Peptide PET Imaging: A Review of Recent Developments and a Look at the Future of Radiometal-Labeled Peptides in Medicine

Abstract

The development of peptide-based, radiometal-labeled PET imaging agents has seen an increase in attention due to the favorable properties the peptide backbone exhibits. These include high selectivity and affinity to proteins and cells directly linked to various types of cancers. In addition, rapid clearance from circulation and low toxicity allow for unique approaches to engineering a viable peptide-based imaging agent. Utilizing peptides as the backbone allows for various modifications to improve metabolic stability, target cell affinity, and image quality and imaging capabilities and reduce toxicity. Select radiolabeled peptides have already been FDA approved, with many more in late-stage trials. This review summarizes the current state of the radiometal-labeled PET peptide imaging field as well as explores methods used by researchers to modify peptides, concluding with a look at the future of peptide-based therapy and diagnostics.

Figure 1

(Top) General application of a peptide-based molecular probe with an imaging or therapeutic radioisotope. These probes can be modified for many purposes. Shown is the schematic of a generic probe with each section color coded. (Bottom) For each section, two different modifications are shown to highlight the diversity of possible combinations.

Figure 2

UR-LS130 peptide with an amino acid structure of MRRPYIL. The Tyr residue has a β–β demethylated R group which was found to have the highest in vivo stability and afforded a high tumor-to-muscle ratio.

Figure 3

PET/CT Imaging of NENs using ⁶⁸Ga-DOTA-NOC (A, B) and ¹⁸F-FDG (C). With the ⁶⁸Ga-DOTA-NOC imaging agent, we see three distinct areas of increased radiotracer uptake (indicated by the blue and white arrows in A and B, respectively) but no increased uptake of the ¹⁸F-FDG (C). Reprinted with permission from ref (43). Copyright 2003 Oxford Academic.

Figure 4

Structure of CM-2 peptide. CM-2 contains a 6-aminohexanoic acid linker group between the DOTA chelator and the peptide backbone. This linker has shown an increase in in vivo stability when compared to non-Ahx CM-2 peptides.

Figure 5

Use of the [⁶⁴Cu]WL12 peptide to image tumor PD-L1 expression in vivo. This figure shows NSG mice with hPD-L1 (red arrow) and CHO tumors (blue arrow) being intravenously given 150 μCi of the [⁶⁴Cu]WL12 tracer. Images were taken 10, 30, 60, and 120 min after injection. Specific accumulation of [⁶⁴Cu]WL12 is shown. Reprinted with permission from ref (99). Copyright 2008 Springer Nature.

Figure 6

SARTATE peptide structure. [⁶⁴Cu]SARTATE utilizes the MeCOSar chelator for ⁶⁴Cu binding. The phenylalanine and tryptophan amino acid residues are in the d configuration, a technique to increase peptide stability. A S–S bridge is also seen between the two cystine residues.

Figure 7

l/d-Amino acid comparison.

Figure 8

Cyclic RGD pentapeptide.