DOTA-nimotuzumab stability was evaluated in human plasma. RESULTS: The radioimmunoconjugate 90Y-DOTA-nimotuzumab was obtained with a radiochemical purity greater than 96%, and showed a good stability at 20°C as well as at 37°C in human plasma. CONCLUSIONS: The optimized conditions for a mild and easy preparation of 90Y-DOTA-nimotuzumab joined to a promising stability under physiological conditions suggest to propose this radioimmunoconjugate as a potential diagnostic radiopharmaceutical for ß- radio-guided surgery.


Subject(s)
Antineoplastic Agents , Immunoconjugates , Antibodies, Monoclonal , Antibodies, Monoclonal, Humanized , Heterocyclic Compounds , Humans , Immunoconjugates/pharmacology , Organometallic Compounds , Radiopharmaceuticals/pharmacology , Yttrium Radioisotopes/therapeutic use
17.
J Cereb Blood Flow Metab ; 42(1): 175-185, 2022 01.
Article in English | MEDLINE | ID: mdl-34496661

ABSTRACT

Only partial deficiency/inhibition of P-glycoprotein (P-gp, ABCB1) function at the blood-brain barrier (BBB) is likely to occur in pathophysiological situations or drug-drug interactions. This raises questions regarding the sensitivity of available PET imaging probes to detect moderate changes in P-gp function at the living BBB. In vitro, the half-maximum inhibitory concentration (IC50) of the potent P-gp inhibitor tariquidar in P-gp-overexpressing cells was significantly different using either [11C]verapamil (44 nM), [11C]N-desmethyl-loperamide (19 nM) or [11C]metoclopramide (4 nM) as substrate probes. In vivo PET imaging in rats showed that the half-maximum inhibition of P-gp-mediated efflux of [11C]metoclopramide, achieved using 1 mg/kg tariquidar (in vivo IC50 = 82 nM in plasma), increased brain exposure by 2.1-fold for [11C]metoclopramide (p < 0.05, n = 4) and 2.4-fold for [11C]verapamil (p < 0.05, n = 4), whereby cerebral uptake of the "avid" substrate [11C]N-desmethyl-loperamide was unaffected (p > 0.05, n = 4). This comparative study points to differences in the "vulnerability" to P-gp inhibition among radiolabeled substrates, which were apparently unrelated to their "avidity" (maximal response to P-gp inhibition). Herein, we advocate that partial inhibition of transporter function, in addition to complete inhibition, should be a primary criterion of evaluation regarding the sensitivity of radiolabeled substrates to detect moderate but physiologically-relevant changes in transporter function in vivo.


Subject(s)
ATP Binding Cassette Transporter, Subfamily B/metabolism , Blood-Brain Barrier , Positron-Emission Tomography , Radiopharmaceuticals/pharmacology , Animals , Biological Transport/drug effects , Blood-Brain Barrier/diagnostic imaging , Blood-Brain Barrier/metabolism , Carbon Radioisotopes/pharmacology , Dogs , Humans , Madin Darby Canine Kidney Cells , Male , Rats , Rats, Sprague-Dawley
18.
Drug Discov Today ; 27(1): 280-291, 2022 01.
Article in English | MEDLINE | ID: mdl-34332093

ABSTRACT

Positron emission tomography (PET) is an extensively used nuclear functional imaging technique, especially for central nervous system (CNS) and oncological disorders. Currently, drug development is a lengthy and costly pursuit. Imaging with PET radiotracers could be an effective way to hasten drug discovery and advancement, because it facilitates the monitoring of key facets, such as receptor occupancy quantification, drug biodistribution, pharmacokinetic (PK) analyses, validation of target engagement, treatment monitoring, and measurement of neurotransmitter concentrations. These parameters demand careful analyses for the robust appraisal of newly formulated drugs during preclinical and clinical trials. In this review, we discuss the usage of PET imaging in radiopharmaceutical development; drug development approaches with PET imaging; and PET developments in oncological and cardiac drug discovery.


Subject(s)
Drug Development/methods , Drug Discovery/methods , Positron-Emission Tomography/methods , Radiopharmaceuticals/pharmacology , Antineoplastic Agents/pharmacology , Cardiovascular Agents/pharmacology , Drug Monitoring/methods , Humans , Radioactive Tracers
19.
J Med Chem ; 65(2): 1342-1351, 2022 01 27.
Article in English | MEDLINE | ID: mdl-34464131

ABSTRACT

Herein we present the evaluation of 11C-labeled-maleimides as radiotracers for positron emission tomography imaging of GSK-3 associated with Alzheimer's disease (AD). 3-Acetyl-4-(1-[11C]-methyl-1H-indol-3-yl)[1H]pyrrole-2,5-dione ([11C]-2) was obtained by direct methylation using [11C]-CH3I and Cs2CO3 in DMF with a 31 ± 4% radiochemical yield and a radiochemical purity of 97.7 ± 0.8%. [11C]-2 was stable both in its final formulation and in human plasma for 120 min and had a plasma protein binding of 70 ± 1% and a LogD7.4 value of 1.84 ± 0.04. [11C]-2 ex vivo biodistributions in healthy animals demonstrated significant brain uptake and retention, showing its ability to penetrate the intact blood-brain barrier. In vivo PET imaging in mice bearing AD showed, with respect to normal animals, significant differences in uptake in the hypothalamus, the striatum, and the amygdala and a significant increase in amygdala uptake in later stages of the pathology. These results are very promising, and further studies are being performed for a complete validation of this compound as novel tracer for AD.


Subject(s)
Alzheimer Disease/drug therapy , Brain/drug effects , Carbon Radioisotopes/metabolism , Glycogen Synthase Kinase 3/antagonists & inhibitors , Maleimides/chemistry , Positron-Emission Tomography/methods , Protein Kinase Inhibitors/pharmacology , Alzheimer Disease/diagnostic imaging , Animals , Brain/metabolism , Female , Humans , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic , Proof of Concept Study , Radiochemistry , Radiopharmaceuticals/pharmacology
20.
J Endocrinol Invest ; 45(2): 317-325, 2022 Feb.
Article in English | MEDLINE | ID: mdl-34282554

ABSTRACT

PURPOSE: Grade 3 neuroendocrine tumor (NET G3) is a novel pathologic category within gastro-entero-pancreatic (GEP) neuroendocrine neoplasms (NENs) but its clinical behavior and therapeutic management still remain challenging. Prognostic and predictive factors aiding NET G3 management are needed. PATIENTS AND METHODS: We performed a retrospective analysis from 2015 to 2020 of all patients with > 20% Ki-67, well-differentiated NETs evaluated within our NEN-dedicated multidisciplinary team. We divided the sample according the timing of NET G3 diagnosis, the radiotracers distribution and Ki-67. We analyzed the correlation between these NET G3 features and clinical outcomes. RESULTS: Among 3238 multidisciplinary discussion reports, we selected 55 patients, 48 from GEP and 7 from an occult GEP origin. In 45 patients, NET G3 diagnosis occurred at the beginning of clinical history (upfront-NET G3), whereas in 10, during the NET G1-G2 clinical history (late-NET G3). Patients with ≤ 30% (34/55) vs. > 30% Ki-67 (21/55) had a better overall survival (OS) (p = 0.042); patients with a homogeneous vs. inhomogeneous/negative 68Gallium(68Ga)-DOTA-Peptide Positron Emission Tomography (PET)/computed tomography (CT) showed a trend to a better OS, and a significant better progression-free survival (PFS) (p = 0.033). A better OS was observed for negative/inhomogeneous vs. homogeneous 18-fluorodeoxyglucose (18FDG)-PET/CT (p = 0.027). A trend to a better OS was reported in late- vs. upfront-NET G3, while the latter showed a significantly better response rate (RR) (p = 0.048). CONCLUSION: Our findings suggested that Ki-67 cutoff, functional imaging and the timing to NET G3 diagnosis may help clinicians in more accurate selection of NET G3 management. Prospective studies are needed.


Subject(s)
Early Detection of Cancer/methods , Intestinal Neoplasms , Ki-67 Antigen/analysis , Neuroendocrine Tumors , Pancreatic Neoplasms , Positron Emission Tomography Computed Tomography , Stomach Neoplasms , Female , Fluorodeoxyglucose F18/pharmacology , Humans , Immunohistochemistry , Intestinal Neoplasms/diagnosis , Intestinal Neoplasms/metabolism , Intestinal Neoplasms/mortality , Intestinal Neoplasms/therapy , Italy/epidemiology , Male , Middle Aged , Neoplasm Grading , Neuroendocrine Tumors/diagnosis , Neuroendocrine Tumors/metabolism , Neuroendocrine Tumors/mortality , Neuroendocrine Tumors/therapy , Organometallic Compounds/pharmacology , Pancreatic Neoplasms/diagnosis , Pancreatic Neoplasms/metabolism , Pancreatic Neoplasms/mortality , Pancreatic Neoplasms/therapy , Patient Selection , Positron Emission Tomography Computed Tomography/methods , Positron Emission Tomography Computed Tomography/statistics & numerical data , Prognosis , Radiopharmaceuticals/pharmacology , Retrospective Studies , Stomach Neoplasms/diagnosis , Stomach Neoplasms/metabolism , Stomach Neoplasms/mortality , Stomach Neoplasms/therapy , Survival Analysis
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