Preparation and evaluation of 99mTc-labeled HYNIC-palbociclib analogs for cyclin-dependent kinase 4/6-positive tumor imaging.

In this study, an intermediate (compound 3), which could be hydrolyzed into the ligand (compound L) consisting of palbociclib as the bioactive molecule and 6-hydrazino nicotinamide (HYNIC) as the bifunctional chelator, was synthesized. Compound L was radiolabeled with 99mTc using tricine/TPPTS or tricine/TPPMS as co-ligands. 99mTc-tricine-TPPTS-L and 99mTc-tricine-TPPMS-L were prepared with high radiochemical purity without postlabeling purification. They had great in vitro stability. Both radiotracers were hydrophilic, but 99mTc-tricine-TPPTS-L had a lower log P value. In vitro cell uptake studies in MCF-7 cells showed that cellular uptake was blocked by preincubation with palbociclib, suggesting a CDK4/6-mediated uptake mechanism. Biodistribution in mice bearing MCF-7 tumors showed that 99mTc-tricine-TPPTS-L had higher tumor uptake than 99mTc-tricine-TPPMS-L, while they had comparable tumor-to-muscle and tumor-to-blood ratios. Radioactivity accumulation in tumors was obvious in micro-SPECT/CT images with 99mTc-tricine-TPPTS-L. When mice were preinjected with palbociclib, tumor uptake of 99mTc-tricine-TPPTS-L significantly decreased and the tumor accumulation was clearly lost, confirming CDK4/6 specificity. All results in this work indicated that 99mTc-tricine-TPPTS-L is a promising tumor imaging agent that targets CDK4/6. PMID: 31926467 [PubMed - as supplied by publisher]
Source: European Journal of Medicinal Chemistry - Category: Chemistry Authors: Tags: Eur J Med Chem Source Type: research