Imaging and targeted radionuclide therapy applications with use of radiometals have increased over the last 2 decades. In particular radiopharmaceuticals incorporating the positron emitters 89Zr, 64Cu and 68Ga for positron emission tomography (PET) are being used increasingly in patients. Gallium-68 has the advantage to be produced from a commercial generator. This allows independence from an on-site cyclotron and provides availability on demand. It has a half-life of 68 min which is compatible with the pharmacokinetics of low molecular weight peptides.  Copper-64 can be produced from small medical cyclotrons and is available commercially; because of  the 12.7 h half-life it may be superior to 68Ga in situations of slow blood or background clearance. In addition 64Cu-radiopharmaceuticals can be produced centrally and shipped to hospitals without GMP-radiopharmacy. Zr-89 (T1/2 =  78.4 h) is being used to label proteins. Important therapeutic radiometals are 90Y, 177Lu, 213Bi, 225Ac.We developed  peptide based chelator-conjugates targeting G-protein coupled receptors (GPCRs) which are overexpressed on major human tumors and are therefore targets to image and treat patients. In this overview the influence of coordination chemical aspects on pharmacology looking at radiometallopeptides targeting the gastrin-releasing peptide receptor and the somatostatin receptors will be presented. Unexpectedly several of the peptides showed high sensitivity not only to the appended chelator but even to the radiometal. For instance radiogallium(III)-based somatostatin receptor binding agonists  show distinctly higher receptor affinity, faster internalisation and better pharmacokinetics compared to their In(III), Lu(III) and Y(III) congeners if DOTA is the chelator. On contrary when antagonistic  peptides are studied the Ga(III) �metallated peptides they exhibit lowest affinity and less suitable pharmacokinetics in terms of tumor uptake and tumor-to-background ratios. An explanation is attempted based on X-structures and 1H-NMR of the relevant metal complexes.Properties of the radiovectors in animal models and in patients will be demonstrated.

Radiometal chelates may strongly influence biological and pharmacological performance of radiopeptides targeting G-protein coupled receptors

248th National Meeting (2014)

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