Endocrine Abstracts

The 68Ge/68Ga generator has the potential to greatly expand positron emission tomography (PET) imaging to benefit more patients, by allowing many PET applications in hospitals without immediate access to cyclotrons and costly radiochemistry facilities. It is often suggested that ‘⁶⁸Ga is the new ^99mTc,’ drawing parallels with conventional radiopharmacy practice where radiopharmaceuticals are prepared with little more complex equipment than a syringe and a vial. However, there are further barriers to overcome to realise this potential, and current ⁶⁸Ga labelling methods are more like those associated with¹⁸F than ^99mTc. Half a century of experience with ^99mTc tells us that simple kit-based chelation chemistry is the key to wider patient benefit. To meet this challenge, we need chemistry that satisfies several requirements: labelling should be complete (>95%) quickly (<5 min) at 20°C without additional steps to concentrate, purify or buffer; high kinetic stability in vivo, against transchelation by Fe3+-chelating endogenous proteins such as transferrin, is needed during the imaging period of a few hours; chelation should compete with hydroxide formation, to which Ga3+ is vulnerable, at near-neutral pH; chelation should be robust and unaffected by common trace metals present in water and equipment; conjugation and labelling should not induce isomerism or high lipophilicity that would delay renal clearance. Most ⁶⁸Ga-chelating chemistries that may already be described as ‘conventional’ do not meet these requirements. This presentation will summarise progress with the tris(hydroxypyridinone) (THP) ligands as representatives of a new generation of chelators designed to address these issues. THP ligands show good selectivity for gallium over other major contaminating biometals except iron. They can be labeled efficiently within a few minutes at room temperature, low concentration, neutral pH, without problems of isomerism. They have been used successfully to label a range of small molecules, peptides and proteins with ⁶⁸Ga, and they perform well in direct competitive experiments alongside a range of other ⁶⁸Ga chelators currently being evaluated.