¹⁷⁷Lu-DOTA-Tyr³-c(Cys-Tyr-Trp-Lys-Thr-Cys)-Thr-Lys(cypate)-NH₂

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).

¹⁷⁷Lu-DOTA-Tyr³-c(Cys-Tyr-Trp-Lys-Thr-Cys)-Thr-Lys(cypate)-NH₂(¹⁷⁷Lu-LS172) is a monomolecular multimodal imaging agent (MOMIA) for single-photon emission computed tomography (SPECT) and optical imaging (3). ¹⁷⁷Lu-LS172 consists of three components: a STT analog Tyr3-octreotate (Y3-TATE) with an additional lysine at the N-terminal as a spacer linker, a complex of ¹⁷⁷Lu-1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (¹⁷⁷Lu-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). ¹⁷⁷Lu is a radionuclide belonging to the group of rare earth isotopes, and it is produced by neutron bombardment of purified target materials in reactors (4). With a half-life of 6.71 days for β^- emission at 498 keV and 78% branch fraction, ¹⁷⁷Lu has been a very promising radionuclide in radiotherapy for effectively destroying small tumors and metastasis (optimal size 1.2–3.0 mm) while sparing normal tissue (5). ¹⁷⁷Lu also emits low energetic gamma rays at 208 and 113 keV with 10% and 6% abundance, respectively, which allows for direct monitoring of the activity distribution by SPECT and subsequent dosimetry (5). ¹⁷⁷Lu-DOTA-Y3-TATE has demonstrated excellent tumor localization, good clearance properties, and significant tumor regression in animal models (6). Cypate (mw 625.34) is a carbocyanine derivative with structure 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, 7). The low light scattering and absorption of endogenous photoactive biomolecules in this region permit photons to penetrate several centimeters into tissues (8, 9). Two carboxyl groups in cypate can be conjugated with amines to generate peptide-based optical imaging agents (10).