Search Results (14)

Background/Objectives: Neurotensin receptors (NTSRs), members of the G protein-coupled receptor (GPCR) family, have been found to be overexpressed in several types of human cancers, including breast, colon, lung, liver, prostate, and pancreatic cancer. In particular, NTSR1 is overexpressed in at least 75% of pancreatic ductal adenocarcinomas. The aim of the present study was the development and evaluation of new ^99mTc-labeled nonpeptide NTSR1-antagonists for SPECT imaging of NTSR-positive tumors. Methods: Multistep syntheses of NTSR1 antagonist derivatives were performed following our previously described procedure. Two different chelating strategies were applied for ^99mTc radiolabeling to provide the [^99mTc]Tc-HYNIC complex [^99mTc]1 and the [^99mTc]Tc-tricarbonyl complex [^99mTc]2. Receptor binding assays were performed using hNTSR1-expressing CHO cells. Radiochemical yields (RCYs) were determined by radio-HPLC. For [^99mTc]1 and [^99mTc]2, log D_7.4, plasma protein binding, stability in human plasma and serum, and cellular uptake in HT-29 cells were determined. Biodistribution studies and small animal SPECT studies were performed in HT-29 tumor-bearing nude mice. Results: The radiosynthesis of [^99mTc]1 (log D_7.4 = −0.27) and [^99mTc]2 (log D_7.4 = 1.00) was successfully performed with RCYs of 94–96% (decay-corrected). Both radioligands were stable in human serum and plasma, showed plasma protein binding of 72% ([^99mTc]1) and 82% ([^99mTc]2), and exhibited high and specific uptake in HT-29 cells. Biodistribution studies in HT-29 tumor-bearing mice showed a higher tumor accumulation of [^99mTc]1 compared to [^99mTc]2 (8.8 ± 3.4 %ID/g vs. 2.7 ± 0.2 %ID/g at 2 h p.i.). [^99mTc]2 showed exceptionally high intestinal accumulation (49 ± 22 %ID/g at 1 h p.i.) and was therefore considered unfavorable. In the SPECT/CT imaging of HT-29 tumor xenografts, [^99mTc]1 showed a higher NTSR1-specific tumor uptake than [^99mTc]2 at all time points after tracer injection, with 12 ± 2.8 %ID/g for [^99mTc]1 vs. 3.1 ± 1.1 %ID/g for [^99mTc]2 at 4 h p.i. and adequate tumor-to-background ratios. Conclusions: In particular, the [^99mTc]Tc-HYNIC ligand ([^99mTc]1) showed promising preclinical results, being a potential candidate for SPECT imaging and, therefore, appropriate for translation into the clinic. Full article

Background/Objectives: Heterodimer peptides targeting more than one receptor can be advantageous, as tumors can simultaneously express more than one receptor type. For human breast cancer, a promising biological target is tumor angiogenesis through α_vβ₃ integrin expression. Another promising target is Neuropeptide Y receptors, considering Y₁R is overexpressed in 90% of human breast tumors. This article details the development and preclinical evaluation, both in vitro and in vivo, of a novel heterodimer peptide dual-receptor-targeting probe, [^99mTc]HYNIC-cRGDfk-NPY, designed for imaging breast tumors. Methods: Female BALB/c healthy mice were used to perform biodistrubution studies and female SCID mice were subcutaneously injected with MCF-7 and MDA-MB-231 tumor cells. [^99mTc]HYNIC-cRGDfk-NPY was intravenously administered to the mice, followed by ex vivo biodistribution studies and small-animal SPECT/CT imaging. Nonspecific tracer uptake in both models was determined by coinjecting an excess of unlabeled HYNIC-cRGDfk-NPY (100 µg) along with the radiolabeled tracer. Results: Imaging and biodistribution data demonstrate good uptake to estrogen receptor-positive (MCF-7) and triple-negative (MDA-MB-231) tumor models. The in vivo tumor uptakes of radiolabeled conjugate were 9.30 ± 3.25% and 4.93 ± 1.01% for MCF-7 and MDA-MB231, respectively. The tumor/muscle ratios were 5.65 ± 0.94 for the MCF-7 model and 7.78 ± 3.20 for MDA-MB231. Conclusions: [^99mTc]HYNIC-cRGDfk-NPY demonstrated rapid blood clearance, renal excretion, and in vivo tumor uptake, highlighting its potential as a tumor imaging agent. Full article

Following the in vivo biodistribution of platelets can contribute to a better understanding of their physiological and pathological roles, and nuclear imaging methods, such as single photon emission tomography (SPECT), provide an excellent method for that. SPECT imaging needs stable labeling of the platelets with a radioisotope. In this study, we report a new method to label platelets with ^99mTc, the most frequently used isotope for SPECT in clinical applications. The proposed radiolabeling procedure uses a membrane-binding peptide, duramycin. Our results show that duramycin does not cause significant platelet activation, and radiolabeling can be carried out with a procedure utilizing a simple labeling step followed by a size-exclusion chromatography-based purification step. The in vivo application of the radiolabeled human platelets in mice yielded quantitative biodistribution images of the spleen and liver and no accumulation in the lungs. The performed small-animal SPECT/CT in vivo imaging investigations revealed good in vivo stability of the labeling, which paves the way for further applications of ^99mTc-labeled-Duramycin in platelet imaging. Full article

Angiogenesis plays a crucial role in tumour progression and metastatic spread; therefore, the development of specific vectors targeting angiogenesis has attracted the attention of several researchers. Since angiogenesis-associated aminopeptidase N (APN/CD13) is highly expressed on the surface of activated endothelial cells of new blood vessels and a wide range of tumour cells, it holds great promise for imaging and therapy in the field of cancer medicine. The selective binding capability of asparagine-glycine-arginine (NGR) motif containing molecules to APN/CD13 makes radiolabelled NGR peptides promising radiopharmaceuticals for the non-invasive, real-time imaging of APN/CD13 overexpressing malignancies at the molecular level. Preclinical small animal model systems are major keystones for the evaluation of the in vivo imaging behaviour of radiolabelled NGR derivatives. Based on existing literature data, several positron emission tomography (PET) and single-photon emission computed tomography (SPECT) radioisotopes have been applied so far for the labelling of tumour vasculature homing NGR sequences such as Gallium-68 (⁶⁸Ga), Copper-64 (⁶⁴Cu), Technetium-99m (^99mTc), Lutetium-177 (¹⁷⁷Lu), Rhenium-188 (¹⁸⁸Re), or Bismuth-213 (²¹³Bi). Herein, a comprehensive overview is provided of the recent preclinical experiences with radiolabelled imaging probes targeting angiogenesis. Full article

PMSA (prostate-specific membrane antigen) is currently the most significant target for diagnosing and treating PCa (prostate cancer). Herein, we reported a series ⁶⁸Ga/¹⁷⁷Lu-labeled multimer PSMA tracer conjugating with PEG chain, including [⁶⁸Ga]Ga-DOTA-(1P-PEG₄), [⁶⁸Ga]Ga-DOTA-(2P-PEG₀), [⁶⁸Ga]Ga-DOTA-(2P-PEG₄), and [⁶⁸Ga]Ga/[¹⁷⁷Lu]Lu-DOTA-(2P-PEG₄)₂, which showed an advantage of a multivalent effect and PEGylation to achieve higher tumor accumulation and faster kidney clearance. To figure out how structural optimizations based on a PSMA multimer and PEGylation influence the probe’s tumor-targeting ability, biodistribution, and metabolism, we examined PSMA molecular probes’ affinities to PC-3 PIP (PSMA-highly-expressed PC-3 cell line), and conducted pharmacokinetics analysis, biodistribution detection, small animal PET/CT, and SPECT/CT imaging. The results showed that PEG₄ and PSMA dimer optimizations enhanced the probes’ tumor-targeting ability in PC-3 PIP tumor-bearing mice models. Compared with the PSMA monomer, the PEGylated PSMA dimer reduced the elimination half-life in the blood and increased uptake in the tumor, and the biodistribution results were consistent with PET/CT imaging results. [⁶⁸Ga]Ga-DOTA-(2P-PEG₄)₂ exhibited higher tumor-to-organ ratios. When labeled by lutetium-177, relatively high accumulation of DOTA-(2P-PEG₄)₂ was still detected in PC-3 PIP tumor-bearing mice models after 48 h, indicating its prolonged tumor retention time. Given the superiority in imaging, simple synthetic processes, and structural stability, DOTA-(2P-PEG₄)₂ is expected to be a promising tumor-targeting diagnostic molecular probe in future clinical practice. Full article

Background: N-cadherin is considered a characteristic protein of EMT and has been found to be closely related to tumor resistance. In this study, a novel molecular imaging probe, ^99mTc-HYNIC-ADH-1, was developed, and its diagnostic value in monitoring drug resistance in NSCLC was preliminarily investigated. Methods: ADH-1 was labeled indirectly with ^99mTc. Radiochemical purity and stability, partition coefficients and pharmacokinetics were evaluated. Additionally, the fluorescent probe of ADH-1 was synthesized to study tumor uptake in cells level and in vivo. Biodistribution analysis and small animal SPECT/CT were performed in PC9GR and PC9 tumor-bearing mice. Results: ^99mTc-HYNIC-ADH-1 was highly stable (radiochemical purity ≥ 98% in PBS and serum after 24 h). A cell binding study and fluorescence imaging showed that the uptake was significantly higher in PC9GR cells (gefitinib-resistant) than in PC9 cells (nonresistant) (p < 0.05). Biodistribution analysis showed rapid blood clearance and significant uptake in the kidney and resistant tumor. Small animal SPECT/CT studies showed that uptake in PC9GR tumors (T/NT = 7.73 ± 0.54) was significantly higher than that in PC9 tumors (T/NT = 3.66 ± 0.78) at 1 h (p = 0.002). Conclusions: The ^99mTc-HYNIC-ADH-1 molecular probe has a short synthesis time, high labeling rate, high radiochemical purity and good stability, does not require purification, is characterized by rapid blood clearance and is mainly excreted through the urinary system. ^99mTc-HYNIC-ADH-1 is considered a promising probe for monitoring drug resistance in NSCLC. Full article

Clinical trials have shown the significant efficacy of [¹⁷⁷Lu]Lu-PSMA-617 for treating prostate cancer. However, the pharmacokinetic characteristics and therapeutic performance of [¹⁷⁷Lu]Lu-PSMA-617 still need further improvement to meet clinical expectations. The aim of this study was to evaluate the feasibility and therapeutic potential of three novel ¹⁷⁷Lu-labeled ligands for the treatment of prostate cancer. The novel ligands were efficiently synthesized and radiolabeled with non-carrier added ¹⁷⁷Lu; the radiochemical purity of the final products was determined by Radio-HPLC. The specific cell-binding affinity to PSMA was evaluated in vitro using prostate cancer cell lines 22Rv1and PC-3. Blood pharmacokinetic analysis, biodistribution experiments, small animal SPCET imaging and treatment experiments were performed on normal and tumor-bearing mice. Among all the novel ligands developed in this study, [¹⁷⁷Lu]Lu-PSMA-Q showed the highest uptake in 22Rv1 cells, while there was almost no uptake in PC-3 cells. As the SPECT imaging tracer, [¹⁷⁷Lu]Lu-PSMA-Q is highly specific in delineating PSMA-positive tumors, with a shorter clearance half-life and higher tumor-to-background ratio than [¹⁷⁷Lu]Lu-PSMA-617. Biodistribution studies verified the SPECT imaging results. Furthermore, [¹⁷⁷Lu]Lu-PSMA-Q serves well as an effective therapeutic ligand to suppress tumor growth and improve the survival rate of tumor-bearing mice. All the results strongly demonstrate that [¹⁷⁷Lu]Lu-PSMA-Q is a PSMA-specific ligand with significant anti-tumor effect in preclinical models, and further clinical evaluation is worth conducting. Full article

The accumulation of high levels of ^99mTc-tetrofosmin (^99mTc-TF) in the hepatobiliary system can lead to imaging artifacts and interference with diagnosis. The present study investigated the transport mechanisms of ^99mTc-TF and attempted to apply competitive inhibition using a specific inhibitor to reduce ^99mTc-TF hepatic accumulation. In this in vitro study, ^99mTc-TF was incubated in HEK293 cells expressing human organic anion transporting polypeptide 1B1 (OATP1B1), OATP1B3, OATP2B1, organic anion transporter 2 (OAT2), organic cation transporter 1 (OCT1), OCT2, and Na⁺-taurocholate cotransporting polypeptide with or without each specific inhibitor to evaluate the contribution of each transporter to ^99mTc-TF transportation. In vivo studies, dynamic planar imaging, and single photon emission computed tomography (SPECT) experiments with rats were performed to observe alterations to ^99mTc-TF pharmacokinetics using cimetidine (CMT) as an OCT1 inhibitor. Time–activity curves in the liver and heart were acquired from dynamic data, and the ^99mTc-TF uptake ratio was calculated from SPECT. From the in vitro study, ^99mTc-TF was found to be transported by OCT1 and OCT2. When CMT-preloaded rats and control rats were compared, the hepatic accumulation of the ^99mTc-TF was reduced, and the time to peak heart count shifted to an earlier stage. The hepatic accumulation of ^99mTc-TF was markedly suppressed, and the heart-to-liver ratio increased 1.6-fold. The pharmacokinetics of ^99mTc-TF were greatly changed by OCT1 inhibitor. Even in humans, the administration of OCT1 inhibitor before cardiac SPECT examination may reduce ^99mTc-TF hepatic accumulation and contribute to the suppression of artifacts and the improvement of SPECT image quality. Full article

Molecular imaging has rapidly developed to answer the need of image contrast in medical diagnostic imaging to go beyond morphological information to include functional differences in imaged tissues at the cellular and molecular levels. Vibrational (infrared (IR) and Raman) imaging has rapidly emerged among the molecular imaging modalities available, due to its label-free combination of high spatial resolution with chemical specificity. This article presents the physical basis of vibrational spectroscopy and imaging, followed by illustration of their preclinical in vitro applications in body fluids and cells, ex vivo tissues and in vivo small animals and ending with a brief discussion of their clinical translation. After comparing the advantages and disadvantages of IR/Raman imaging with the other main modalities, such as magnetic resonance imaging (MRI), computed tomography (CT), positron emission tomography/single-photon emission-computed tomography (PET/SPECT), ultrasound (US) and photoacoustic imaging (PAI), the design of multimodal probes combining vibrational imaging with other modalities is discussed, illustrated by some preclinical proof-of-concept examples. Full article

Barium-131 is a single photon emission computed tomography (SPECT)-compatible radionuclide for nuclear medicine and a promising diagnostic match for radium-223/-224. Herein, we report on the sufficient production route ¹³³Cs(p,3n)¹³¹Ba by using 27.5 MeV proton beams. An average of 190 MBq barium-131 per irradiation was obtained. The SR Resin-based purification process led to barium-131 in high radiochemical purity. An isotopic impurity of 0.01% barium-133 was detectable. For the first time, radiolabeling of the ligand macropa with barium-131 was performed. Radiolabeling methods under mild conditions and reaction controls based on TLC systems were successfully applied. Small animal SPECT/ computed tomography (CT) measurements and biodistribution studies were performed using [¹³¹Ba]Ba(NO₃)₂ as reference and ¹³¹Ba-labeled macropa in healthy mice for the first time. Biodistribution studies revealed the expected rapid bone uptake of [¹³¹Ba]Ba²⁺, whereas ¹³¹Ba-labeled macropa showed a fast clearance from the blood, thereby showing a significantly (p < 0.001) lower accumulation in the bone. We conclude that barium-131 is a promising SPECT radionuclide and delivers appropriate imaging qualities in small animals. Furthermore, the relative stability of the ¹³¹Ba-labeled macropa complex in vivo forms the basis for the development of sufficient new chelators, especially for radium isotopes. Thereby, barium-131 will attain its goal as a diagnostic match to the alpha emitters radium-223 and radium-224. Full article

The bioorthogonal reaction between a tetrazine and strained trans-cyclooctene (TCO) has garnered success in pretargeted imaging. This reaction was first validated in nuclear imaging using an ¹¹¹In-labeled 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-linked bispyridyl tetrazine (Tz) ([¹¹¹In]In-DOTA-PEG₁₁-Tz) and a TCO functionalized CC49 antibody. Given the initial success of this Tz, it has been paired with TCO functionalized small molecules, diabodies, and affibodies for in vivo pretargeted studies. Furthermore, the single photon emission tomography (SPECT) radionuclide, ¹¹¹In, has been replaced with the β-emitter, ¹⁷⁷Lu and α-emitter, ²¹²Pb, both yielding the opportunity for targeted radiotherapy. Despite use of the ‘universal chelator’, DOTA, there is yet to be an analogue suitable for positron emission tomography (PET) using a widely available radionuclide. Here, a ⁶⁸Ga-labeled variant ([⁶⁸Ga]Ga-DOTA-PEG₁₁-Tz) was developed and evaluated using two different in vivo pretargeting systems (Aln-TCO and TCO-CC49). Small animal imaging and ex vivo biodistribution studies were performed and revealed target specific uptake of [⁶⁸Ga]Ga-DOTA-PEG₁₁-Tz in the bone (3.7 %ID/g, knee) in mice pretreated with Aln-TCO and tumor specific uptake (5.8 %ID/g) with TCO-CC49 in mice bearing LS174 xenografts. Given the results of this study, [⁶⁸Ga]Ga-DOTA-PEG₁₁-Tz can serve as an alternative to [¹¹¹In]In-DOTA-PEG₁₁-Tz. Full article

Radiation therapy (RT) has traditionally not been widely used in the management of hepatic malignancies for fear of toxicity in the form of radiation-induced liver disease (RILD). Pre-clinical hepatic irradiation models can provide clinicians with better understanding of the radiation tolerance of the liver, which in turn may lead to the development of more effective cancer treatments. Previous models of hepatic irradiation are limited by either invasive laparotomy procedures, or the need to irradiate the whole or large parts of the liver using external skin markers. In the setting of modern-day radiation oncology, a truly translational animal model would require the ability to deliver RT to specific parts of the liver, through non-invasive image guidance methods. To this end, we developed a targeted hepatic irradiation model on the Small Animal Radiation Research Platform (SARRP) using contrast-enhanced cone-beam computed tomography image guidance. Using this model, we showed evidence of the early development of region-specific RILD through functional single photon emission computed tomography (SPECT) imaging. Full article

A magnetic resonance (MR)-, computed tomography (CT)-, single-photon emission computed tomography (SPECT)-, and positron emission tomography (PET)-compatible carbon-fiber sheet resistor for temperature maintenance in small animals where space limitations prevent the use of circulating fluids was developed. A 250 Ω carbon-fiber sheet resistor was mounted to the underside of an imaging cradle. Alternating current, operating at 99 kHz, and with a power of 1-2 W, was applied to the resistor providing a cradle base temperature of ∼37 °C. Temperature control was implemented with a proportional–integral–derivative controller, and temperature maintenance was demonstrated in 4 mice positioned in both MR and PET/SPECT/CT scanners. MR and CT compatibility were also shown, and multimodal MR-CT-PET-SPECT imaging of the mouse abdomen was performed in vivo. Core temperature was maintained at 35.5 °C ± 0.2 °C. No line-shape, frequency, or image distortions attributable to the current flow through the heater were observed on MR. Upon CT imaging, no heater-related artifacts were observed when carbon-fiber was used. Multimodal imaging was performed and images could be easily coregistered, displayed, analyzed, and presented. Carbon fiber sheet resistors powered with high-frequency alternating current allow homeothermic maintenance that is compatible with multimodal imaging. The heater is small, and it is easy to produce and integrate into multimodal imaging cradles. Full article

In this paper, we propose a wobbling method to correct bad pixels in cadmium zinc telluride (CZT) detectors, using information of related images. We build up an automated device that realizes the wobbling correction for small animal Single Photon Emission Computed Tomography (SPECT) imaging. The wobbling correction method is applied to various constellations of defective pixels. The corrected images are compared with the results of conventional interpolation method, and the correction effectiveness is evaluated quantitatively using the factor of peak signal-to-noise ratio (PSNR) and structural similarity (SSIM). In summary, the proposed wobbling method, equipped with the automatic mechanical system, provides a better image quality for correcting defective pixels, which could be used for all pixelated detectors for molecular imaging. Full article