Abstract
Calcium minerals such as hydroxyapatite (HAp) can be detected noninvasively in vivo using nuclear imaging agents such as [18F]NaF (available from cyclotrons), for positron emission tomography (PET) and 99mTc-radiolabeled bisphosphonates (BP; available from 99mTc generators for single photon emission computed tomography (SPECT) or scintigraphy). These two types of imaging agents allow detection of bone metastases (based on the presence of HAp) and vascular calcification lesions (that contain HAp and other calcium minerals). With the aim of developing a cyclotron-independent PET radiotracer for these lesions, with broad calcium mineral affinity and simple one-step radiolabeling, we developed [68Ga]Ga-THP-Pam. Radiolabeling with 68Ga is achieved using a mild single-step kit (5 min, room temperature, pH 7) to high radiochemical yield and purity (>95%). NMR studies demonstrate that Ga binds via the THP chelator, leaving the BP free to bind to its biological target. [68Ga]Ga-THP-Pam shows high stability in human serum. The calcium mineral binding of [68Ga]Ga-THP-Pam was compared in vitro to two other 68Ga-BPs which have been successfully evaluated in humans, [68Ga]Ga-NO2APBP and [68Ga]Ga-BPAMD, as well as [18F]NaF. Interestingly, we found that all 68Ga-BPs have a high affinity for a broad range of calcium minerals implicated in vascular calcification disease, while [18F]NaF is selective for HAp. Using healthy young mice as a model of metabolically active growing calcium mineral in vivo, we compared the pharmacokinetics and biodistribution of [68Ga]Ga-THP-Pam with [18F]NaF as well as [68Ga]NO2APBP. These studies revealed that [68Ga]Ga-THP-Pam has high in vivo affinity for bone tissue (high bone/muscle and bone/blood ratios) and fast blood clearance (t1/2 < 10 min) comparable to both [68Ga]NO2APBP and [18F]NaF. Overall, [68Ga]Ga-THP-Pam shows high potential for clinical translation as a cyclotron-independent calcium mineral PET radiotracer, with simple and efficient radiochemistry that can be easily implemented in any radiopharmacy.
Highlights
Calcium is an essential element in human biology and the most abundant metallic element in the body by weight.[1,2] The majority of body calcium is in the form of a solid mineral, hydroxyapatite (HAp; Ca5(PO4)3(OH)) in bones.[3]
The calcium mineral binding of [68Ga]Ga-THP-Pam was compared in vitro to two other 68Ga-BPs which have been successfully evaluated in humans, [68Ga]Ga-NO2APBP and [68Ga]Ga-BPAMD, as well as [18F]NaF
We found that all 68Ga-BPs have a high affinity for a broad range of calcium minerals implicated in vascular calcification disease, while [18F]NaF is selective for HAp
Summary
Calcium is an essential element in human biology and the most abundant metallic element in the body by weight.[1,2] The majority of body calcium is in the form of a solid mineral, hydroxyapatite (HAp; Ca5(PO4)3(OH)) in bones.[3]. Despite the advantages of [18F]NaF as a PET radiotracer, its binding mechanism and in vitro/vivo data indicate that its target in vivo is HAp (Scheme 1A) and not other calcium minerals that have been identified in vascular calcification lesions.[22,23] BPs on the other hand are not selective for HAp, showing broader calcium mineral affinity.[24,25] there is considerable interest in the development of BP-based PET radiotracers These should allow the detection of bone lesions, as recently demonstrated in patients,[5,26,27,28,29,30] and calcified vasculature which we have discussed above may contain different types of calcium minerals besides HAp and may benefit from the broader calcium mineral affinity of BPs. From the radiopharmacy and clinical translation perspective, a disadvantage of current BP-based PET radiotracers is a relatively complex radiochemistry. We describe the development of [68Ga]GaTHP-Pam, a 68Ga complex of the efficient gallium chelator (tris)hydroxypyridinone (THP),[44, 47,48,49,50,51,52,53,54,55,56,57] conjugated with the clinically used BP pamidronate (Pam) (Figure 1A) and its comparison with [18F]NaF and two other 68Ga-labelled BPs—BPAMD (Figure 1B) and NO2APBP (Figure 1C)—which have undergone extensive evaluation including first in human studies.[5, 26,27,28, 31,32,33],
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