Novel 99mTc labeled σ receptor ligand as a potential tumor imaging agent

A novel ^99mTc labeled complex, [N-[2-((2-oxo-2-(4-(3-phenylpropyl)piperazin-1-yl)ethyl) (2-mercaptoethyl)amino)acetyl]-2-aminoethanethiolato]Technetium(V) oxide (PPPE-MAMA’-^99mTcO) ([ ^99m Tc]-2) has been designed and prepared based on the integrated approach. The corresponding rhenium complex (PPPE-MAMA’-ReO)(Re-2) has been prepared and characterized. In vitro competition binding assays show moderate affinity of Re-2 towards σ₁ and σ₂ receptors with K _i values of 8.67 ± 0.07 and 5.71 ± 1.88 μmol, respectively. Planar images obtained at 0.5 h, 4 h, 20 h after i.v. injection indicate the accumulation of [ ^99m Tc]-2 in MCF-7 human breast tumor bearing mice at 20 h. Furthermore, the accumulation of [ ^99m Tc]-2 has been inhibited at 20 h after co-injection of [ ^99m Tc]-2 plus haloperidol (1 mg/kg). Biodistribution studies of [ ^99m Tc]-2 display an in vivo tumor uptake of 0.14% ± 0.01% ID/g at 24 h post i.v. injection with a tumor/muscle ratio of 6.02 ± 0.87. The above results suggest that [ ^99m Tc]-2, derived from a previously published lead compound, retains certain tumor uptake and affinity for σ receptors. [ ^99m Tc]-2 may be used as a basis for further structural modifications to develop tumor imaging agents with high affinity for σ receptors.     

Enzymatic Methods for the Site-Specific Radiolabeling of Targeting Proteins

Site-specific conjugation of proteins is currently required to produce homogenous derivatives for medicine applications. Proteins derivatized at specific positions of the polypeptide chain can actually show higher stability, superior pharmacokinetics, and activity in vivo, as compared with conjugates modified at heterogeneous sites. Moreover, they can be better characterized regarding the composition of the derivatization sites as well as the conformational and activity properties. To this aim, several site-specific derivatization approaches have been developed. Among these, enzymes are powerful tools that efficiently allow the generation of homogenous protein–drug conjugates under physiological conditions, thus preserving their native structure and activity. This review will summarize the progress made over the last decade on the use of enzymatic-based methodologies for the production of site-specific labeled immunoconjugates of interest for nuclear medicine. Enzymes used in this field, including microbial transglutaminase, sortase, galactosyltransferase, and lipoic acid ligase, will be overviewed and their recent applications in the radiopharmaceutical field will be described. Since nuclear medicine can benefit greatly from the production of homogenous derivatives, we hope that this review will aid the use of enzymes for the development of better radio-conjugates for diagnostic and therapeutic purposes.     

Correction for Shift-variant Characteristics of Single Photon Emission Computed Tomography Acquisition System Using Sensitivity Functions

The single photon emission computed tomography (SPECT) imaging system has shift-variant characteristics due to non-uniform attenuation of gamma-ray, collimator design, scattered photons, etc. In order to provide quantitatively accurate SPECT images, these characteristics should be compensated in the reconstruction. This paper presents a new method to correct the shift-variant characteristics, which is based on a continuous-discrete mapping model and filtered backprojection (FBP) method, in which the projection data are assumed to be acquired by narrow ray sum beams in the FBP method and the assumed data set is expressed as a linear combination of the actual projection data. Narrow ray sum beams are approximated by a weighted sum of the original sensitivity functions. Thus, at the reconstruction the projection data are first modified using an approximation and the FBP method is then applied to the corrected projection data and a SPECT image is reconstructed. We further propose a technique that requires the inversion of smaller matrices than the conventional algebraic method; the amount of calculation and memory space become smaller and the stability of the calculation is greatly improved as well. The results of the numerical simulations are also demonstrated.     

SPECT均匀衰减投影数据的反演公式

依据近年来公开发表的有关单光子发射断层成像(SPECT)成像技术的文献,探索SPECT均匀衰减投影数据的反投影问题.主要采用指数型拉动变换的性质和构造特殊函数—–δ函数的方法,进而应用δ函数的特殊性得到了一个精确的反演公式.结果表明,由这种方法得到的反演公式能够更加有效和精确地实现图像的重建.     

Preparation and Evaluation of Novel Folate Isonitrile 99mTc Complexes as Potential Tumor Imaging Agents to Target Folate Receptors

In order to seek novel technetium-99m folate receptor-targeting agents, two folate derivatives (CN5FA and CNPFA) were synthesized and radiolabeled to obtain [^99mTc]Tc-CN5FA and [^99mTc]Tc-CNPFA complexes, which exhibited high radiochemical purity (>95%) without purification, hydrophilicity, and good stability in vitro. The KB cell competitive binding experiments indicated that [^99mTc]Tc-CN5FA and [^99mTc]Tc-CNPFA had specificity to folate receptor. Biodistribution studies in KB tumor-bearing mice illustrated that [^99mTc]Tc-CN5FA and [^99mTc]Tc-CNPFA had specific tumor uptake. Compared with [^99mTc]Tc-CN5FA, the tumor/muscle ratios of [^99mTc]Tc-CNPFA were higher, resulting in a better SPECT/CT imaging background. According to the results, the two ^99mTc complexes have potential as tumor imaging agents to target folate receptors.     

Preparation and Biological Evaluation of [99mTc]Tc-CNGU as a PSMA-Targeted Radiotracer for the Imaging of Prostate Cancer

Prostate-specific membrane antigen (PSMA) is a well-established biological target that is overexpressed on the surface of prostate cancer lesions. Radionuclide-labeled small-molecule PSMA inhibitors have been shown to be promising PSMA-specific agents for the diagnosis and therapy of prostate cancer. In this study, a glutamate-urea-based PSMA-targeted ligand containing an isonitrile (CNGU) was synthesized and labeled with ^99mTc to prepare [^99mTc]Tc-CNGU with a high radiochemical purity (RCP). The CNGU ligand showed a high affinity toward PSMA (K_i value is 8.79 nM) in LNCaP cells. The [^99mTc]Tc-CNGU exhibited a good stability in vitro and hydrophilicity (log P = −1.97 ± 0.03). In biodistribution studies, BALB/c nude mice bearing LNCaP xenografts showed that the complex had a high tumor uptake with 4.86 ± 1.19% ID/g, which decreased to 1.74 ± 0.90% ID/g after a pre-injection of the selective PSMA inhibitor ZJ-43, suggesting that it was a PSMA-specific agent. Micro-SPECT imaging demonstrated that the [^99mTc]Tc-CNGU had a tumor uptake and that the uptake was reduced in the image after blocking with ZJ-43, further confirming its PSMA specificity. All of the results in this work indicated that [^99mTc]Tc-CNGU is a promising PSMA-specific tracer for the imaging of prostate cancer.     

Modeling Scatter in Multiple Energy Windows to Incorporate Scattered Radiation Information in Single Photon Emission Computed Tomography Imaging

Using scattered radiation as useful information to improve radioisotope image quality is a topic attracting many researchers. Some reports showed that incorporating scattered components offers a possibility to improve image quality. The general method is modeling scatter in multiple energy windows and incorporating that information into the reconstruction process. However, what the performance will be and how noise will behave when using scattered radiation in reconstruction are not yet well answered. In this paper, we investigate a method of modeling scatter in multiple energy windows in cases of a few projection views. The system performance is analyzed using singular value decomposition and resolution kernels. For noise behavior investigation, reconstructions are accomplished by estimating the variance of reconstructed voxel values and the effectiveness of using scatter is evaluated by resolution kernel analysis. The results show there are improvements in normalized mean-square error of the images and the resolution kernels. When photon counts fall below about one million, it is still effective to use scatter for some cases of a few projections     

Performance evaluation of a parallel-hole collimated detector module for animal SPECT imaging

We have built and investigated a detector module for animal SPECT imaging, especially for use in large field of view (FOV) conditions. The module consists of a PMT-based detector and a parallel-hole collimator with an effective area of 80 mm × 80 mm. The detector is composed of a NaI scintillation crystal array coupled to four H8500 position sensitive photomultiplier tubes (PS-PMT). The intrinsic energy resolution of the detector is 11.5% at 140 keV on average. The planar spatial resolution of the module changes from 2.2 mm to 5.1 mm at different source-to-collimator distances with an unchanged sensitivity of about 34cps/MBq. Additionally, the SPECT Micro Deluxe Phantom imaging was performed with a radius of rotation (ROR) of 40 mm. Using the FBP reconstruction algorithm, a high performance image was obtained, indicating the feasibility of this detector module.     

基于Boltzmann输运方程的SPECT系统解析建模方法

在单光子发射断层成像(SPECT)中, 为了校正劣化因素的影响, 提高图像质量, 需要对SPECT成像的物理过程进行准确建模. 本文提出了基于Boltzmann输运方程及其Neumann级数解理论的SPECT系统解析建模方法, 并采用数论高维数值积分算法对解析建模公式进行数值求解. 分别对点源、均匀圆柱体模型和NCAT模型进行SPECT投影过程计算, 将其结果与传统的Monte Carlo建模方法进行比较. 结果表明解析建模方法的计算速度和精度综合性能优于Monte Carlo建模方法, 且具有不受统计噪声影响的优点, 因而更适于进行SPECT成像过程的建模.     

111In-DOTA-mAb109单克隆抗体探针的制备及其分子显像的研究

以具有肿瘤靶向的新型单克隆抗体mAb109, 借助其表面的氨基偶联双功能螯合剂获得可用于放射标记的DOTA-mAb109, 制备了¹¹¹In-DOTA-mAb109分子探针. Radio-HPLC分析结果表明, 其标记率96%, 放化纯度大于98%. 体外稳定性实验结果表明¹¹¹In-DOTA-mAb109在NaAc、PBS缓冲溶液以及5%人血清白蛋白溶液中均具有很高的稳定性. 建立 PANC-1胰腺癌裸鼠模型, 通过Nano-SPECT设备观察其在模型动物体内的代谢情况: 在静脉注射18.5 MBq ¹¹¹In-DOTA-mAb109探针分别于24 h, 48 h, 72 h进行SPECT/CT的显像, 随着时间的延长, 其在肿瘤组织表现出代谢摄取的增高. 通过断层显像, 进一步分析, 可见从特点层面观察到肿瘤组织具有明显的放射性摄取. 上述研究结果表明, ¹¹¹In-DOTA-mAb109分子探针有望发展成为一种具有肿瘤靶向性的新型分子探针.