Somatostatin (SST) (somatotropin release-inhibiting hormone, somatotropin release-inhibiting factor) is a cyclic disulphide-containing peptide hormone of 14 amino acids (1). SST inhibits hormone secretion, cell proliferation, and promotes apoptosis through binding to specific cell-surface somatostatin receptors (SSTRs) (2). Five SSTR subtypes are identified in the central nervous system (CNS), gastrointestinal tract, and a variety of benign and malignant tumors (2). All subtypes of SSTRs belong to the family of G protein–coupled receptors, and exhibit high affinity to SST by recognizing the β-turn in the peptide sequence of SST including Phe7, Trp8, Lys9, and Thr10 (2). The structural difference between SSTRs generates specific pharmacological and physiological properties for each subtype, which allows targeting of SSTRs with subtype-specific SST analogs (1). For example, octreotide, a SST analog with a peptide sequence of eight amino acids (D-Phe-c(Cys-Tyr-D-Trp-Lys-Thr-Cys)-Thr(ol)), possesses a much higher affinity (~2 nM) binding to SSTR-2, -3, and -5 than binding to SSTR-1 and -4 (>1,000 nM). In addition to symptomatic treatment of tumors in clinic, these analogs are also labeled with a variety of probes for imaging (1).
64Cu-DOTA-Tyr3-c(Cys-Tyr-Trp-Lys-Thr-Cys)-Thr-Lys(cypate)-NH2 (64Cu-LS172) is a monomolecular multimodal imaging agent (MOMIA) for positron emission tomography (PET) and optical imaging (3). 64Cu-LS172 consists of three components: the STT analog Tyr3-octreotate (Y3-TATE) with an additional lysine at the N-terminal as a spacer linker, a complex of 64Cu-1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (64Cu-DOTA) attached at the C-terminal of Y3-TATE, and a cypate attached at the ε-amine group of the spacer lysine at the N-terminal of Y3-TATE. As a STT analog, TATE is produced by replacing the C-terminal threoninol in the octreotide with threonine, which substantially increases the binding affinity for SSTR-2 (1). 64Cu is a radionuclide belonged to IIB group with a half-life of 12.7 h. 64Cu has been a promising radionuclide in radiotherapy for effective short-range cell killing in tumors through β- emission (578 keV; 38%). 64Cu is also a β+ emitter (653 keV) with modest positron yield (18%), which provides an adequate flux of annihilation photons for imaging its biodistribution by PET (4). Cypate (mw 625.34) is a carbocyanine derivative withstructure and optical properties very similar to indocyanine green dye (ICG). Cypate exhibits a high extinction coefficient (224,000 M-1cm-1) in the near-infrared (NIR) region (700–900 nm) (3, 6). The low light scattering and absorption of endogenous photoactive biomolecules in this region permit photons to penetrate several centimeters into tissues (7, 8). Two carboxyl groups in cypate can be conjugated with amines to generate peptide-based optical imaging agents (9).