[68Ga]Ga-THP-Pam: A Bisphosphonate PET tracer with Facile Radiolabelling and Broad Calcium Mineral Affinity

George Patrick Keeling, Billie Sherin, Jana Kim, Belinda Sanjuan, Tillman Grus, Thomas Roger Eykyn, Frank Roesch, Gareth Smith, Philip J Blower, Samantha Y A Terry, Rafael T M de Rosales

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Calcium minerals such as hydroxyapatite (HAp) can be detected non-invasively in vivo using nuclear imaging agents such as [18F]NaF (available from cyclotrons), for positron emission tomography (PET) and 99mTc-radiolabelled 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 radiolabelling, we developed [68Ga]Ga-THP-Pam. Radiolabelling 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.

Original languageEnglish
JournalBioconjugate Chemistry
Early online date6 Aug 2020
Publication statusE-pub ahead of print - 6 Aug 2020


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