Mehdi Akhlaghi

Purpose: Amyloid-Beta (Aβ) plaque imaging can serve as a desirable tool for early detection of Alzheimer’s disease (AD). This study presents a new dimer of a chalcone-based scaffold, [68Ga]Ga-DTPA[Ch-DE]2, as a potential radiotracer for Aβ plaques imaging. Methods:The synthesis of DTPA[Ch-DE]2 and its radiolabeling with gallium-68 were characterized using techniques such as 1H-NMR, mass spectrometry, HPLC, and instant thin-layer chromatography. Neurotoxicity of DTPA[Ch-DE]2 was evaluated using the MTT assay. The stability of radiotracer was tested in various buffer systems and human serum albumin (HSA). The binding affinity of the radiotracer to Aβ aggregations was evaluted on the brain sections from both normal and AD rat models. Positron emission tomography-computed tomography (PET/CT) of brain imaging and Thioflavin S staining characterized the AD model. Biodistribution studies and PET/CT scans were performed on normal and AD rats. Computational studies also were conducted. Results: [68Ga]Ga-DTPA[Ch-DE]2 was synthesized with over 93% radiochemical purity. It showed high stability in various buffer systems and HSA after 2 hours. The binding assay revealed strong affinity to Aβ42 aggregations. Biodistribution studies and PET/CT imaging indicated favorable brain uptake: 0.54% ID/g and 0.59% ID/g at 2 minutes in normal and AD rats, respectively. Computational studies indicated that DTPA[Ch-DE]2 binds specifically to the Aβ fibrils while maintaining the receptor's architectural integrity. In vivo studies show that [68Ga]Ga-DTPA[Ch-DE]2 has good brain uptake and retention in AD rats compared with normal. Conclusion: Thus, results suggest that [68Ga]Ga-DTPA[Ch-DE]2 could be a promising radiotracer for Aβ targeting and early diagnosis of AD.

As angiogenesis plays a pivotal role in tumor progression and metastasis, leading to more cancer-related deaths, the angiogenic process can be considered as a target for diagnostic and therapeutic applications. The vascular endothelial growth factor receptor-1 (VEGR-1) and VEGFR-2 have high expression on breast cancer cells and contribute to angiogenesis and tumor development. Thus, early diagnosis through VEGFR-1/2 detection is an excellent strategy that can significantly increase a patient’s chance of survival. In this study, the VEGFR1/2-targeting peptide VGB3 was conjugated with 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), using 6-aminohexanoic acid (Ahx) as a spacer to prevent steric hindrance in binding. DOTA-Ahx-VGB3 was radiolabeled with Gallium-68 (⁶⁸Ga) efficiently. An in vitro cell binding assay was assessed in the 4T1 cell line. The tumor-targeting potential of [⁶⁸Ga]Ga-DOTA-Ahx-VGB3 was conducted for 4T1 tumor-bearing mice. Consequently, high radiochemical purity [⁶⁸Ga]Ga-DOTA-Ahx-VGB3 (RCP = 98%) was prepared and stabilized in different buffer systems. Approximately 17% of the radiopeptide was internalized after 2 h incubation and receptor binding as characterized by the IC₅₀ value being about 867 nM. The biodistribution and PET/CT studies revealed that [⁶⁸Ga]Ga-DOTA-Ahx-VGB3 reached the tumor site and was excreted rapidly by the renal system. These features convey [⁶⁸Ga]Ga-DOTA-Ahx-VGB3 as a suitable agent for the noninvasive visualization of VEGFR-1/2 expression.

Gallium-68 radiolabeled DOTA- acetyl-PAMAM coated iron oxide nanoparticles (NPs) were developed as dual-modality agents for PET-MR imaging. The increase in the chelator content, acetylation step, and radiolabeling condition had distinctive effects on the physical, biological, and radiochemical properties of NPs. The r2 relaxivity coefficient value of the NPs was 96.7 mM⁻¹s⁻¹. High accumulation of candidate NPs was in the liver and spleen and about 3.4% ID/g uptake (tissue sampling), and a distinctive uptake (PET-CT image) were observed in the tumor site. These NPs could be used as the dual-modality agent for the diagnosis of the tumors via PET-MR imaging.

⁶⁸Ga-DOTATATE positron emission tomography (PET)/computed tomography (CT) has shown promising results in imaging of neural crest tumors (NCT). Herein, we compared the performance of ⁶⁸Ga-DOTATATE PET/CT and ¹³¹I-MIBG single photon emission computed tomography (SPECT)/CT in the initial diagnosis, staging and follow-up of patients with NCTs. Twenty-five patients (males:females=8:17; age range=2-71 years) with clinically proven or suspicious neuroblastoma, pheochromocytoma (PCC) or paraganglioma (PGL) were enrolled in this prospective study and underwent both ⁶⁸Ga-DOTATATE PET/CT and ¹³¹I-MIBG SPECT/CT. A composite reference standard derived from histopathological information, together with anatomical and functional imaging findings, was used to validate the results. Imaging findings were assessed on a per-patient and on a per-lesion basis. Sensitivity and accuracy were assessed using McNemar's test. Referring to radiological imaging and histopathological findings as reference standard, ⁶⁸Ga-DOTATATE and ¹³¹I-MIBG scans showed a sensitivity and accuracy of (100%, 96%) and (86.7%, 88%), respectively, on a per-patient basis. In PCC/PGL patients, on a per-patient basis, the sensitivity of ⁶⁸Ga-DOTATATE was 100% and that of ¹³¹I-MIBG was 77.8%. In neuroblastoma patients, on a per-patient basis, the sensitivities of both ⁶⁸Ga-DOTATATE and ¹³¹I-MIBG were 100%. Overall, in this patient cohort, ⁶⁸Ga-DOTATATE PET/CT identified 52 lesions and ¹³¹I-MIBG SPECT/CT identified only 30 lesions. On a per-lesion analysis, ⁶⁸Ga-DOTATATE was found to be superior to ¹³¹I-MIBG in detecting lesions in all anatomical locations, particularly osseous lesions. According to the McNemar test results, differences were not statistically significant. This relatively small patient cohort suggests ⁶⁸Ga-DOTATATE PET/CT be superior to ¹³¹I-MIBG SPECT/CT in providing particularly valuable information for both primary staging and follow-up in patients with NCT.