Abstract 2430: PET imaging of c-Met expression in non-human primates using [18F]AH113804
Authors: Lindhe Örjan , Thibblin Alf , Antoni Gunnar , Indrevoll Bård , Evans Paul , Morrison Matthew , Dalsgaard Grethe Tang , Johannesen Edvin 
Published: August 2012

[18F]AH113804 is a peptide based molecular imaging agent with high affinity for the human c-Met receptor. The objective of this study was to investigate the biodistribution, specific uptake and elimination of [18F]AH113804 in the non-human primate. Cynomolgus monkey (Macaca fascicularis) was selected since [18F]AH113804 retains high affinity to c-Met in this species. The route of administration was intravenous as this is the route of administration in humans. The target compound was prepared in a two-step synthesis route starting with synthesis of 4-[18F]fluorobenzaldehyde which was reacted with the peptide precursor to produce the corresponding oxime. Following semipreparative HPLC purification the pure product was obtained. Frozen section autoradiography using Rhesus monkey (Macaca mulatta) liver (relatively high c-Met expression) and muscle (relatively low c-Met) was performed in PBS buffer with [18F]AH113804 (2.5 kBq/ml) and with and without 0.5 μg/ml of AH113804 to establish specific binding in vitro. In vivo dynamic and repeated whole body PET/CT [18F]AH113804 imaging was performed (GE Discovery16 ST scanner, General Electric, USA), in female Cynomolgus monkeys (n=3) before and after administration of 0.15 mg/ml AH113804 or AH112361 (a scrambled peptide i.e. a negative control). The binding of [18F]AH113804 in Rhesus monkey liver sections was blocked by 40% following co-incubation of unlabelled AH113804 (&gt;1000-fold excess) whereas binding in muscle was unaffected. This result demonstrated specific binding in vitro in Rhesus monkey liver with a certain amount of unspecific binding. In vivo PET imaging studies in the Cynomolgus monkey showed rapid uptake in liver which was reduced by 42% after co-injection of 0.15 mg/kg of AH113804. Consistent with in vitro results, there was no noteworthy muscle retention in vivo. In liver the individual SUV varied but the magnitude of effect by blockade was similar. The ratio of baseline to blockade scans in liver was 1.7, suggesting the presence of specific binding. [18F]AH113804 uptake in liver or muscle was however not significantly reduced after co-injection of 0.15 mg/kg of AH112361 (negative control), the ratio of baseline and blockade scans in liver was &lt;1.25. These results further confirmed that the reduction in [18F]AH113804 liver uptake and retention observed after competition with non-radioactive AH113804 reflects specific binding of [18F]AH113804. Dynamic distribution studies showed a rapid uptake in liver and kidney and mainly urinary excretion. There were no obvious effects on body temperature, blood pressure or heart rate following co-injection of 0.15 mg/kg of AH113804. Overall, these results confirmed that [18F]AH113804 has desirable properties for a c-Met targeted molecular imaging agent. Since there are a number of anti-c-Met therapies in clinical development, [18F]AH113804 has potential to be used as an aid in therapy selection and/or monitoring.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2430. doi:1538-7445.AM2012-2430