Preparation, Characterization, and Radiolabeling of [68Ga]Ga-NODAGA-Pamidronic Acid: A Potential PET Bone Imaging Agent

Abstract

Early diagnosis of bone metastases is crucial to prevent skeletal-related events, and for that, the non-invasive techniques to diagnose bone metastases that make use of image-guided radiopharmaceuticals are being employed as an alternative to traditional biopsies. Hence, in the present work, we tested the efficacy of a gallium-68 (68Ga)-based compound as a radiopharmaceutical agent towards the bone imaging in positron emitting tomography (PET). For that, we prepared, thoroughly characterized, and radiolabeled [68Ga]Ga-NODAGA-pamidronic acid radiopharmaceutical, a 68Ga precursor for PET bone cancer imaging applications. The preparation of NODAGA-pamidronic acid was performed via the N-Hydroxysuccinimide (NHS) ester strategy and was characterized using liquid chromatography-mass spectrometry (LC-MS) and tandem mass spectrometry (MSn). The unreacted NODAGA chelator was separated using the ion-suppression reverse phase-high performance liquid chromatography (RP-HPLC) method, and the freeze-dried NODAGA-pamidronic acid was radiolabeled with 68Ga. The radiolabeling condition was found to be most optimum at a pH ranging from 4 to 4.5 and a temperature of above 60 °C. From previous work, we found that the pamidronic acid itself has a good bone binding affinity. Moreover, from the analysis of the results, the ionic structure of radiolabeled [68Ga]Ga-NODAGA-pamidronic acid has the ability to improve the blood clearance and may exert good renal excretion, enhance the bone-to-background ratio, and consequently the final image quality. This was reflected by both the in vitro bone binding assay and in vivo animal biodistribution presented in this research.

Bisphosphonates as Radiopharmaceuticals: Spotlight on the Development and Clinical Use of DOTAZOL in Diagnostics and Palliative Radionuclide Therapy

“…More specifically, compounds containing a nine-membered cyclic chelator related to NOTA or NODA were designed for easy radiolabeling with 68 Ga and were used as PET imaging agents (Figure 7). These include NODAGA-Alendronate [138], NODAGA-Pamidronate [139] and NO2AP-Bisphosphonate [140], which has demonstrated high diagnostic efficiency in humans, with bone metastasis detection properties comparable to [ 18 F]NaF [141]. Another compound, NODAGA-Zoledronate, also achieved quantitative yields when radiolabeled with 68 Ga [142] and demonstrated its clinical value in the de-tection of bone metastases in prostate cancer patients who experienced PSA progression on PSMA-based radioligand therapy or in the setting of restaging [143,144].…”

Validation Calibration Factor of Single Photon Emission Computed Tomography for Iodine-131 using Non-Spherical Targeted Volume

“…In particular, SPECT can be advantageous for measuring the reserve of myocardial blood flow, diagnosis of multivessel diseases, and quantitative assessment of the kidneys, brain, lungs, and other organs. Moreover, activity quantitation plays a leading role in targeted radionuclide therapies, specifically in personalized medicine [2].…”

Cyclotron Production of Gallium-68 Radiopharmaceuticals Using the 68Zn(p,n)68Ga Reaction and Their Regulatory Aspects

“…A Scopus search shows that the number of publications on 68 Ga has exponentially increased from 2000 to 2021 ( Figure 1 A). Interest in 68 Ga radiopharmaceuticals further came into the limelight with the introduction of radiopharmaceuticals for neuroendocrine tumor imaging (NET), i.e., [ 68 Ga]Ga-DOTA-TOC, [ 68 Ga]Ga-DOTA-NOC, and [ 68 Ga]Ga-DOTA-TATE [ 1 , 2 , 3 , 4 , 5 ]. 68 Ga-DOTA-TATE was approved by the United States Food and Drug Administration (USFDA) in 2016 [ 6 ], followed by 68 Ga-DOTA-TOC in 2019 [ 7 ].…”