Radiopharmaceutical compositions targeting somatostatin receptors and uses thereof

Abstract

Provided herein are cyclic peptides having avidity for somatostatin receptors and having increased renal clearance. In some embodiments, the cyclic peptides comprise a non-natural tryptophan-lysine dipeptide. In addition, provided herein are radiopharmaceuticals and conjugates comprising the cyclic peptides.

Description

Attorney Docket No.01277-0079-00PCT RADIOPHARMACEUTICAL COMPOSITIONS TARGETING SOMATOSTATIN RECEPTORS AND USES THEREOF CROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims the benefit of priority of US Provisional Patent Application No. 63 / 614,482, filed December 22, 2023, which is incorporated by reference herein in its entirety for all purposes. SEQUENCE LISTING

[0002] The instant application contains a Sequence Listing which has been submitted electronically in XML format and is hereby incorporated by reference in its entirety. Said XML file, created on December 19, 2024, is named “01277-0079-00PCT_SL.xml,” and is 189,625 bytes in size. BACKGROUND

[0003] Radiopharmaceuticals used for cancer therapy are highly selective, designed to kill malignant cells and spare healthy tissues. Side effect rates are generally less than other treatments, but it is still the utmost concern to minimize normal organ toxicity and maximize radiation dose to the target lesions in applying radiopharmaceutical therapies (RPTs). Most commonly affected normal organs include bone marrow, kidneys and liver. Peptide receptor radionuclide therapy (PRRT) has the potential to induce nephrotoxicity because PRRT radiopharmaceuticals are primarily cleared thorough glomerular filtration, and reabsorption / retainment of them at the renal proximal tubules exposes kidneys to additional radiation. Amino acid co-infusion is the standard regimen for competitive inhibition of tubular reabsorption of PRRT radiopharmaceuticals to mitigate nephrotoxicity. Other measures to protect renal function include hydration, use of plasma expander or radioprotectant, personalized renal dosimetry to limit renal radiation dose and close monitoring of renal function.

[0004] Due to the potential for nephrotoxicity, new strategies are needed to increase PRRT clearance and reduce kidney exposure to additional radiation. SUMMARY

[0005] In one aspect, described herein is a cyclic peptide, or a pharmaceutically acceptable salt thereof, comprising a non-natural tryptophan-lysine dipeptide moiety, wherein the non-natural tryptophan-lysine dipeptide moiety comprises: (i) a non-natural lysine derivative, wherein the non-natural lysine derivative is a non-natural amino acid having a side chain comprising an amine; or (ii) a non-natural tryptophan derivative, wherein the non-natural tryptophan derivative isan amino acid comprising an aromatic moiety; and wherein the cyclic peptide or a pharmaceutically acceptable salt thereof has an avidity for a somatostatin receptor. In some embodiments, the non-natural tryptophan-lysine dipeptide moiety comprises (i) the non-natural lysine derivative and (ii) the non-natural tryptophan derivative. In some embodiments, the peptide is monocyclic. In some embodiments, the peptide comprises 5-40 amino acids in the cyclic portion of theAttorney Docket No.01277-0079-00PCT peptide. In some embodiments, the peptide consists of 5-40 amino acids in the cyclic portion of the peptide. In some embodiments, the peptide comprises 6-14 amino acids in the cyclic portion of the peptide. In some embodiments, the peptide consists of 6-14 amino acids in the cyclic portion of the peptide. In some embodiments, the peptide is selected from SEQ ID NO: 1-77, except that the tryptophan-lysine dipeptide moiety is replaced with the non-natural tryptophan-lysine dipeptide moiety described herein. In some embodiments, the peptide is selected from SEQ ID NO 1-85, except that the lysine moiety is replaced with the non-natural lysine described herein.

[0006] In one aspect, described herein is a cyclic peptide, or a pharmaceutically acceptable salt thereof, comprising a non-natural tryptophan-lysine dipeptide moiety, wherein the cyclic peptide or a pharmaceutically acceptable salt thereof comprises a sequence that has one or more amino acid replacements based on a sequence having SEQ ID NO: 1-77, and wherein the one or more replacements comprise: (i) a replacement of a lysine in the sequence with a non-natural lysine derivative, wherein the non-natural lysine derivative is a non-natural amino acid having a side chain comprising an amine; or (ii) a replacement of a tryptophan in the sequence with a non-natural tryptophan derivative, wherein the non-natural tryptophan derivative is an amino acid comprising an aromatic moiety. In some embodiments, the one or more replacements comprise the replacement of a lysine in the sequence with a non-natural lysine derivative and the replacement of a tryptophan in the sequence with a non-natural tryptophan derivative. In some embodiments, the peptide is monocyclic. In some embodiments, the peptide comprises 5-40 amino acids in the cyclic portion of the peptide. In some embodiments, the peptide consists of 5-40 amino acids in the cyclic portion of the peptide. In some embodiments, the peptide comprises 6-14 amino acids in the cyclic portion of the peptide. In some embodiments, the peptide consists of 6-14 amino acids in the cyclic portion of the peptide. In some embodiments, the peptide is selected from SEQ ID NO: 1-77, except that the tryptophan-lysine dipeptide moiety is replaced with the non-natural tryptophan-lysine dipeptide moiety described herein. In some embodiments, the peptide is selected from SEQ ID NO 1-85, except that the lysine moiety is replaced with the non-natural lysine described herein.

[0007] In one aspect, described herein is a cyclic peptide, or a pharmaceutically acceptable salt thereof, comprising a non-natural lysine derivative, wherein the non-natural lysine derivative is a non-natural amino acid having a side chain comprising an amine, and wherein the cyclic peptide or a pharmaceutically acceptable salt thereof has an avidity for a somatostatin receptor. In some embodiments, the peptide is monocyclic. In some embodiments, the peptide comprises 5-40 amino acids in the cyclic portion of the peptide. In some embodiments, the peptide consists of 5-40Attorney Docket No.01277-0079-00PCT amino acids in the cyclic portion of the peptide. In some embodiments, the peptide comprises 6-14 amino acids in the cyclic portion of the peptide. In some embodiments, the peptide consists of 6-14 amino acids in the cyclic portion of the peptide. In some embodiments, the peptide is selected from SEQ ID NO: 1- 77, except that the tryptophan-lysine dipeptide moiety is replaced with the non-natural tryptophan-lysine dipeptide moiety described herein. In some embodiments, the peptide is selected from SEQ ID NO 1-85, except that the lysine moiety is replaced with the non-natural lysine described herein.

[0008] In some embodiments, the non-natural tryptophan derivative is an amino acid comprising an optionally substituted N-containing 5- to 10- membered heteroaryl. In some embodiments, the non- natural tryptophan derivative is a non-natural amino acid comprising an optionally substituted N- containing 5- to 10- membered heteroaryl. In some embodiments, the non-natural tryptophan derivative is D-Trp, NMe-D-Trp, (S-βMe)D-Trp, (S-βMe)Trp, (R-βMe)D-Trp, (R-βMe)Trp, Aza-Trp, Aza-D-Trp, D-6F-Trp, or D-Aph(Cbm), each of which is further optionally substituted. In some embodiments, the non-natural tryptophan derivative is D-Trp, (S-βMe)D-Trp, (S-βMe)-Trp, (R-βMe)D-Trp, or (R-βMe)- Trp. In some embodiments, the non-natural tryptophan derivative is (S-βMe)D-Trp. In some embodiments, the non-natural tryptophan derivative is D-Trp. In some embodiments, the non-natural tryptophan derivative has a structure of:, wherein: R31is hydrogen or C1-C5alkyl optionally substituted with one to three substituents independently selected from Rf; each Rfis independently halogen, -CN, -NO2, -ORa, -SRaor -NRcRd; LX3is a bond, -O-, -S-, -NR33-, C1-C3alkylene, or C1-C3heteroalkylene, wherein the alkylene or heteroalkylene is optionally substituted with one or more RX3a; ring A3 is an aryl or heteroaryl; each R32is independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1- C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, halogen, -CN, -NO2, -ORa, -SRa, -SF5, -NRcRd, -P(=O)(ORc)(ORd), -P(=O)RcRd, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, wherein each of the alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more R32a; orAttorney Docket No.01277-0079-00PCT two R32are taken together to form =O, =S, or =N(Ra); m3 is 0, 1, 2, 3, 4, or 5; each R32ais independently halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1- C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -CN, -NO2, -ORa, -SRa, -NRcRd, - S(=O)Ra, -S(=O)2Ra, -SF5, -S(=O)2NRcRd, -S(=O)(=NRa)Ra, -N=S(=O)RcRd, -NRaS(=O)2Ra, amidinyl, -NRaC(=NH)(NRa)2, -NRaS(=O)2NRcRd, -C(=O)Ra, -C(=O)ORa, -OC(=O)Ra, - OC(=O)ORa, -OC(=O)NRcRd, -NRaC(=O)Ra, -NRaC(=O)ORa, -NRaC(=O)NRcRd, -C(=O)NRcRd, -P(=O)(ORc)(ORd), -P(=O)RcRd, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, =O, =S, or =N(Ra), wherein each of the alkyl, heteroalkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more Re; R33is hydrogen or C1-C3alkyl; R34is hydrogen or C1-C3alkyl; RX3ais halogen, -CN, -NO2, -ORa, -NRcRd, C1-C6alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1-C6alkylene(heteroaryl), wherein each of the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more Re; or two RX3agroups attached to the same or different atoms are taken together to form a cycloalkyl or heterocycloalkyl ring, each of which is optionally substituted with one or more Re; each Rais independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1-C6alkylene(heteroaryl), wherein each of the alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more Re; each Reis independently halogen, -CN, -OH, oxo, -O-C1-C6alkyl, -SF5, -S(=O)C1-C6alkyl, - S(=O)2C1-C6alkyl, -S(=O)2NH2, -S(=O)2-halogen, -S(=O)2NHC1-C6alkyl, -S(=O)2N(C1-C6alkyl)2, -NH2, -NHC1-C6alkyl, -N(C1-C6alkyl)2, -NHC(=NH)NH2, -NHC(=O)OC1-C6alkyl, -C(=O)C1- C6alkyl, -C(=O)OH, C1-C6alkyl-C(=O)OH, -C(=O)OC1-C6alkyl, -C(=O)NH2, -C(=O)N(C1- C6alkyl)2, -C(=O)NHC1-C6alkyl, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1- C6aminoalkyl, or C1-C6heteroalkyl; and each Rcand Rdare independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1-C6alkylene(heteroaryl), wherein each of the alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more Re; or Rcand Rdare taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more Re;Attorney Docket No.01277-0079-00PCT wherein represents the point of attachment to the rest of the peptide.

[0009] In some embodiments, the non-natural lysine derivative is a non-natural amino acid having a side chain comprising an amine. In some embodiments, the amine comprises a primary amine, a secondary amine, or a tertiary amine. In some embodiments, the amine comprises a secondary amine or a tertiary amine. In some embodiments, the non-natural lysine derivative is a non-natural lysine derivative having a side chain comprising an amine, and wherein the side chain comprises azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl. In some embodiments, the non-natural lysine derivative is Cba3N, Chg4N, Cha4N, Cha4NH2, Ser(3-azetidine), PipzaA, 3-Azetidine-hAla, or Pic4. In some embodiments, the non-natural lysine derivative is NMe-Lys, Lys(Me), Lys(diMe), Lys(iPr), Chg4N, Cha4N, 4-oxa-Lys, or 3-Azetidine-hAla. In some embodiments, the non-natural lysine derivative is Cba3N, Chg4N, Cha4N, Cha4NH2, Ser(3-azetidine), PipzaA, 3-Azetidine-hAla, Pic4, NMe-Lys, Lys(Me), Lys(diMe), Lys(iPr), or 4-oxa-Lys In some embodiments, the non-natural lysine derivative is PipzaA, 3-Azetidine-hAla, Lys(Me), Chg4N or Cha4N. In some embodiments, the non-natural lysine derivative has a structure of:, wherein, R41is hydrogen or C1-C5alkyl optionally substituted with one to three substituents independently selected from Rf; each Rfis independently halogen, -CN, -NO2, -ORa, -SRaor -NRcRd; LX4is a bond, -O-, -S-, -NR43-, C1-C6alkylene, C1-C6heteroalkylene, C3-C6cycloalkyl, or 3- to 6- membered heterocycloalkyl, wherein the alkylene, heteroalkylene, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more RX4a; R42is -NR44R45or a heterocycloalkyl comprising one or more ring nitrogen atoms, wherein the heterocycloalkyl is optionally substituted with one or more R42a; each R42ais independently halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1- C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -CN, -NO2, -ORa, -SRa, -NRcRd, - S(=O)Ra, -S(=O)2Ra, -SF5, -S(=O)2NRcRd, -S(=O)(=NRa)Ra, -N=S(=O)RcRd, -NRaS(=O)2Ra, amidinyl, -NRaC(=NH)(NRa)2, -NRaS(=O)2NRcRd, -C(=O)Ra, -C(=O)ORa, -OC(=O)Ra, - OC(=O)ORa, -OC(=O)NRcRd, -NRaC(=O)Ra, -NRaC(=O)ORa, -NRaC(=O)NRcRd, -C(=O)NRcRd, -P(=O)(ORc)(ORd), -P(=O)RcRd, =O, =S, or =N(Ra), wherein each of the alkyl, heteroalkyl, alkenyl, and alkynyl is optionally substituted with one or more Re; R43is hydrogen or C1-C3alkyl;Attorney Docket No.01277-0079-00PCT R44and R45are each independently hydrogen, C1-C3alkyl, aryl, heteroaryl, -C1-C3alkylene-aryl, or - C1-C3alkylene-heteroaryl; or R44and R45are taken together to form a 3- to 6- membered heterocycloalkyl, wherein each of the alkyl, aryl, heteroaryl, and heterocycloalkyl are optionally substituted with one or more R42a; each RX4ais independently halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1- C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -CN, -NO2, -ORa, -SRa, -NRcRd, --P(=O)(ORc)(ORd), -P(=O)RcRd, =O, =S, or =N(Ra), wherein each of the alkyl, heteroalkyl, alkenyl, and alkynyl is optionally substituted with one or more Re; or or two RX4agroups attached to the same or different atoms are taken together to form a cycloalkyl or heterocycloalkyl ring, each of which is optionally substituted with one or more Re; each Rais independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1-C6alkylene(heteroaryl), wherein each of the alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more Re; each Reis independently halogen, -CN, -OH, oxo, -O-C1-C6alkyl, -SF5, -S(=O)C1-C6alkyl, - S(=O)2C1-C6alkyl, -S(=O)2NH2, -S(=O)2-halogen, -S(=O)2NHC1-C6alkyl, -S(=O)2N(C1-C6alkyl)2, -NH2, -NHC1-C6alkyl, -N(C1-C6alkyl)2, -NHC(=NH)NH2, -NHC(=O)OC1-C6alkyl, - C(=O)C1-C6alkyl, -C(=O)OH, C1-C6alkyl-C(=O)OH, -C(=O)OC1-C6alkyl, -C(=O)NH2, - C(=O)N(C1-C6alkyl)2, -C(=O)NHC1-C6alkyl, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl; and each Rcand Rdare independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1-C6alkylene(heteroaryl), wherein each of the alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more Re; or Rcand Rdare taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more Re; and wherein represents the point of attachment to the rest of the peptide.

[0010] In one aspect described herein is a conjugate, or a pharmaceutically acceptable salt thereof, comprising a cyclic peptide, or a pharmaceutically acceptable salt thereof described herein, a metal chelator, and optionally a linker that covalently connects the cyclic peptide and the metal chelator. In some embodiments, the metal chelator comprises DOTA, DOTA-GA, pBn-DOTA, pBn-SCN-DOTA,Attorney Docket No.01277-0079-00PCT NH2-DOTA, NH2-DOTA-GA, p-NCS-Bn-DOTA-GA, p-NH2-Bn-oxo-DO3A, p-SCN-Bn-oxo-DO3A, NOTA, NODA-GA, NH2-NODA-GA, p-NCS-Bn-NODA-GA, p-NH2-Bn-NOTA, p-SCN-Bn-NOTA, NCS-MP-NODA, NH2-MPAA-NODA, PCTA, p-NH2-Bn-PCTA, p-SCN-Bn-PCTA, p-SCN-Bn- HEHA, H2-MACROPA-NCS, H1-MACROPA, H2-MACROPA-NH2, H4-OCTAPA, tetra-(S, S, S, S)- Me-DOTA, tetra-(S, S, S, S)-Et-DOTA, tetra-(S, S, S, S)-iBu-DOTA, or maleimide-nBu-DOTA. In some embodiments, the metal chelator is connected to the monocyclic peptide through a linker. In some embodiments, the linker has a structure of Formula (V-1)Formula (V-1) wherein each L is independently -O-, –NRL-, –N(RL)2-, -OP(=O)(ORL)O-, -S-, -S(=O)-, -S(=O)2-, =CH-, -C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)O-, -C(=O)NRL-, -NRLC(=O)-, -OC(=O)NRL-, - NRLC(=O)O-, -NRLC(=O)NRL-, -NRLC(=S)NRL-, -CRL=N-, -N=CRL, -NRLS(=O)2-, - S(=O)2NRL-, -C(=O)NRLS(=O)2-, -S(=O)2NRLC(=O)-, substituted or unsubstituted C3-15cycloalkyl, substituted or unsubstituted C1-12heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C1-30alkylene, substituted or unsubstituted C2-30alkenylene, substituted or unsubstituted C2-30alkynylene, substituted or unsubstituted C1-30heteroalkylene, -(C1-30alkylene)-O-, -O-(C1-30alkylene)-, -(C1-30alkylene)- NRL-, -NRL-(C1-30alkylene)-, -(C1-30alkylene)-N(RL)2-, or -N(RL)2-(C1-30alkylene)-, or a click chemistry residue; and each RLis independently hydrogen, substituted or unsubstituted C1-4alkyl, substituted or unsubstituted C1-4heteroalkyl, substituted or unsubstituted C2-6alkenyl, substituted or unsubstituted C2-5alkynyl, substituted or unsubstituted C3-8cycloalkyl, substituted or unsubstituted C2-7heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and n is 1 to 20.

[0011] In some embodiments, the linker is a bond.

[0012] In some embodiments, the conjugate further comprises a radionuclide bound to the metal chelator. In some embodiments, the radionuclide is an alpha particle-emitting radionuclide. In some embodiments, the alpha particle-emitting radionuclide is Ac-225, Bi-213, Bi-209, Tb-149, Ra-223, Th- 227, Fr-223, Gd-148, Th-229, Pb-212, At-211, or Po-213. In some embodiments, the alpha particle- emitting radionuclide is Ac-225, Bi-213, Bi-209, Tb-149, Ra-223, Th-227, Fr-223, Gd-148, Th-229, Pb- 212, or Po-213. In some embodiments, the radionuclide is a beta particle-emitting radionuclide. In some embodiments, the beta particle-emitting radionuclide is Cu-67, Lu-177, Y-90, Rh-105, Yb-175, Tm-167, Pm-153, Sm-153, or In-111. In some embodiments, the radionuclide is a positron-emitting radionuclide. In some embodiments, the positron-emitting radionuclide is Ga-68, Cu-62, Cu-64, Zr-89, Tb-152.

[0013] In one aspect, the present disclosure relates to a method of increasing renal clearance of a cyclicAttorney Docket No.01277-0079-00PCT somatostatin receptor binding peptide, or a conjugate or radiopharmaceuticalcomprising a cyclic somatostatin receptor binding peptide, wherein the binding peptide comprises a one or more lysine residues, the method comprising independently replacing the one or more lysine residues with a non- natural lysine derivative disclosed herein. In some embodiments, the somatostatin binding peptide is selected from SEQ ID NO: 1-85. In some embodiments, the peptide or conjugate comprising the non- natural lysine derivative described herein has increased renal clearance compared to the peptide where the lysine is not replaced.

[0014] In one aspect, the present disclosure relates to a method of treating a disease or disorder characterized by overexpression of SSTR, in a subject in need of treatment, the method comprising administering to the subject the peptide, conjugate, or radiopharmaceutical, or pharmaceutically acceptable salt thereof as described herein. In some embodiments, the disease or disorder is cancer. In some embodiments, the disease or disorder is a somatostatin receptor-positive (SSTR+) tumor. In some embodiments, provided herein is a method of killing an SSTR+ cell, comprising contacting the cell with a peptide or conjugate or radiopharmaceutical described herein.

[0015] In one aspect, the present disclosure relates to the use of the peptide, conjugate, or radiopharmaceutical, or pharmaceutically acceptable salt thereof, as described herein in the manufacture of a medicament for diagnosing and / or treating a disease or disorder characterized by an overexpression or a decreased expression of SSTR.

[0016] In one aspect, the present disclosure relates to the use of the peptide, conjugate, or radiopharmaceutical, or pharmaceutically acceptable salt thereof, as described herein for use in diagnosing and / or treating a disease or disorder characterized by an overexpression or a decreased expression of SSTR.

[0017] In one aspect, the present disclosure relates to the use of the peptide, conjugate, or radiopharmaceutical, or pharmaceutically acceptable salt thereof as described herein in the manufacture of a medicament with increased renal clearance. INCORPORATION BY REFERENCE

[0018] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference for the specific purposes identified herein. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] The novel features of the disclosure are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present disclosure will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the disclosure are utilized, and the accompanying drawing (also “figure” and “FIG.” herein), of which:

[0020] FIG.1A illustrates exemplary metal chelators of the present disclosure, wherein represents the attachment point of a metal chelator to the remaining conjugate. FIG.1B illustrates the same metalAttorney Docket No.01277-0079-00PCT chelators as FIG.1A, except that a part of the linker or the peptide covalently connected to the metal chelator is shown in the dashed circle .

[0021] FIG.2A illustrates exemplary metal chelators of the present disclosure, whereinrepresents the attachment point of a metal chelator to the remaining conjugate. FIG.2B illustrates the same metal chelators as FIG.2A, except that a part of the linker or the peptide covalently connected to the metal chelator is shown in the dashed circle.

[0022] FIG.3A illustrates exemplary metal chelators of the present disclosure, whereinrepresents the attachment point of a metal chelator to the remaining conjugate. FIG.3B illustrates the same metal chelators as FIG.3A, except that a part of the linker or the peptide covalently connected to the metal chelator is shown in the dashed circle.

[0023] FIG.4A illustrates exemplary metal chelators of the present disclosure, whereinrepresents the attachment point of a metal chelator to the remaining conjugate. FIG.4B illustrates the same metal chelators as FIG.4A, except that a part of the linker or the peptide covalently connected to the metal chelator is shown in the dashed circle.

[0024] FIG.5A illustrates exemplary metal chelators of the present disclosure, whereinrepresents the attachment point of a metal chelator to the remaining conjugate. FIG.5B illustrates the same metal chelators as FIG.5A, except that a part of the linker or the peptide covalently connected to the metal chelator is shown in the dashed circle, and R represents hydrogen, alkyl (such as methyl) or other suitable group on the nitrogen.

[0025] FIG.6 illustrates the structures of representative metal chelators.

[0026] FIG.7 illustrates the structures of representative metal chelators.

[0027] FIG.8 illustrates the structures of representative metal chelators.

[0028] FIG.9 illustrates the structures of representative metal chelators.

[0029] FIG.10 illustrates the structures of representative metal chelators.

[0030] FIG.11 illustrates the structures of representative metal chelators.

[0031] FIG.12 illustrates the structures of representative metal chelators.

[0032] FIG.13 illustrates the structures of representative metal chelators.

[0033] FIG.14 illustrates the structures of representative metal chelators.

[0034] FIG.15 illustrates the structures of representative metal chelators.

[0035] FIG.16 illustrates the structures of representative metal chelators.

[0036] FIG.17 illustrates the structures of representative metal chelators.

[0037] FIG.18 illustrates the structures of representative metal chelators.

[0038] FIG.19 illustrates the structures of representative metal chelators.

[0039] FIG.20 illustrates the structures of representative metal chelators.

[0040] FIG.21 illustrates the structures of representative metal chelators.Attorney Docket No.01277-0079-00PCT

[0041] FIG.22 illustrates the structures of representative metal chelators.

[0042] FIG.23 illustrates the structures of representative metal chelators.

[0043] FIG.24 illustrates the structures of representative metal chelators.

[0044] FIG.25 illustrates the structures of representative metal chelators.

[0045] FIGs.26A to 26D illustrate the structures of exemplary conjugates of the present disclosure. FIG.26A illustrates a conjugate comprising a monocyclic peptide of 11 amino acid residues, a linker, and a metal chelator. FIG.26B illustrates a conjugate comprising a monocyclic peptide of 12 amino acid residues, a linker, a metal chelator, and 225-Ac bound to the metal chelator. FIG.26C illustrates a conjugate comprising a monocyclic peptide of 12 amino acid residues that is attached directly to a metal chelator. FIG.26D illustrates a conjugate comprising a linker with three motifs, a metal chelator, and two peptides. DETAILED DESCRIPTION

[0046] The following description and examples illustrate embodiments of the present disclosure in detail. It is to be understood that this present disclosure is not limited to the particular embodiments described herein and as such can vary. Those of skill in the art will recognize that there are numerous variations and modifications of this present disclosure, which are encompassed within its scope.

[0047] Although various features of the present disclosure may be described in the context of a single embodiment, the features may also be provided separately or in any suitable combination. Conversely, although the present disclosure may be described herein in the context of separate embodiments for clarity, the present disclosure may also be implemented in a single embodiment.

[0048] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0049] All terms are intended to be understood as they would be understood by a person skilled in the art. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the disclosure pertains.

[0050] The following definitions supplement those in the art and are directed to the current application and are not to be imputed to any related or unrelated case, e.g., to any commonly owned patent or application. Although any methods and materials similar or equivalent to those described herein can be used in the practice for testing of the present disclosure, the preferred materials and methods are described herein. Accordingly, the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting. I. Definitions

[0051] As used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated below.

[0052] As used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “an agent” includes a plurality of such agents, reference to “a stabilizer” includes a plurality of such stabilizers, andAttorney Docket No.01277-0079-00PCT reference to “the cell” includes reference to one or more cells (or to a plurality of cells) and equivalents thereof known to those skilled in the art, and so forth. When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulae, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included.

[0053] The term “about” or “approximately” can mean within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, “about” can mean within 1 or more than 1 standard deviation, per the practice in the art. Alternatively, “about” can mean a range of up to 20%, up to 15%, up to 10%, up to 5%, or up to 1% of a given value. Alternatively, particularly with respect to biological systems or processes, the term can mean within an order of magnitude, within 5-fold, or within 2-fold, of a value.

[0054] The term “comprising” (and related terms such as “comprise” or “comprises” or “having” or “including”) is not intended to exclude that in other certain embodiments, for example, an embodiment of any composition of matter, composition, method, or process, or the like, described herein, “consist of” or “consist essentially of” the described features.

[0055] “Amine” refers to a moiety formally derived from ammonia (NH3) by replacing one, two, or three hydrogen atoms. In some embodiments, the amine is a primary amine, a secondary amine, a tertiary amine, or a quaternary amine. In some embodiment, the amine is present in a heterocycloalkyl. In some embodiments, the amine is present in an aminoalkyl. In some embodiments, the amine is present in an alkylamino. In some embodiments, the amine is present in an amino group. In some embodiments, “Amine” refers to a moiety having the formula N(Ra)2where Rais hydrogen or an alkyl radical as defined herein, or two Ra, taken together with the nitrogen atom, can form a substituted or unsubstituted C2-C7heterocyloalkyl ring. In some embodiments, the side chain comprising an amine is a side chain comprising a primary amine, a secondary amine, a tertiary amine, or a quaternary amine. In some embodiments, the side chain comprising an amine is a side chain comprising a heterocycloalkyl. In some embodiments, the side chain comprising an amine is a side chain comprising an aminoalkyl. In some embodiments, the side chain comprising an amine is a side chain comprising an alkylamino.

[0056] "Amino" refers to the –NH2radical.

[0057] "Cyano" refers to the CN radical.

[0058] "Nitro" refers to the NO2radical.

[0059] "Oxo" refers to the =O radical.

[0060] "Imino" refers to the =N-H radical.

[0061] "Oximo" refers to the =N-OH radical.

[0062] "Hydrazino" refers to the =N-NH2radical.

[0063] “Hydroxy” or “hydroxyl” refers to the -OH radical.

[0064] “Acyl” refers to a substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstitutedAttorney Docket No.01277-0079-00PCT cycloalkylcarbonyl, substituted or unsubstituted heterocycloalkylcarbonyl, substituted or unsubstituted arylcarbonyl, substituted or unsubstituted heteroarylcarbonyl, amide, or ester, wherein the carbonyl atom of the carbonyl group is the point of attachment. Unless stated otherwise specifically in the specification, an alkylcarbonyl group, alkenylcarbonyl group, alkynylcarbonyl group, cycloalkylcarbonyl group, amide group, or ester group is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.

[0065] “Alkyl” refers to an optionally substituted straight-chain, or optionally substituted branched- chain saturated hydrocarbon monoradical. An alkyl group can have from one to about twenty carbon atoms, from one to about ten carbon atoms, or from one to six carbon atoms. Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1- butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3- dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl, and hexyl, and longer alkyl groups, such as heptyl, octyl, and the like. Whenever it appears herein, a numerical range such as “C1-C6alkyl” means that the alkyl group consists of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated. In some embodiments, the alkyl is a C1-C10alkyl, a C1-C9alkyl, a C1-C8alkyl, a C1-C7alkyl, a C1-C6alkyl, a C1- C5alkyl, a C1-C4alkyl, a C1-C3alkyl, a C1-C2alkyl, or a C1alkyl. Unless stated otherwise specifically in the specification, an alkyl group is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkyl is optionally substituted with oxo, halogen, -CN, -CF3, OH, -OMe, NH2, -NO2, or -C≡CH. In some embodiments, the alkyl is optionally substituted with oxo, halogen, -CN, -CF3, OH, or - OMe. In some embodiments, the alkyl is optionally substituted with halogen.

[0066] “Alkylene” refers to a straight or branched divalent hydrocarbon chain. Unless stated otherwise specifically in the specification, an alkylene group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkylene is optionally substituted with oxo, halogen, -CN, -CF3, OH, -OMe, NH2, or -NO2. In some embodiments, an alkylene is optionally substituted with oxo, halogen, -CN, -CF3, OH, or -OMe. In some embodiments, the alkylene is optionally substituted with halogen. In some embodiments, the alkylene is -CH2-, -CH2CH2-, -CH2CH2CH2-, or -CH2CH(CH3)CH2-. In some embodiments, the alkylene is -CH2-. In some embodiments, the alkylene is -CH2CH2-. In some embodiments, the alkylene is -CH2CH2CH2-.

[0067] “Alkenyl” refers to an optionally substituted straight-chain, or optionally substituted branched- chain hydrocarbon monoradical having one or more carbon-carbon double-bonds. In some embodiments, an alkenyl group has from two to about ten carbon atoms, or two to about six carbon atoms. The group may be in either the cis or trans configuration about the double bond(s), and should be understood to include both isomers. Examples include, but are not limited to, ethenyl (CH=CH2), 1-propenylAttorney Docket No.01277-0079-00PCT (CH2CH=CH2), isopropenyl [C(CH3)=CH2], butenyl, 1,3-butadienyl, and the like. Whenever it appears herein, a numerical range such as “C2-C6alkenyl” means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkenyl” where no numerical range is designated. In some embodiments, the alkenyl is a C2-C10alkenyl, a C2-C9alkenyl, a C2-C8alkenyl, a C2-C7alkenyl, a C2-C6alkenyl, a C2-C5alkenyl, a C2-C4alkenyl, a C2-C3alkenyl, or a C2alkenyl. Unless stated otherwise specifically in the specification, an alkenyl group is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkenyl is optionally substituted with oxo, halogen, -CN, -CF3, OH, -OMe, NH2, or -NO2. In some embodiments, an alkenyl is optionally substituted with oxo, halogen, - CN, -CF3, OH, or -OMe. In some embodiments, the alkenyl is optionally substituted with halogen.

[0068] The term “alkenylene” or “alkenylene chain” refers to an optionally substituted straight or branched divalent hydrocarbon chain in which at least one carbon-carbon double bond is present linking the rest of the molecule to a radical group. In some embodiments, the alkenylene is –CH=CH-, - CH2CH=CH-, or –CH=CHCH2-. In some embodiments, the alkenylene is –CH=CH-. In some embodiments, the alkenylene is –CH2CH=CH-. In some embodiments, the alkenylene is –CH=CHCH2-.

[0069] “Alkynyl” refers to an optionally substituted straight-chain or optionally substituted branched- chain hydrocarbon monoradical having one or more carbon-carbon triple-bonds. In some embodiments, an alkynyl group has from two to about ten carbon atoms, more preferably from two to about six carbon atoms. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl, and the like. Whenever it appears herein, a numerical range such as “C2-C6alkynyl” means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkynyl” where no numerical range is designated. In some embodiments, the alkynyl is a C2-C10alkynyl, a C2-C9alkynyl, a C2-C8alkynyl, a C2-C7alkynyl, a C2-C6alkynyl, a C2-C5alkynyl, a C2-C4alkynyl, a C2-C3alkynyl, or a C2alkynyl. Unless stated otherwise specifically in the specification, an alkynyl group is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkynyl is optionally substituted with oxo, halogen, -CN, -CF3, OH, -OMe, NH2, or -NO2. In some embodiments, an alkynyl is optionally substituted with oxo, halogen, -CN, -CF3, OH, or -OMe. In some embodiments, the alkynyl is optionally substituted with halogen. The term “alkynylene” refers to an optionally substituted straight- chain or optionally substituted branched-chain divalent hydrocarbon having one or more carbon-carbon triple-bonds.

[0070] “Alkylamino” refers to a radical of the formula N(Ra)2where Rais an alkyl radical as defined, or two Ra, taken together with the nitrogen atom, can form a substituted or unsubstituted C2-C7heterocyloalkyl ring. Unless stated otherwise specifically in the specification, an alkylamino group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkylaminoAttorney Docket No.01277-0079-00PCT is optionally substituted with oxo, halogen, -CN, -CF3, OH, -OMe, NH2, or -NO2. In some embodiments, an alkylamino is optionally substituted with oxo, halogen, -CN, -CF3, OH, or -OMe. In some embodiments, the alkylamino is optionally substituted with halogen.

[0071] “Alkoxy” refers to a radical of the formula ORawhere Rais an alkyl radical as defined. Unless stated otherwise specifically in the specification, an alkoxy group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkoxy is optionally substituted with oxo, halogen, -CN, -CF3, OH, -OMe, NH2, or -NO2. In some embodiments, an alkoxy is optionally substituted with oxo, halogen, -CN, -CF3, OH, or -OMe. In some embodiments, the alkoxy is optionally substituted with halogen.

[0072] “Aminoalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more amines. In some embodiments, the alkyl is substituted with one amine. In some embodiments, the alkyl is substituted with one, two, or three amines. aminoalkyl include, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl is aminomethyl. An aminoalkyl group may be a primary aminoalkyl group, e.g., a radical of the formula -alkyl-NH2, a secondary aminoalkyl group, e.g., a radical of the formula -alkyl-NHRa, a tertiary aminoalkyl group, e.g., a radical of formula -alkyl-N(Ra)2, or a quaternary aminoalkyl group, e.g., a radical of formula -alkyl- N+(Ra)3, wherein Rais an alkyl radical as defined herein, or two Ra, taken together with the nitrogen atom, can form a substituted or unsubstituted C2-C7heterocyloalkyl ring. Unless stated otherwise specifically in the specification, an aminoalkyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an aminoalkyl is optionally substituted with oxo, halogen, -CN, -CF3, OH, -OMe, NH2, or -NO2. In some embodiments, an aminoalkyl is optionally substituted with oxo, halogen, -CN, -CF3, OH, or -OMe. In some embodiments, the aminoalkyl is optionally substituted with halogen.

[0073] “Hydroxyalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more hydroxyl groups. In some embodiments, the alkyl is substituted with one hydroxyl. In some embodiments, the alkyl is substituted with one, two, or three hydroxyls. Hydroxyalkyls include, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl.

[0074] The term “aryl” refers to a radical comprising at least one aromatic ring wherein each of the atoms forming the ring is a carbon atom. Aryl groups can be optionally substituted. Examples of aryl groups include, but are not limited to phenyl, and naphthyl. In some embodiments, the aryl is phenyl. Depending on the structure, an aryl group can be a monoradical or a diradical (i.e., an arylene group). Unless stated otherwise specifically in the specification, the term “aryl” or the prefix “ar-”(such as in “aralkyl”) is meant to include aryl radicals that are optionally substituted. In some embodiments, an aryl group comprises a partially reduced cycloalkyl group defined herein (e.g., 1,2-dihydronaphthalene). In some embodiments, an aryl group comprises a fully reduced cycloalkyl group defined herein (e.g.,Attorney Docket No.01277-0079-00PCT 1,2,3,4-tetrahydronaphthalene). When aryl comprises a cycloalkyl group, the aryl is bonded to the rest of the molecule through an aromatic ring carbon atom. An aryl radical can be a monocyclic or polycyclic (e.g., bicyclic, tricyclic, or tetracyclic) ring system, which may include fused, spiro or bridged ring systems. Unless stated otherwise specifically in the specification, an aryl may be optionally substituted, for example, with halogen, amino, alkylamino, aminoalkyl, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, -S(O)2NH-C1- C6alkyl, and the like. In some embodiments, an aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, OH, -OMe, NH2, -NO2, -S(O)2NH2, -S(O)2NHCH3,-S(O)2NHCH2CH3, -S(O)2NHCH(CH3)2, - S(O)2N(CH3)2, or -S(O)2NHC(CH3)3. In some embodiments, an aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, OH, or -OMe. In some embodiments, the aryl is optionally substituted with halogen. In some embodiments, the aryl is substituted with alkyl, alkenyl, alkynyl, haloalkyl, or heteroalkyl, wherein each alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl is independently unsubstituted, or substituted with halogen, methyl, ethyl, -CN, -CF3, OH, -OMe, NH2, or -NO2.

[0075] The term “cycloalkyl” refers to a monocyclic or polycyclic non-aromatic radical, wherein each of the atoms forming the ring (i.e., skeletal atoms) is a carbon atom. In some embodiments, cycloalkyls are saturated or partially unsaturated. In some embodiments, a cycloalkyl is fully saturated. In some embodiments, a cycloalkyl is partially saturated (e.g., comprising more or more carbon-carbon double bond). In some embodiments, cycloalkyls are spirocyclic or bridged compounds. In some embodiments, cycloalkyls are fused with an aromatic ring (in which case the cycloalkyl is bonded through a non- aromatic ring carbon atom). Cycloalkyl groups include groups having from 3 to 10 ring atoms. Representative cycloalkyls include, but are not limited to, cycloalkyls having from three to ten carbon atoms, from three to eight carbon atoms, from three to six carbon atoms, or from three to five carbon atoms. Monocyclic cycloalkyl radicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In some embodiments, the monocyclic cycloalkyl is cyclopentyl. In some embodiments, the monocyclic cycloalkyl is cyclopentenyl or cyclohexenyl. In some embodiments, the monocyclic cycloalkyl is cyclopentenyl. Polycyclic radicals include, for example, adamantyl, 1,2-dihydronaphthalenyl, 1,4-dihydronaphthalenyl, tetrainyl, decalinyl, 3,4- dihydronaphthalenyl-1(2H)-one, spiro[2.2]pentyl, norbornyl and bicycle[1.1.1]pentyl. Unless otherwise stated specifically in the specification, a cycloalkyl group may be optionally substituted. Representative cycloalkyls include, but are not limited to, cycloalkyls having from three to fifteen carbon atoms (C3-C15cycloalkyl), from three to ten carbon atoms (C3-C10cycloalkyl), from three to eight carbon atoms (C3-C8cycloalkyl), from three to six carbon atoms (C3-C6cycloalkyl), from three to five carbon atoms (C3-C5cycloalkyl), or three to four carbon atoms (C3-C4cycloalkyl). A cycloalkyl can comprise a fused, spiro or bridged ring system. In some embodiments, the cycloalkyl comprises a fused ring system. In some embodiments, the cycloalkyl comprises a spiro ring system. In some embodiments, the cycloalkyl comprises a bridged ring system. In some embodiments, the cycloalkyl is a 3- to 6-membered cycloalkyl. In some embodiments, the cycloalkyl is a 5- to 6-membered cycloalkyl. Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. PolycyclicAttorney Docket No.01277-0079-00PCT cycloalkyls or carbocycles include, for example, adamantyl, norbornyl, decalinyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decalin, trans-decalin, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane, and 7,7-dimethyl-bicyclo[2.2.1]heptanyl. Partially saturated cycloalkyls include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless stated otherwise specifically in the specification, a cycloalkyl is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, - CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the cycloalkyl is optionally substituted with halogen.

[0076] “Halo” or “halogen” refers to bromo, chloro, fluoro, or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.

[0077] “Haloalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more halogens. In some embodiments, the alkyl is substituted with one, two, or three halogens. In some embodiments, the alkyl is substituted with one, two, three, four, five, or six halogens. Haloalkyl can include, for example, iodoalkyl, bromoalkyl, chloroalkyl, and fluoroalkyl. For example, "fluoroalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, as defined above, for example, trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2trifluoroethyl, 1fluoromethyl2fluoroethyl, and the like. In some embodiments, the alkyl part of the fluoroalkyl radical is optionally substituted as defined above for an alkyl group.

[0078] “Heteroalkyl” refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, or combinations thereof. A heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. In one aspect, a heteroalkyl is a C1-C6heteroalkyl wherein the heteroalkyl is comprised of 1 to 6 carbon atoms and one or more atoms other than carbon, e.g., oxygen, nitrogen (e.g. -NH-, -N(alkyl)- ), sulfur, or combinations thereof wherein the heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. Examples of heteroalkyl are, for example, –CH2-O-CH3, –CH2-N(alkyl)- CH3, –CH2-N(aryl)-CH3-OCH2CH2OH, –OCH2CH2OCH2CH2OH, or – OCH2CH2OCH2CH2OCH2CH2OH. Unless stated otherwise specifically in the specification, a heteroalkyl is optionally substituted for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, OH, - OMe, NH2, or -NO2. In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, OH, or -OMe. In some embodiments, the heteroalkyl is optionally substituted with halogen.

[0079] As used herein, a “heteroalkylene” refers to divalent heteroalkyl group. Examples of such heteroalkylene are, for example, -CH2-O-CH2-, -CH2-N(alkyl)-CH2-, -CH2-N(aryl)-CH2-, -OCH2CH2O-, -Attorney Docket No.01277-0079-00PCT OCH2CH2OCH2CH2O-, or -OCH2CH2OCH2CH2OCH2CH2O-.

[0080] The term “heterocycloalkyl” refers to a cycloalkyl group that includes at least one heteroatom selected from nitrogen, oxygen, and sulfur. Unless stated otherwise specifically in the specification, the heterocycloalkyl radical may be a monocyclic, or bicyclic ring system, which may include fused (when fused with an aryl or a heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom) or bridged ring systems. The nitrogen, carbon or sulfur atoms in the heterocyclyl radical may be optionally oxidized. The nitrogen atom may be optionally quaternized. The heterocycloalkyl radical is partially or fully saturated. In some embodiments, a heterocycloalkyl is fully saturated. In some embodiments, a heterocycloalkyl is partially saturated. Examples of heterocycloalkyl radicals include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, tetrahydroquinolyl, tetrahydroisoquinolyl, decahydroquinolyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2oxopiperazinyl, 2oxopiperidinyl, 2oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1oxothiomorpholinyl, 1,1dioxothiomorpholinyl. The term heterocycloalkyl also includes all ring forms of carbohydrates, including but not limited to monosaccharides, disaccharides and oligosaccharides. Unless otherwise noted, heterocycloalkyls have from 2 to 12 carbons in the ring. In some embodiments, heterocycloalkyls have from 2 to 10 carbons in the ring. In some embodiments, heterocycloalkyls have from 2 to 10 carbons in the ring and 1 or 2 N atoms. In some embodiments, heterocycloalkyls have from 2 to 10 carbons in the ring and 3 or 4 N atoms. In some embodiments, heterocycloalkyls have from 2 to 12 carbons, 0-2 N atoms, 0-2 O atoms, 0-2 P atoms, and 0-1 S atoms in the ring. In some embodiments, heterocycloalkyls have from 2 to 12 carbons, 1-3 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (i.e., skeletal atoms of the heterocycloalkyl ring). Unless stated otherwise specifically in the specification, a heterocycloalkyl is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, OH, -OMe, NH2, or -NO2. In some embodiments, a heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, OH, or -OMe. In some embodiments, the heterocycloalkyl is optionally substituted with halogen.

[0081] “Heteroaryl” refers to a ring system radical comprising carbon atom(s) and one or more ring heteroatoms that selected from the group consisting of nitrogen, oxygen, phosphorous, and sulfur, and at least one aromatic ring. In some embodiments, heteroaryl is monocyclic, bicyclic or polycyclic. Illustrative examples of monocyclic heteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, furazanyl, indolizine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolizine, quinoline, isoquinoline, cinnoline,Attorney Docket No.01277-0079-00PCT phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine, and pteridine. Illustrative examples of monocyclic heteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, and furazanyl. Illustrative examples of bicyclic heteroaryls include indolizine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine, and pteridine. In some embodiments, heteroaryl is pyridinyl, pyrazinyl, pyrimidinyl, thiazolyl, thienyl, thiadiazolyl or furyl. In some embodiments, a heteroaryl contains 0-6 N atoms in the ring. In some embodiments, a heteroaryl contains 1-4 N atoms in the ring. In some embodiments, a heteroaryl contains 4-6 N atoms in the ring. In some embodiments, a heteroaryl contains 0-4 N atoms, 0-1 O atoms, 0-1 P atoms, and 0-1 S atoms in the ring. In some embodiments, a heteroaryl contains 1-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. In some embodiments, heteroaryl is a C1-C9heteroaryl. In some embodiments, monocyclic heteroaryl is a C1-C5heteroaryl. In some embodiments, monocyclic heteroaryl is a 5-membered or 6-membered heteroaryl. In some embodiments, a bicyclic heteroaryl is a C6-C9heteroaryl. In some embodiments, a heteroaryl group comprises a partially reduced cycloalkyl or heterocycloalkyl group defined herein (e.g., 7,8-dihydroquinoline). In some embodiments, a heteroaryl group comprises a fully reduced cycloalkyl or heterocycloalkyl group defined herein (e.g., 5,6,7,8-tetrahydroquinoline). When heteroaryl comprises a cycloalkyl or heterocycloalkyl group, the heteroaryl is bonded to the rest of the molecule through a heteroaromatic ring carbon or hetero atom. A heteroaryl radical can be a monocyclic or polycyclic (e.g., bicyclic, tricyclic, or tetracyclic) ring system, which may include fused, spiro or bridged ring systems. Unless stated otherwise specifically in the specification, a heteroaryl is optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, OH, -OMe, NH2, or -NO2. In some embodiments, a heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, OH, or -OMe. In some embodiments, the heteroaryl is optionally substituted with halogen.

[0082] The term “moiety” refers to a specific segment or functional group of a molecule. Chemical moieties are often recognized chemical entities embedded in or appended to a molecule.

[0083] The terms “treat,” “prevent,” “ameliorate,” and “inhibit,” as well as words stemming therefrom, as used herein, do not necessarily imply 100% or complete treatment, prevention, amelioration, or inhibition. Rather, there are varying degrees of treatment, prevention, amelioration, and inhibition of which one of ordinary skill in the art recognizes as having a potential benefit or therapeutic effect. In this respect, the disclosed methods can provide any amount of any level of treatment, prevention, amelioration, or inhibition of the disorder in a mammal. For example, a disorder, including symptoms or conditions thereof, may be reduced by, for example, about 100%, about 90%, about 80%, about 70%, about 60%, about 50%, about 40%, about 30%, about 20%, or about 10%. Furthermore, the treatment, prevention, amelioration, or inhibition provided by the methods disclosed herein can include treatment, prevention, amelioration, or inhibition of one or more conditions or symptoms of the disorder, e.g.,Attorney Docket No.01277-0079-00PCT cancer.

[0084] In certain embodiments, “treating” includes the concepts of “alleviating”, which refers to lessening the frequency of occurrence or recurrence, or the severity, of any symptoms or other ill effects related to a disorder and / or the associated side effects. The term “treating” also encompasses the concept of “managing” which refers to reducing the severity of a particular disease or disorder in a patient or delaying its recurrence, e.g., lengthening the period of remission in a patient who had suffered from the disease.

[0085] The term "therapeutically effective amount" as used herein to refer to an amount effective at the dosage and duration necessary to achieve the desired therapeutic result. A therapeutically effective amount of the composition may vary depending on factors such as the individual's condition, age, sex, and weight, and the ability of the protein to elicit the desired response of the individual. A therapeutically effective amount can also be an amount that exceeds any toxic or deleterious effect of the composition that would have a beneficial effect on the treatment.

[0086] The term “optional” or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. For example, “optionally substituted alkyl” means either “alkyl” or “substituted alkyl” as defined above. Further, an optionally substituted group may be un- substituted (e.g., -CH2CH3), fully substituted (e.g., -CF2CF3), mono-substituted (e.g., -CH2CH2F) or substituted at a level anywhere in-between fully substituted and mono-substituted (e.g., -CH2CHF2, - CH2CF3, -CF2CH3, -CFHCHF2, etc.).

[0087] As used herein, the term "substituent" means positional variables on the atoms of a core molecule that are substituted at a designated atom position, replacing one or more hydrogens on the designated atom, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds. A person of ordinary skill in the art should note that any carbon as well as heteroatom with valences that appear to be unsatisfied as described or shown herein is assumed to have a sufficient number of hydrogen atom(s) to satisfy the valences described or shown. In certain instances one or more substituents having a double bond (e.g., "oxo" or "=O") as the point of attachment may be described, shown or listed herein within a substituent group, wherein the structure may only show a single bond as the point of attachment to the core structure. A person of ordinary skill in the art would understand that, while only a single bond is shown, a double bond is intended for those substituents.

[0088] The term “optionally substituted” or “substituted” means that the referenced group is optionally substituted with one or more additional group(s). For example, “optionally substituted” or “substituted” can mean that the referenced group is optionally substituted with one or more substituents individually and independently selected from halogen, -CN, -NH2, -NH(alkyl), -N(alkyl)2, -OH, oxo, -CO2H, - CO2alkyl, -C(=O)NH2, -C(=O)NH(alkyl), -C(=O)N(alkyl)2, -S(=O)2NH2, -S(=O)2NH(alkyl), - S(=O)2N(alkyl)2, alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone. InAttorney Docket No.01277-0079-00PCT some other embodiments, optional substituents are independently selected from halogen, -CN, -NH2, - NH(CH3), -N(CH3)2, -OH, oxo, -CO2H, -CO2(C1-C4alkyl), -C(=O)NH2, -C(=O)NH(C1-C4alkyl), - C(=O)N(C1-C4alkyl)2, -S(=O)2NH2, -S(=O)2NH(C1-C4alkyl), -S(=O)2N(C1-C4alkyl)2, C1-C4alkyl, C3- C6cycloalkyl, C1-C4fluoroalkyl, C1-C4heteroalkyl, C1-C4alkoxy, C1-C4fluoroalkoxy, -SC1-C4alkyl, - S(=O)C1-C4alkyl, and -S(=O)2C1-C4alkyl. In some embodiments, an “optionally substituted” group is independently substitued with 1-6 substituents selected from halogen, -CN, oxo, -OH, -SF5, -SH, - S(=O)C1-C3alkyl, -S(=O)2C1-C3alkyl, -S(=O)2NH2, -S(=O)2NHC1-C3alkyl, -S(=O)2N(C1-C3alkyl)2, - S(=O)(=NC1-C3alkyl)(C1-C3alkyl), -NH2, -NHC1-C3alkyl, -N(C1-C3alkyl)2, -N=S(=O)(C1-C3alkyl)2, - C(=O)C1-C3alkyl, -C(=O)OH, -C(=O)OC1-C3alkyl, -C(=O)NH2, -C(=O)NHC1-C3alkyl, -C(=O)N(C1- C3alkyl)2, -P(=O)(C1-C3alkyl)2, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, C1- C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, aryl, heteroaryl, heterocycloalkyl and cycloalkyl. In some embodiments, an “optionally substituted” group is independently substitued with 1-6 substituents selected from halogen, -CN, oxo, -OH, -SF5, -SH, -S(=O)C1-C3alkyl, -S(=O)2C1-C3alkyl, -S(=O)2NH2, - S(=O)2NHC1-C3alkyl, -S(=O)2N(C1-C3alkyl)2, -S(=O)(=NC1-C3alkyl)(C1-C3alkyl), -NH2, -NHC1-C3alkyl, -N(C1-C3alkyl)2, -N=S(=O)(C1-C3alkyl)2, -C(=O)C1-C3alkyl, -C(=O)OH, -C(=O)OC1-C3alkyl, - C(=O)NH2, -C(=O)NHC1-C3alkyl, -C(=O)N(C1-C3alkyl)2, -P(=O)(C1-C3alkyl)2, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, C1-C3haloalkoxy, C1-C3hydroxyalkyl, C1-C3aminoalkyl, C1-C3heteroalkyl, 5- to 6- membered heterocycloalkyl and C3-C6cycloalkyl. In some embodiments, an “optionally substituted” group is independently substitued with 1-6 substituents selected from halogen, oxo, -OH, -NH2, -NHC1- C3alkyl, -N(C1-C3alkyl)2, -C(=O)OH, -C(=O)NH2, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, C1- C3haloalkoxy, C1-C3hydroxyalkyl, C1-C3aminoalkyl, C1-C3heteroalkyl, and C3-C6cycloalkyl. In some embodiments, optional substituents are independently selected from D, halogen, -CN, -NH2, -OH, - NH(CH3), -N(CH3)2, -NH(cyclopropyl), -CH3, -CH2CH3, -CF3, -OCH3, and -OCF3. In some embodiments, substituted groups are substituted with one or two of the preceding groups. In some embodiments, an optional substituent on an aliphatic carbon atom (acyclic or cyclic) includes oxo (=O). When indicating the number of substituents, the term “one or more” means from one substituent to the highest possible number of substitutions, i.e. replacement of one hydrogen up to replacement of all hydrogens by substituents. In some embodiments, an “optionally substituted” group is unsubstituted. In some embodiments, an “optionally substituted” group is independently substitued with 1-6 substituents. In some embodiments, an “optionally substituted” group is independently substitued with 1-3 substituents. In some embodiments, an “optionally substituted” group is independently substitued with 1- 2 substituents.

[0089] The term “unsubstituted” means that the specified group bears no substituents.

[0090] Certain compounds described herein may exist in tautomeric forms, and all such tautomeric forms of the compounds being within the scope of the disclosure.

[0091] Unless otherwise stated, structures depicted herein are also meant to include all stereochemical forms of the structure; i.e., the R and S configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compoundsAttorney Docket No.01277-0079-00PCT are within the scope of the disclosure.

[0092] In the present disclosure, the term “amino acid” is used in its broadest meaning and it embraces not only natural amino acids but also derivatives thereof and unnatural amino acids. For example, the term “amino acid” encompasses unnatural or non-natural amino acids, and peptoids.

[0093] As used herein, the term “unnatural amino acid” or “non-natural amino acid” refers to an amino acid other than the 20 canonical amino acids. The 20 canonical amino acids refer to alanine (ala or A), arginine (arg or R), asparagine (asn or N), aspartic acid (asp or D), cysteine (cys or C), glutamine (gln or Q), glutamic acid (glu or E), glycine (gly or G), histidine (his or H), isoleucine (ile or I), leucine (leu or L), lysine (lys or K), methionine (met or M), phenylalanine (phe or F), proline (pro or P), serine (ser or S), threonine (thr or T), tryptophan (trp or W), tyrosine (tyr or Y), and valine (val or V). As used herein, canonical amino acids are L- amino acids.

[0094] In some embodiments, an amino acid described herein can be replaced with a derivative thereof. Examples of an amino acid derivatives include derivatives having an amine, amide, ester, or carboxyl group as the C-terminus and / or N-terminus thereof. An amino acid derivative further encompasses amino acid isomers, including D-amino acids. An amino acid derivative further encompasses alkylated amino acids, for example N-alkylation (e.g., N-methylation), beta-carbon alkylation or alpha-carbon alkylation. In some embodiments, a derivative of an amino acid is the amino acid with alpha-carbon alkylation. In some embodiments, a derivative of an amino acid is the amino acid with beta-carbon alkylation. In some embodiments, a derivative of an amino acid is the amino acid with N-alkylation. An amino acid derivative further encompasses the amino acids that have the same functional groups but with different lengths of the side chain (e.g., LysAc vs. OrnAc and cysteine vs. homocysteine). An amino acid derivative further encompasses amino acids with heteroatoms in the side chain (e.g., O-(aminomethyl)- homoserine is a derivative of lysine and serine). An amino acid derivative further encompasses amino acids containing conjugation groups, including azides and alkynes. For example, propargylglycine is a derivative of alanine, and azidolysine is a derivative of lysine. An amino acid derivative further encompasses amino acids with a different aromatic moiety compared to the canonical amino acid (e.g., the indole in tryptophan vs the 7-azaindole in 7-AzaTrp; the phenyl in phenylalanine vs the pyridine in 4Py). An amino acid derivative further encompasses amino acids with optional substituents, i.e., optionally substituted amino acid.

[0095] In some embodiments, an amino acid derivative refers to an optionally substituted amino acid. In some embodiments, an optionally substituted amino acid is optionally substituted with one or more substituents described herein. For example, in some embodiments, an optionally substituted amino acid is optionally substituted with one or more substituents independently selected from halogen, hydroxyl, cyano, amino, amide, nitro, ureido, C1-C6alkyl, C1-C6alkoxy, C6-C10aryl, C3-C6cycloalkyl, 6- to 10- membered heterocycloalkyl, and 6-to 10- membered heteroaryl. In some embodiments, the optionally substituted amino acid is optionally substituted with one or more substituents independently selected from halogen, -CN, -NH2, -NH(alkyl), -N(alkyl)2, oxo, -OH, -CO2H, -CO2alkyl, -C(=O)NH2, - C(=O)NH(alkyl), -C(=O)N(alkyl)2, -S(=O)2NH2, -S(=O)2NH(alkyl), -S(=O)2N(alkyl)2, alkyl, cycloalkyl,Attorney Docket No.01277-0079-00PCT fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone. In some embodiments, substituents may include any substituents described herein, for example: halogen, hydroxy, oxo (=O), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=N-H), oximo (=N-OH), hydrazino (=N-NH2), SF5, RbORa, RbOC(O)Ra, RbOC(O)ORa, RbOC(O)N(Ra)2, RbN(Ra)2, RbC(O)Ra, RbC(O)ORa, RbC(O)N(Ra)2, RbORcC(O)N(Ra)2, RbN(Ra)C(O)ORa, RbN(Ra)C(O)Ra, RbN(Ra)S(O)tRa(where t is 1 or 2), RbS(O)tRa(where t is 1 or 2), RbS(O)tORa(where t is 1 or 2), and RbS(O)tN(Ra)2(where t is 1 or 2); and alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, cycloalkylalkyl, and heterocycle, any of which may be optionally substituted by alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=O), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=N-H), oximo (=N-OH), hydrazine (=N-NH2), RbORa, RbOC(O)Ra, RbOC(O)ORa, RbOC(O)N(Ra)2, RbN(Ra)2, RbC(O)Ra, RbC(O)ORa, RbC(O)N(Ra)2, RbORcC(O)N(Ra)2, RbN(Ra)C(O)ORa, RbN(Ra)C(O)Ra, RbN(Ra)S(O)tRa(where t is 1 or 2), RbS(O)tRa(where t is 1 or 2), RbS(O)tORa(where t is 1 or 2) and RbS(O)tN(Ra)2(where t is 1 or 2); wherein each Rais independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, and heterocycle, wherein each Ra, valence permitting, may be optionally substituted with alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=O), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=N-H), oximo (=N-OH), hydrazine (=N-NH2), RbORa, RbOC(O)Ra, RbOC(O)ORa, RbOC(O)N(Ra)2, RbN(Ra)2, RbC(O)Ra, RbC(O)ORa, RbC(O)N(Ra)2, RbORcC(O)N(Ra)2, RbN(Ra)C(O)ORa, RbN(Ra)C(O)Ra, RbN(Ra)S(O)tRa(where t is 1 or 2), RbS(O)tRa(where t is 1 or 2), RbS(O)tORa(where t is 1 or 2) and RbS(O)tN(Ra)2(where t is 1 or 2); and wherein each Rbis independently selected from a direct bond or a straight or branched alkylene, alkenylene, or alkynylene chain, and each Rcis a straight or branched alkylene, alkenylene or alkynylene chain. Additional examples of amino acid / peptide derivatives include those obtained by modification such as phosphorylation, alkylation (e.g., methylation), acetylation, adenylylation, ADP-ribosylation, or glycosylation. These derivatives can be prepared by those skilled in the art in a known manner or a method based thereon.

[0096] In some embodiments, an amino acid comprising a cycloalkyl group can be a derivative of another amino acid having a cycloalkyl group. In some embodiments, an amino acid comprising a heterocycloalkyl group can be a derivative of another amino acid having a heterocycloalkyl group.

[0097] In some embodiments, a derivative of an amino acid is selected from amino acids that have similar polarity and / or charge with the amino acid. For example, in some embodiments, a polar, uncharged amino acid can be a derivative of another polar, uncharged amino acid (e.g., Hgn, Q, S, T, Qglucamine).

[0098] In some embodiments, a derivative of an amino acid has the same number of hydrogen donor as the amino acid. In some embodiments, a derivative of an amino acid has the same number of hydrogen acceptor as the amino acid.

[0099] In some embodiments, the amino acid derivative has a molecular weight that does not vary for more than 14, 28, 30, 45, or 60 g / mol compared to the amino acid. In some embodiments, the derivativeAttorney Docket No.01277-0079-00PCT has a molecular weight that does not vary for more than 14 g / mol compared to the amino acid. In some embodiments, the derivative has a molecular weight that does not vary for more than 50 g / mol compared to the amino acid. In some embodiments, the derivative has a molecular weight that does not vary for more than 28 g / mol compared to the amino acid.

[0100] An amino acid derivative further encompasses amino acids wherein a functional group is substituted with another functional group having similar properties, e.g., a cysteine can be substituted with a homocysteine. In some embodiments, an aryl functional group can be substituted with an aryl or heteroaryl group. In some embodiments, a heteroaryl functional group can be substituted with an aryl or heteroaryl group. In some embodiments, an amino functional group can be substituted with an NH(alkyl) group.

[0101] The term “protein” as used herein refers to a polypeptide (i.e., a string of at least 3 amino acids linked to one another by peptide bonds). Proteins can include moieties other than amino acids (e.g., may be glycoproteins, proteoglycans, etc.) and / or can be otherwise processed or modified. A protein can be a complete polypeptide as produced by and / or active in a cell (with or without a signal sequence). In some embodiments, a protein is or comprises a characteristic portion such as a polypeptide as produced by and / or active in a cell. A protein can include more than one polypeptide chain. For example, polypeptide chains can be linked by one or more disulfide bonds or associated by other means.

[0102] The term “peptide” as used herein refers to a compound that includes two or more amino acids. A peptide described herein can comprise one or more unnatural amino acids. The term “peptide” also encompasses peptide mimetics.

[0103] The term “peptide mimetic” or “mimetic” refers to biologically active compounds that mimic the biological activity of a peptide or a protein but are no longer entirely peptidic in chemical nature, e.g., they can contain non-peptide bonds (that are, bonds other than amide bonds between amino acids). As used herein, the term peptide mimetic is used in a broader sense to include molecules that are no longer completely peptidic in nature, such as pseudo-peptides, semi-peptides and peptoids. Whether completely or partially non-peptide, peptide mimetics described herein can provide a spatial arrangement of reactive chemical moieties that closely resemble the three-dimensional arrangement of active groups in the subject amino acid sequence or subject molecule on which the peptide mimetic is based. As a result of this similar active-site geometry, the peptide mimetic can have effects on biological systems that are similar to the biological activity of the subject entity.

[0104] In some embodiments, the peptide mimetics are substantially similar in both three-dimensional shape and biological activity to the subject amino acid sequence or subject molecule on which the peptide mimetic is based. Examples of methods of structurally modifying a peptide to create a peptide mimetic include the inversion of backbone chiral centers leading to D-amino acid residue structures that may, particularly at the N-terminus, lead to enhanced stability for proteolytical degradation without adversely affecting activity. An example is described in the paper “Tritiated D-ala1-Peptide T Binding”, Smith C. S. et al., Drug Development Res., 15, pp.371-379 (1988). A second method is altering cyclic structure for stability, such as N to C interchain imides and lactames (Ede et al. in Smith and Rivier (Eds.)Attorney Docket No.01277-0079-00PCT “Peptides: Chemistry and Biology”, Escom, Leiden (1991), pp.268-270). An example of this is provided in conformationally restricted thymopentin-like compounds, such as those disclosed in US4457489. A third method is to substitute peptide bonds in the subject entity by pseudopeptide bonds that confer resistance to proteolysis.

[0105] The term “organic atoms” refers to atoms which would be found in organic compounds, such as carbon, hydrogen, nitrogen, oxygen, sulfur, phosphorus, fluorine, chlorine, bromine, or iodine. In some embodiments, “organic atoms” refers to carbon, nitrogen, oxygen, sulfur, or phosphorus.

[0106] Ranges provided herein are understood to be shorthand for all of the values within the range. For example, a range of 1 to 50 is understood to include any number, combination of numbers, or sub-range from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50, as well as all intervening decimal values between the aforementioned integers such as, for example, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, and 1.9. With respect to sub-ranges, “nested sub-ranges” that extend from either end point of the range are specifically contemplated. For example, a nested sub-range of an exemplary range of 1 to 50 may comprise 1 to 10, 1 to 20, 1 to 30, and 1 to 40 in one direction, or 50 to 40, 50 to 30, 50 to 20, and 50 to 10 in the other direction.

[0107] As used herein, C1-Cx (or C1-x) includes C1-C2, C1-C3... C1-Cx. By way of example only, a group designated as “C1-C4” indicates that there are one to four carbon atoms in the moiety, i.e., groups containing 1 carbon atom, 2 carbon atoms, 3 carbon atoms or 4 carbon atoms. Thus, by way of example only, “C1-C4alkyl” indicates that there are one to four carbon atoms in the alkyl group, i.e., the alkyl group is selected from among methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl. Also, by way of example, C0-C2alkylene includes a direct bond, -CH2-, and -CH2CH2- linkages.

[0108] The term “cyclized” or “cyclization” as used herein means that two amino acids apart from each other by at least one amino acid bind directly or bind indirectly to each other in one peptide to form a cyclic structure in the molecule. In some cases, the two amino acids bind via a linker or the like.

[0109] The term “subject” or “patient” encompasses mammals. Examples of mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. In one aspect, the mammal is a companion animal such as a dog or a cat. In one aspect, the mammal is a human.

[0110] Percent sequence identity can be calculated using computer programs or direct sequence comparison. Preferred computer program methods to determine identity between two sequences include, but are not limited to, the GCG program package, FASTA, BLASTP, and TBLASTN (see, e.g., D. W. Mount, 2001, Bioinformatics: Sequence and Genome Analysis, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y.). The BLASTP and TBLASTN programs are publicly available from NCBI and other sources. The Smith Waterman algorithm can also be used to determine percent identity. Exemplary parameters for amino acid sequence comparison include the following: 1) algorithm fromAttorney Docket No.01277-0079-00PCT Needleman and Wunsch (J. Mol. Biol., 48:443-453 (1970)); 2) BLOSSUM62 comparison matrix from Hentikoff and Hentikoff (Proc. Nat. Acad. Sci. USA., 89:10915-10919 (1992)) 3) gap penalty=12; and 4) gap length penalty=4. A program useful with these parameters can be publicly available as the “gap” program (Genetics Computer Group, Madison, Wis.). The aforementioned parameters are the default parameters for polypeptide comparisons (with no penalty for end gaps). Alternatively, polypeptide sequence identity can be calculated using the following equation: % identity – (the number of identical residues) / (alignment length in amino acid residues)*100. For this calculation, alignment length includes internal gaps but does not include terminal gaps.

[0111] It is appreciated that certain features of the disclosure, which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features of the disclosure, which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable sub combination. For example, a conjugate of this disclosure can comprise any peptide ligand described herein (e.g., a peptide ligand of Table 1 or Table 2, wherein the lysine, or tryptophan-lysine dipeptide is replaced with a non-natural lysine or a non-natural tryptophan-lysine dipeptide moiety described herein), any metal chelator described herein (e.g., a metal chelator selected from FIGs 1A, 1B, 2A, 2B, 3A, 3B, 4A, 4B, 5A, 5B, and 6-25), optionally a linker described herein (e.g., a linker of Formula (V-1), (V-1a), or (V-1b)), and optionally a radionuclide described herein (e.g., a radionuclide of Table 3)

[0112] Unless special definitions are given, the terminology used in relation to analytical chemistry, synthetic organic chemistry, and medical chemistry and pharmaceutical chemistry described in the present specification, as well as their procedures and techniques, are well known and commonly used in the field of the present art. Standard techniques may be used for chemical synthesis and chemical analysis. Those defined from among such techniques and procedures can be found in, for example, “K.J. Jensen, P.T. Shelton, S.L. Pedersen, Peptide Synthesis and Applications, 2nd Edition, Springer, 2013” and the like, and these are incorporated into the present specification by reference for all purposes. All patents, applications, published applications, and other publications, and other data referred to throughout the entire disclosure, when permitted, are incorporated into the present specification by reference. II. Peptides and Radiopharmaceutical Conjugates

[0113] Targeted Radiopharmaceuticals (TRP) are a new generation of nuclear medicine for cancer treatment or diagnosis. A TRP can selectively deliver high concentrations of radionuclide-containing molecules to the target cells such as a tumor, and no or very low concentrations to the undesired cells present in normal, healthy tissues. The process can be achieved by engineering the drug molecule with the high-affinity binder (e.g., targeting ligand) and linking it to the radioactive isotope. The biological targets of these binders are highly expressed on tumor cells and have low or no expression in healthy tissues and organs. When the radioisotope decays, it emits highly energic ionizing radiation in form of alpha, beta, and / or gamma particles. The released energy at the target sites can cause damage or death of the target tissues or be visualized by imaging scanner to achieve therapeutic or diagnostic purposes.Attorney Docket No.01277-0079-00PCT Minimizing TRP residence time in off-target tissues is important for reducing undesired toxicities.

[0114] Provided herein are conjugates (e.g., radiopharmaceutical conjugates or radiopharmaceuticals), or a pharmaceutically acceptable salt thereof, that have avidity for the somatostatin receptor and have increased renal clearance, and pharmaceutical compositions comprising the conjugates. Also provided herein are peptides, or a pharmaceutically acceptable salt thereof, that have avidity for the somatostatin receptor and have increased renal clearance, and pharmaceutical compositions comprising the peptides. The conjugates, peptides, and compositions can be useful for treating cancer. The conjugates, peptides, and compositions can also be useful in imaging and disease diagnosis.

[0115] Peptides and conjugates described herein have avidity for a somatostatin receptor (SSTR). An SSTR can be a mammalian SSTR. A mammalian SSTR can be a human SSTR. A human SSTR can comprise somatostatin receptor type 1 (SSTR1), somatostatin receptor type 2 (SSTR2), somatostatin receptor type 3 (SSTR3), somatostatin receptor type 4 (SSTR4), and / or somatostatin receptor type 5 (SSTR5). An SSTR can be a human somatostatin receptor type 2 (SSTR2). In some embodiments, the peptide or conjugate binds to a human somatostatin receptor type 2 (SSTR2). The peptide or conjugate can be an agonist of the SSTR. The peptide or conjugate can be an antagonist of the SSTR. The agonist of the SSTR can comprise a partial agonist of the SSTR. The agonist of the SSTR can comprise a full agonist of the SSTR. The agonist of the SSTR can comprise an inverse agonist of the SSTR. The antagonist of the SSTR can comprise a competitive antagonist of the SSTR. The peptide or conjugate can comprise an allosteric modulator of the SSTR. The allosteric modulator of the SSTR can be an allosteric agonist of SSTR. The allosteric modulator of the SSTR can be an allosteric antagonist of SSTR.

[0116] In one aspect, described herein is a cyclic peptide, or a pharmaceutically acceptable salt thereof, comprising a non-natural tryptophan-lysine dipeptide moiety, wherein the non-natural tryptophan-lysine dipeptide moiety comprises: (i) a non-natural lysine derivative, wherein the non-natural lysine derivative is a non- natural amino acid having a side chain comprising an amine; or (ii) a non-natural tryptophan derivative, wherein the non-natural tryptophan derivative is an amino acid comprising an aromatic moiety; and wherein the cyclic peptide or a pharmaceutically acceptable salt thereof has an avidity for a somatostatin receptor.

[0117] In some embodiments, the non-natural tryptophan-lysine dipeptide moiety comprises (i) the non- natural lysine derivative and (ii) the non-natural tryptophan derivative. In some embodiments, the non- natural tryptophan-lysine dipeptide moiety comprises the non-natural lysine derivative. In some embodiments, the non-natural tryptophan-lysine dipeptide moiety comprises the non-natural tryptophan derivative.

[0118] In one aspect, described herein is a cyclic peptide, or a pharmaceutically acceptable salt thereof, comprising a non-natural tryptophan-lysine dipeptide moiety, wherein the cyclic peptide or a pharmaceutically acceptable salt thereof comprises a sequence that has one or more amino acid replacements based on a sequence having SEQ ID: 1-77. In some embodiments, the one or moreAttorney Docket No.01277-0079-00PCT replacements comprise a replacement of a lysine in the sequence with a non-natural lysine derivative, wherein the non-natural lysine derivative is a non-natural amino acid having a side chain comprising an amine. In some embodiments, the one or more replacements comprise a replacement of a tryptophan, a D-tryptophan, a phenylalanine, or a 2Nal in the sequence with a non-natural tryptophan derivative, wherein the non-natural tryptophan derivative is an amino acid comprising an aromatic moiety.

[0119] In one aspect, described herein is a cyclic peptide, or a pharmaceutically acceptable salt thereof, comprising a non-natural tryptophan-lysine dipeptide moiety, wherein the cyclic peptide or a pharmaceutically acceptable salt thereof comprises a sequence that has one or more amino acid replacements based on a sequence having SEQ ID: 1-77, and wherein the one or more replacements comprise: (i) a replacement of a lysine in the sequence with a non-natural lysine derivative, wherein the non-natural lysine derivative is a non-natural amino acid having a side chain comprising an amine; or (ii) a replacement of a tryptophan in the sequence with a non-natural tryptophan derivative, wherein the non-natural tryptophan derivative is an amino acid comprising an aromatic moiety. In some embodiments, the one or more replacements comprise the replacement of a lysine in the sequence with a non-natural lysine derivative and the replacement of a tryptophan in the sequence with a non-natural tryptophan derivative. In some embodiments, the one or more replacements comprise the replacement of a lysine in the sequence with a non-natural lysine derivative, and the tryptophan is not replaced. In some embodiments, the one or more replacements comprise the replacement of a tryptophan in the sequence with a non-natural tryptophan derivative, and the lysine is not replaced. In some embodiments, the cyclic peptide, or a pharmaceutically acceptable salt thereof, has avidity for a somatostatin receptor.

[0120] In one aspect, described herein is a cyclic peptide, or a pharmaceutically acceptable salt thereof, comprising a non-natural lysine derivative, wherein the non-natural lysine derivative is a non-natural amino acid having a side chain comprising an amine, and wherein the cyclic peptide or a pharmaceutically acceptable salt thereof has an avidity for a somatostatin receptor. In some embodiments, the cyclic peptide is monocyclic. In some embodiments, the cyclic peptide is polycyclic. In some embodiments, the cyclic peptide is bicyclic. In some embodiments, the cyclic peptide comprises 5-40 amino acids in the cyclic portion of the peptide. In some embodiments, the cyclic peptide consists of 5-40 amino acids in the cyclic portion of the peptide. In some embodiments, the cyclic peptide comprises 6-14 amino acids in the cyclic portion of the peptide. In some embodiments, the cyclic peptide consists of 6-14 amino acids in the cyclic portion of the peptide. In some embodiments, the cyclic peptide comprises 6-12 amino acids in the cyclic portion of the peptide. In some embodiments, the cyclic peptideAttorney Docket No.01277-0079-00PCT consists of 6-12 amino acids in the cyclic portion of the peptide. In some embodiments, the cyclic peptide, or a pharmaceutically acceptable salt thereof, comprises a sequence that has one or more amino acid replacements based on a sequence having SEQ ID NO: 1-85.

[0121] In some embodiments the non-natural tryptophan derivative in a peptide or conjugate described herein is a non-natural amino acid comprising an optionally substituted N-containing 5- to 10- membered heteroaryl. In some embodiments, the non-natural tryptophan derivative is a non-natural amino acid comprising an optionally substituted pyridinyl, an optionally substituted indolyl, an optionally substituted azaindolyl, an optionally substituted indazolyl, an optionally substituted benzimidazolyl, an optionally substituted pyrimidazolyl, an optionally substituted pyrazolo[1,5-a]pyridinyl, an optionally substituted quinolinyl, or an optionally substituted isoquinolinyl. In some embodiments, the non-natural tryptophan derivative is D-Trp, NMe-D-Trp, (S-βMe)D-Trp, (S-βMe)Trp, (βGeminal methyl)D-Trp, (βGeminal methyl)Trp, (S-βPropyl)D-Trp, (S-βPropyl)Trp, (S-βIsopropyl)D-Trp, (S-βIsopropyl)Trp, (S- βCyclopropyl)D-Trp, (S-βCyclopropyl)Trp, (S-βIsobutyl)D-Trp, (S-βIsobutyl)Trp, (S-βSecbutyl)D-Trp, (S-βSecbutyl)Trp, (S-βNeopentyl)D-Trp, (S-βNeopentyl)Trp, (S-βPhenyl)D-Trp, (S-βPhenyl)Trp, (S- βBenzyl)D-Trp, (S-βBenzyl)Trp, (R-βMe)D-Trp, (R-βMe)Trp, (R-βPropyl)D-Trp, (R-βPropyl)Trp, (R- βIsopropyl)D-Trp, (R-βIsopropyl)Trp, (R-βCyclopropyl)D-Trp, (R-βCyclopropyl)Trp, (R-βIsobutyl)D- Trp, (R-βIsobutyl)Trp, (R-βSecbutyl)D-Trp, (R-βSecbutyl)Trp, (R-βNeopentyl)D-Trp, (R- βNeopentyl)Trp, (R-βPhenyl)D-Trp, (R-βPhenyl)Trp, (R-βBenzyl)D-Trp, (R-βBenzyl)Trp, Aza-Trp, Aza-D-Trp, D-6F-Trp, (5-Cl) D-Trp, (5-Me) D-Trp, (5-MeO) D-Trp, (6-Me) D-Trp, (7-Me) D-Trp, Bzt, D-Tpi, or D-Aph(Cbm), each of which is further optionally substituted. In some embodiments, the Aza- Trp is 2-aza-Trp, 4-aza-Trp, 5-aza-Trp, 6-aza-Trp, or 7-aza-Trp. In some embodiments, the non-natural tryptophan derivative is D-Trp, NMe-D-Trp, (S-βMe)D-Trp, (S-βMe)Trp, (R-βMe)D-Trp, (R-βMe)Trp, Aza-Trp, Aza-D-Trp, D-6F-Trp, or D-Aph(Cbm), each of which is further optionally substituted. In some embodiments, the non-natural tryptophan derivative is optionally substituted D-Trp. In some embodiments, the non-natural tryptophan derivative is optionally substituted NMe-D-Trp. In some embodiments, the non-natural tryptophan derivative is optionally substituted (S-βMe)D-Trp. In some embodiments, the non-natural tryptophan derivative is optionally substituted (S-βMe)Trp. In some embodiments, the non-natural tryptophan derivative is optionally substituted (βGeminal methyl)D-Trp. In some embodiments, the non-natural tryptophan derivative is optionally substituted (βGeminal methyl)Trp. In some embodiments, the non-natural tryptophan derivative is optionally substituted (S- βPropyl)D-Trp. In some embodiments, the non-natural tryptophan derivative is optionally substituted (S- βPropyl)Trp. In some embodiments, the non-natural tryptophan derivative is optionally substituted (S- βIsopropyl)D-Trp. In some embodiments, the non-natural tryptophan derivative is optionally substituted (S-βIsopropyl)Trp. In some embodiments, the non-natural tryptophan derivative is optionally substituted (S-βCyclopropyl)D-Trp. In some embodiments, the non-natural tryptophan derivative is optionally substituted (S-βCyclopropyl)Trp. In some embodiments, the non-natural tryptophan derivative is optionally substituted (S-βIsobutyl)D-Trp. In some embodiments, the non-natural tryptophan derivative is optionally substituted (S-βIsobutyl)Trp. In some embodiments, the non-natural tryptophan derivative isAttorney Docket No.01277-0079-00PCT optionally substituted (S-βSecbutyl)D-Trp. In some embodiments, the non-natural tryptophan derivative is optionally substituted (S-βSecbutyl)Trp. In some embodiments, the non-natural tryptophan derivative is optionally substituted (S-βNeopentyl)D-Trp. In some embodiments, the non-natural tryptophan derivative is optionally substituted (S-βNeopentyl)Trp. In some embodiments, the non-natural tryptophan derivative is optionally substituted (S-βPhenyl)D-Trp. In some embodiments, the non-natural tryptophan derivative is optionally substituted (S-βPhenyl)Trp. In some embodiments, the non-natural tryptophan derivative is optionally substituted (S-βBenzyl)D-Trp. In some embodiments, the non-natural tryptophan derivative is optionally substituted (S-βBenzyl)Trp. In some embodiments, the non-natural tryptophan derivative is optionally substituted (R-βMe)D-Trp. In some embodiments, the non-natural tryptophan derivative is optionally substituted (R-βMe)Trp. (R-βPropyl)D-Trp. In some embodiments, the non- natural tryptophan derivative is optionally substituted (R-βPropyl)Trp. In some embodiments, the non- natural tryptophan derivative is optionally substituted (R-βIsopropyl)D-Trp. In some embodiments, the non-natural tryptophan derivative is optionally substituted (R-βIsopropyl)Trp. In some embodiments, the non-natural tryptophan derivative is optionally substituted (R-βCyclopropyl)D-Trp. In some embodiments, the non-natural tryptophan derivative is optionally substituted (R-βCyclopropyl)Trp. In some embodiments, the non-natural tryptophan derivative is optionally substituted (R-βIsobutyl)D-Trp. In some embodiments, the non-natural tryptophan derivative is optionally substituted (R-βIsobutyl)Trp. In some embodiments, the non-natural tryptophan derivative is optionally substituted (R-βSecbutyl)D- Trp. In some embodiments, the non-natural tryptophan derivative is optionally substituted (R- βSecbutyl)Trp. In some embodiments, the non-natural tryptophan derivative is optionally substituted (R- βNeopentyl)D-Trp. In some embodiments, the non-natural tryptophan derivative is optionally substituted (R-βNeopentyl)Trp. In some embodiments, the non-natural tryptophan derivative is optionally substituted (R-βPhenyl)D-Trp. In some embodiments, the non-natural tryptophan derivative is optionally substituted (R-βPhenyl)Trp. In some embodiments, the non-natural tryptophan derivative is optionally substituted (R-βBenzyl)D-Trp. In some embodiments, the non-natural tryptophan derivative is optionally substituted (R-βBenzyl)Trp. In some embodiments, the non-natural tryptophan derivative is optionally substituted Aza-Trp. In some embodiments, the non-natural tryptophan derivative is optionally substituted Aza-D- Trp. In some embodiments, the non-natural tryptophan derivative is optionally substituted Bzt. In some embodiments, the non-natural tryptophan derivative is optionally substituted D-6F-Trp. In some embodiments, the non-natural tryptophan derivative is optionally substituted or D-Aph(Cbm). In some embodiments, the non-natural tryptophan derivative is (S-βMe)D-Trp, (R-βMe)D-Trp, or D-Trp. In some embodiments, the non-natural tryptophan derivative is (S-βMe)D-Trp. In some embodiments, X3 is (R- βMe)D-Trp. In some embodiments, the non-natural tryptophan derivative is D-Trp.

[0122] In some embodiments, the non-natural tryptophan derivative in a peptide or conjugate described herein has a structure of:Attorney Docket No.01277-0079-00PCT, wherein: R31is hydrogen or C1-C5alkyl optionally substituted with one to three substituents independently selected from Rf; each Rfis independently halogen, -CN, -NO2, -ORa, -SRaor -NRcRd; LX3is a bond, -O-, -S-, -NR33-, C1-C3alkylene, or C1-C3heteroalkylene, wherein the alkylene or heteroalkylene is optionally substituted with one or more RX3a; ring A3 is an aryl or heteroaryl; each R32is independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1- C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, halogen, -CN, -NO2, -ORa, -SRa, -SF5, -NRcRd, -P(=O)(ORc)(ORd), -P(=O)RcRd, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, wherein each of the alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more R32a; or two R32are taken together to form =O, =S, or =N(Ra); m3 is 0, 1, 2, 3, 4, or 5; each R32ais independently halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1- C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -CN, -NO2, -ORa, -SRa, -NRcRd, --P(=O)(ORc)(ORd), -P(=O)RcRd, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, =O, =S, or =N(Ra), wherein each of the alkyl, heteroalkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more Re; R33is hydrogen or C1-C3alkyl; R34is hydrogen or C1-C3alkyl; RX3ais halogen, -CN, -NO2, -ORa, -NRcRd, C1-C6alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1-C6alkylene(heteroaryl), wherein each of the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more Re;Attorney Docket No.01277-0079-00PCT or two RX3agroups attached to the same or different atoms are taken together to form a cycloalkyl or heterocycloalkyl ring, each of which is optionally substituted with one or more Re; each Rais independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1-C6alkylene(heteroaryl), wherein each of the alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more Re; each Reis independently halogen, -CN, -OH, oxo, -O-C1-C6alkyl, -SF5, -S(=O)C1-C6alkyl, - S(=O)2C1-C6alkyl, -S(=O)2NH2, -S(=O)2-halogen, -S(=O)2NHC1-C6alkyl, -S(=O)2N(C1-C6alkyl)2, -NH2, -NHC1-C6alkyl, -N(C1-C6alkyl)2, -NHC(=NH)NH2, -NHC(=O)OC1-C6alkyl, -C(=O)C1- C6alkyl, -C(=O)OH, C1-C6alkyl-C(=O)OH, -C(=O)OC1-C6alkyl, -C(=O)NH2, -C(=O)N(C1- C6alkyl)2, -C(=O)NHC1-C6alkyl, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1- C6aminoalkyl, or C1-C6heteroalkyl, and each Rcand Rdare independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1-C6alkylene(heteroaryl), wherein each of the alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more Re; or Rcand Rdare taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more Re.

[0123] In some embodiments, ring A3 is a C6-C10aryl or a 5- 10- membered heteroaryl. In some embodiments, ring A3 is a C6-C10aryl. In some embodiments, ring A3 is a 5- 10- membered heteroaryl. In some embodiments, ring A3 is a phenyl, naphthyl, pyridinyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, pyrimidazolyl, pyrazolo[1,5-a]pyridinyl, benzofuran, benzothiophene, quinolinyl, or isoquinolinyl. In some embodiments, ring A3 is phenyl or naphthyl. In some embodiments, ring A3 is indolyl or azaindolyl. In some embodiments, ring A3 is a phenyl. In some embodiments, ring A3 is a naphthyl. In some embodiments, ring A3 is a pyridinyl. In some embodiments, ring A3 is a benzofuran. In some embodiments, ring A3 is a benzothiophene. In some embodiments, ring A3 is an indolyl. In some embodiments, ring A3 is an azaindolyl. In some embodiments, ring A3 is an indazolyl. In some embodiments, ring A3 is a benzimidazolyl. In some embodiments, ring A3 is a pyrimidazolyl. In some embodiments, ring A3 is a pyrazolo[1,5-a]pyridinyl. In some embodiments, ring A3 is a quinolinyl. In some embodiments, ring A3 is an isoquinolinyl. In some embodiments, m3 is 0 or 1. In some embodiments, m3 is 0. In some embodiments, m3 is 1.

[0124] In some embodiments, the non-natural tryptophan derivative in a peptide or conjugate described herein has a structure of:Attorney Docket No.01277-0079-00PCT ,Y32is N, CH, or CR32; Y33is N, CH, or CR32; Y34is N, CH, or CR32; Y35is N, or C; Y36is N or C; Y37is N, CH, or CR32; and Y38is O, S, N or NH.

[0125] In some embodiments, no more than two of Y31, Y32, Y33, Y34, Y35, Y36, and Y37are N. In some embodiments, Y31is N. In some embodiments, Y31is CH. In some embodiments, Y32is N. In some embodiments, Y32is CH. In some embodiments, Y33is N. In some embodiments, Y33is CH. In some embodiments, Y34is N. In some embodiments, Y34is CH. In some embodiments, Y35is N. In some embodiments, Y35is C. In some embodiments, Y36is N. In some embodiments, Y36is C. In some embodiments, Y37is N. In some embodiments, Y37is CH. In some embodiments, Y38is N. In some embodiments, Y38is NH. In some embodiments, Y38is S. In some embodiments, Y38is O.

[0126] In some embodiments, each R32is independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, halogen, CN, -NO2, -ORa, -SRa, -SF5, or -NRcRd, wherein each of the alkyl and heteroalkyl is optionally substituted with one or more R32a. In some embodiments, each R32is independently C1-C6alkyl, C1-C6haloalkyl, halogen, CN, -ORa, -SRa, or -NRcRd, wherein each of the alkyl and heteroalkyl is optionally substituted with one or more R32a. In some embodiments, R32is hydrogen or halogen. In some embodiments, R32is hydrogen or fluoro. In some embodiments, R32is halogen. In some embodiments, R32is fluoro.

[0127] In some embodiments, R31is hydrogen or C1-C3alkyl optionally substituted with one to three substituents independently selected from Rf. In some embodiments, R31is hydrogen. In some embodiments, R31is C1-C3alkyl. In some embodiments, R31is methyl.

[0128] In some embodiments, LX3is C1-C3alkylene, optionally substituted with one to three RX3aselected from C1-C3alkyl (e.g., methyl), phenyl, C1-C3alkylene(phenyl), C3-C6cycloalkyl, or C1- C3alkylene(C3-C6cycloalkyl). In some embodiments, LX3is -CH2-, -CH(CH3)-, -C(CH3)2-, -CH(iPr)-, CH(benzyl)-, -CH(cyclopropyl)-, -CH(CH2-CH(CH3)2)-, -CH(CH2-C(CH3)3)-, or -CH(CH2-CH2-CH3)-. In some embodiments, LX3is -CH2- or -CH(CH3)-.Attorney Docket No.01277-0079-00PCT

[0129] In some embodiments, the non-natural tryptophan derivative in a peptide or conjugate described herein has a structure of:wherein each R32is independently C1-C6alkyl, C1-C6haloalkyl, halogen, -CN, -ORa, -SRa, or -NRcRd; and m3 is 0, 1, or 2. In some embodiments, the non-natural tryptophan derivativesome embodiments, each R32is independently methyl, ethyl, isopropyl, C1-C2haloalkyl, halogen, -CN, -Attorney Docket No.01277-0079-00PCT OH, -OMe, -SH, -SMe, -NH2, -NHMe, or -N(Me)2. In some embodiments, m3 is 0. In some embodiments, m3 is 1 or 2. In some embodiments, m3 is 1. In some embodiments, m3 is 2. In some embodiments, R32is halogen and m3 is 1.

[0130] Without being bound to any one particular theory, it was discovered that modifications to peptidyl lysine in cyclic peptides and radiopharmaceutical conjugates having avidity for a somatostatin receptor have improved renal clearance and tissue biodistribution. In some embodiments, modifications to a non-natural lysine derivative improves peptide or conjugate biodistribution as determined by measuring concentrations in tissues by mass spectrometry, SPECT imaging, or gamma counting. A conjugate or peptide having improved biodistribution exhibits distribution in desired tissues (e.g., tumor tissue) and decreased distribution in undesired tissues (e.g., kidneys). In some embodiments, a peptide or conjugate described herein has improved biodistribution as determined by measuring tissue pharmacokinetics when a peptidyl lysine is replaced with a non-natural amino acid having a side chain comprising an amine. In some embodiments, the amine comprises a primary amine, a secondary amine, a tertiary amine, or a quaternary amine. In some embodiments, the amine comprises a primary amine, a secondary amine, or a tertiary amine. In some embodiments, the amine comprises a primary amine. In some embodiments, the amine comprises a secondary amine or a tertiary amine. In some embodiments, the amine comprises a secondary amine. In some embodiments, the amine comprises a tertiary amine. In some embodiments, a peptide or conjugate described herein has improved biodistribution as determined by tissue pharmacokinetics when the non-natural lysine derivative is an amino acid comprising azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl.

[0131] In some embodiments, the non-natural lysine derivative in a peptide or conjugate described herein is the non-natural lysine derivative is a non-natural amino acid having a side chain comprising an amine. In some embodiments, the amine comprises a primary amine, a secondary amine, a tertiary amine, or a quaternary amine. In some embodiments, the amine comprises a primary amine, a secondary amine, or a tertiary amine. In some embodiments, the amine comprises a primary amine. In some embodiments, the amine comprises a secondary amine or a tertiary amine. In some embodiments, the amine comprises a secondary amine. In some embodiments, the amine comprises a tertiary amine. In some embodiments, the non-natural lysine derivative is a non-natural amino acid having a side chain comprising an amine, and wherein the side chain comprises azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl. In some embodiments, the non-natural lysine derivative is Cba3N, Chg4N, Cha4N, Cha4NH2, Ser(3- azetidine), PipzaA, 3-Azetidine-hAla, or Pic4, each of which is further optionally substituted. In some embodiments, the non-natural lysine derivative is NMe-Lys, Lys(Me), Lys(diMe), Lys(iPr), Chg4N, Cha4N, 4-oxa-Lys, or 3-Azetidine-hAla. In some embodiments, the non-natural lysine derivative is Cba3N, Chg4N, Cha4N, Cha4NH2, Ser(3-azetidine), PipzaA, 3-Azetidine-hAla, Pic4, NMe-Lys, Lys(Me), Lys(diMe), Lys(iPr), or 4-oxa-Lys. In some embodiments, the non-natural lysine derivative is (D / L) Hly. In some embodiments, the non-natural lysine derivative is optionally substituted Chg4N. In some embodiments, the non-natural lysine derivative is optionally substituted Cha4N. In some embodiments, the non-natural lysine derivative is optionally substituted Ser(3-azetidine). In someAttorney Docket No.01277-0079-00PCT embodiments, the non-natural lysine derivative is optionally substituted PipzaA. In some embodiments, the non-natural lysine derivative is optionally substituted 3-Azetidine-hAla. In some embodiments, the non-natural lysine derivative is optionally substituted NMe-Lys. In some embodiments, the non-natural lysine derivative is optionally substituted Lys(Me). In some embodiments, the non-natural lysine derivative is optionally substituted Lys(iPr). In some embodiments, the non-natural lysine derivative is optionally substituted 4-oxa-Lys. In some embodiments, the non-natural lysine derivative is Chg4N. In some embodiments, the non-natural lysine derivative is Cha4N. In some embodiments, the non-natural lysine derivative is Ser(3-azetidine). In some embodiments, the non-natural lysine derivative is PipzaA. In some embodiments, the non-natural lysine derivative is 3-Azetidine-hAla. In some embodiments, the non-natural lysine derivative is Pic4. In some embodiments, the non-natural lysine derivative NMe-Lys. In some embodiments, the non-natural lysine derivative is Lys(Me). In some embodiments, the non- natural lysine derivative is Lys(iPr). In some embodiments, the non-natural lysine derivative is 4-oxa- Lys. In some embodiments, the non-natural lysine derivative is D-Lys. In some embodiments, the non- natural lysine derivative is azaLys. In some embodiments, the non-natural lysine derivative is Lys(triMe). In some embodiments, the non-natural lysine derivative is Nva(NH-NH2).

[0132] In some embodiments, the non-natural lysine derivative in a peptide or conjugate described herein has a structure of:, wherein, R41is hydrogen or C1-C5alkyl optionally substituted with one to three substituents independently selected from Rf; each Rfis independently halogen, -CN, -NO2, -ORa, -SRaor -NRcRd; LX4is a bond, -O-, -S-, -NR43-, C1-C6alkylene, C1-C6heteroalkylene, C3-C6cycloalkyl, or 3- to 6- membered heterocycloalkyl, wherein the alkylene, heteroalkylene, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more RX4a; R42is -NR44R45, a heterocycloalkyl comprising one or more ring nitrogen atoms, or cycloalkylene- NR44R45, wherein the heterocycloalkyl and cycloalkylene are optionally substituted with one or more R42a; each R42ais independently halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1- C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -CN, -NO2, -ORa, -SRa, -NRcRd, - S(=O)Ra, -S(=O)2Ra, -SF5, -S(=O)2NRcRd, -S(=O)(=NRa)Ra, -N=S(=O)RcRd, -NRaS(=O)2Ra, amidinyl, -NRaC(=NH)(NRa)2, -NRaS(=O)2NRcRd, -C(=O)Ra, -C(=O)ORa, -OC(=O)Ra, - OC(=O)ORa, -OC(=O)NRcRd, -NRaC(=O)Ra, -NRaC(=O)ORa, -NRaC(=O)NRcRd, -C(=O)NRcRd,Attorney Docket No.01277-0079-00PCT -P(=O)(ORc)(ORd), -P(=O)RcRd, =O, =S, or =N(Ra), wherein each of the alkyl, heteroalkyl, alkenyl, and alkynyl is optionally substituted with one or more Re; R43is hydrogen or C1-C3alkyl; R44and R45are each independently hydrogen, C1-C3alkyl, aryl, heteroaryl, -C1-C3alkylene-aryl, -C1- C3alkylene-heteroaryl, or -NH2; or R44and R45are taken together to form a 3- to 6- membered heterocycloalkyl, wherein each of the alkyl, aryl, heteroaryl, and heterocycloalkyl are optionally substituted with one or more R42a; each RX4ais independently halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1- C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -CN, -NO2, -ORa, -SRa, -NRcRd, -- , - or , alkenyl, and alkynyl is optionally substituted with one or more Re; or or two RX4agroups attached to the same or different atoms are taken together to form a cycloalkyl or heterocycloalkyl ring, each of which is optionally substituted with one or more Re; each Rais independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1-C6alkylene(heteroaryl), wherein each of the alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more Re; each Reis independently halogen, -CN, -OH, oxo, -O-C1-C6alkyl, -SF5, -S(=O)C1-C6alkyl, - S(=O)2C1-C6alkyl, -S(=O)2NH2, -S(=O)2-halogen, -S(=O)2NHC1-C6alkyl, -S(=O)2N(C1-C6alkyl)2, -NH2, -NHC1-C6alkyl, -N(C1-C6alkyl)2, -NHC(=NH)NH2, -NHC(=O)OC1-C6alkyl, - C(=O)C1-C6alkyl, -C(=O)OH, C1-C6alkyl-C(=O)OH, -C(=O)OC1-C6alkyl, -C(=O)NH2, - C(=O)N(C1-C6alkyl)2, -C(=O)NHC1-C6alkyl, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl; and each Rcand Rdare independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1-C6alkylene(heteroaryl), wherein each of the alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more Re; or Rcand Rdare taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more Re.

[0133] In some embodiments, R42is -NR44R45or a heterocycloalkyl comprising one or more ring nitrogen atoms, wherein the heterocycloalkyl is optionally substituted with one or more R42a. In some embodiments, R42is a 4- to 6- membered N-containing heterocycloalkyl, which is optionally substitutedAttorney Docket No.01277-0079-00PCT with one or more R42a. In some embodiments, R42is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, which is optionally substituted with one to four R42a. In some embodiments, R42is azetidinyl, piperidinyl, or piperazinyl, each of which is optionally substituted with one to four R42a. In some embodiments, R42is azetidinyl optionally substituted with one to four R42a. In some embodiments, R42is pyrrolidinyl optionally substituted with one to four R42a. In some embodiments, R42is piperidinyl optionally substituted with one to four R42a. In some embodiments, R42is piperazinyl optionally substituted with one to four R42a. In some embodiments, R42is morpholinyl optionally substituted with one to four R42a. In some embodiments, R42is, each of which is optionally substituted with 1 or 2 substituents selected from R42a. In some embodiments, R42isoptionally substituted with 1 or 2 substituents selected from R42a. In some embodiments, R42is,optionally substituted with 1 or 2 substituents selected fromR42a. In some embodiments, R42 isoptionally substituted with 1 or 2 substituents selectedfrom R42a. In some embodiments, R42isoptionally substituted with 1 or 2 substituents selected from R42a. In some embodiments, each R42ais independently halogen, C1-C6alkyl, C1- C6haloalkyl, -ORa, or =O. In some embodiments, each R42ais C1-C3alkyl, C1-C3haloalkyl. -OH, or =O. In some embodiments, R42ais C1-C3alkyl. In some embodiments, R42is -NR44R45.

[0134] In some embodiments, R44and R45are each independently hydrogen, C1-C3alkyl, aryl, heteroaryl, -C1-C3alkylene-aryl, or -C1-C3alkylene-heteroaryl; or R44and R45are taken together to form a 3- to 6- membered heterocycloalkyl, wherein each of the alkyl, aryl, heteroaryl, and heterocycloalkyl are optionally substituted with one or more R42a. In some embodiments, R44and R45are each independently hydrogen, methyl, ethyl, isopropyl, phenyl, C1-C3alkylene-phenyl, or -NH2, wherein each of the methyl, ethyl, isopropyl, phenyl, and alkyl are each optionally substituted with 1 or 2 substituents selected from R42a. In some embodiments, R44and R45are each independently hydrogen, methyl, ethyl, isopropyl, phenyl, -C1-C3alkylene-phenyl, or -NH2. In some embodiments, R44and R45are each independently hydrogen, methyl, ethyl, or isopropyl. In some embodiments, R44and R45are each independently hydrogen or methyl. In some embodiments, R44and R45are each independently hydrogen or ethyl. In some embodiments, R44and R45are each independently hydrogen or isopropyl. In some embodiments, R44and R45are each independently hydrogen or phenyl. In some embodiments, R44and R45are each independently hydrogen or -C1-C3alkylene-phenyl. In some embodiments, R44and R45are each independently hydrogen or -NH2.Attorney Docket No.01277-0079-00PCT

[0135] In some embodiments, LX4is a bond. In some embodiments, LX4is a C1-C4alkylene (e.g., -CH2-), wherein the alkylene is optionally substituted with 1 or 2 substituents independently selected from RX4a. In some embodiments, LX4is a C1-C4heteroalkylene (e.g., -CH2OCH2CH2-) wherein the heteroalkylene is optionally substituted with 1 or 2 substituents independently selected from RX4a. In some embodiments, RX4ais-F, -Me, or -OH.

[0136] In some embodiments, R41is hydrogen or C1-C3alkyl optionally substituted with one to three substituents independently selected from Rf. In some embodiments, R41is hydrogen. In some embodiments, R41is C1-C3alkyl. In some embodiments, R41is methyl.

[0137] In some embodiments, the non-natural lysine derivative in a peptide or conjugate describedAttorney Docket No.01277-0079-00PCT In some embodiments, the non-natural lysine derivative in a peptide or conjugate described herein isembodiments, the non-natural lysine derivative in a peptide or conjugate described herein isembodiments, the non-natural lysine derivative in a peptide or conjugate described herein isembodiments, the non-natural lysine derivative in a peptide or conjugate described herein isAttorney Docket No.01277-0079-00PCTsome embodiments, the non-natural lysine derivative in a peptide orconjugate described herein

[0138] In some embodiments, the non-natural lysine derivative in a peptide or conjugate describedIn some embodiments, the non-natural lysine derivative in a peptide or conjugate described herein issome embodiments, the non-natural lysine derivative in a peptide or conjugate described hereinsome embodiments, the non-natural lysine derivative in a peptideAttorney Docket No.01277-0079-00PCT or conjugate described hereinsome embodiments, the non-natural lysine derivative in a peptide or conjugate described hereinsome embodiments, the non- natural lysine derivative in a peptide or conjugate described hereinembodiments, the non-natural lysine derivative in a peptide or conjugate described herein is.

[0139] The structures of exemplary peptides having avidity for a somatostatin receptor and comprising an aromatic-amino acid-lysine dipeptide moiety can be found in Table 1. Table 1.Attorney Docket No.01277-0079-00PCTAttorney Docket No.01277-0079-00PCT

[0140] The structures of exemplary peptides having avidity for a somatostatin receptor and comprising a lysine residue can be found in Table 2. Table 2.Attorney Docket No.01277-0079-00PCT

[0141] The structures of exemplary cyclic peptides having avidity for a somatostatin receptor and comprising a non-natural tryptophan-lysine dipeptide moiety can be found in Table 2A. The structures of exemplary conjugates comprising the cyclic peptides of Table 2A can be found in Table 2B. The structures of exemplary conjugates of Table 2B comprising a metal nuclide can be found in Table 2C. In Tables 2A-2C, cyclization is via positions 2 and 7. The sequences in Tables 2A-2C are cyclized via a peptide amide bond formed between the N-terminus of the amino acid at position 2 and the C-terminus of the amino acid at position 7. In Tables 2B and 2C, Dah refers to -N(H)(CH2)6N(H)-, wherein one N(H) forms a peptide bond with the carbonyl of COCH2 at position 1 of the associated sequence; and PEG3 refers to -N(H)(CH2CH2O)3CH2CH2N(H)-, wherein one N(H) forms a peptide bond with the carbonyl of COCH2 at position 1 of the associated sequence.TCP00-9700-77210.oN et he e e eePhPhPhPhPkcorhrhrhrhrhD T T T T Tyenarlot ) A)he )-ni2tAeM)H i Aedid an tN-( zp idezH sy iPita-N(Lez3(aA-r3e vS N(prTp-rp D p p p)r r rprprpr3(S niahreh3h h h h h h hpk rpCnaG Ea a a a a a aTr e iD D D D D D -T dL P D D pp p p p p- irDr r rp DS 4T-prT)r r reT-T-T-T-T-T-)eD MbD D D D D D M -bS- n (S(iahpA A A A A A A A A 3ryryryryryryryryrTyrTyCaT T T T T T T T T TeC O O O O O O O O O T T T T T T TdiD D D D D D D D D S ycycycycycycycycycyc2H- H H H H H H H e -e-e-e-e-e-e- H e - H e -eD M M M M M M M M M MI.O9001112 3 4 5 6 7N N N N N N N N N N Q1 1 1 1 1 1E N1 1 1 1 1 1 1 1 11S . OeNtag 9 4 5 9001020506DI 984959909011021051061080 ujDI8-9-9-9-1-1-1-10-1- Q1 1nC C C C C C C C C EoS CTCP00-9700-77210.oNtekcoDyenrottA)e 4T-prT)eT-T-T-T-T-T-)eMbD M D D D D D -bD M S -b(S-(S(ryrT3 yryryryryryr r r r. T T T T T TyTyTyTyT ycC2 ycycy y y y y y y yH- ec c c c c c c clH eb -H- H- H- H- H- H- H- H- H- Ma 2 e e e e e e e e e eT M M M M M M M M M M N N N N N N N N N N N 22 2 2 2 2 2 2 2 2 2H C1H H H H H H H H H H C C C C C C C C C C O O O O O O O O O O O C C C C C C C C C C C nihar3aheCkhDeni aGhahahahahahahahaD E P D D D D D D D D diL S nia uLuLuLuLuLuLuLuLu uA T hp- - - - - - - -L-L- O CaA A A A A A A A A A T T T T T Ded C T T T T T i O O O O O O O O O O S D D D D D D D D D D 8 DI1.O900 1 2 3 4 5 6 7 81Q111111111111 1 1 1E N1 1 1 1S e8t0au u u u u u uLuLuLuLL1g -L-L L L L-ujDI-9- - - 0 1-2-5-6-884 5 9 0 0 0 0 0 0Cno -9C -9C -9-1-1-1-1-1-1- C C C C C C C C CAttorney Docket No.01277-0079-00PCT Radiopharmaceutical Conjugates

[0142] In some embodiments, described herein are radiopharmaceutical conjugates, or pharmaceutically acceptable salts thereof, comprising a cyclic peptide disclosed herein (e.g., a peptide of SEQ ID NO: 1-85 wherein one or more lysine residues are replaced with a non-natural lysine derivative described herein, or a peptide of SEQ ID NO: 1-77, wherein an aromatic-amino acid-lysine dipeptide moiety is replaced with a non-natural tryptophan-lysine dipeptide moiety described herein), a metal chelator, and optionally a linker that covalently connects the cyclic peptide and the metal chelator. Linker

[0143] A conjugate described herein can comprise one or more linkers. In some embodiments, the linker covalently attaches the peptide with the metal chelator. In some embodiments, the peptide attaches directly to the metal chelator without a linker.

[0144] In some embodiments, the present disclosure describes linkers that function as a spacer. A linker can comprise a number of intervening atoms (on a linear chain, excluding pendant groups or substituents) between the metal chelator and the binding peptide thereby creating a distance between the metal chelator and the binding peptide. In some embodiments, a linker comprises 10-100 intervening atoms between the metal chelator and the binding peptide. In some embodiments, a linker comprises 2-60 intervening atoms between the metal chelator and the binding peptide. In some embodiments, a linker comprises 2 to 20, 2 to 50, 5 to 15, 5 to 25, 10 to 40, 30 to 60, or 10 to 20 intervening atoms between the metal chelator and the binding peptide. In some embodiments, a linker comprises 3 to 30 intervening atoms between the metal chelator and the binding peptide. In some embodiments, a linker comprises 5 to 25 intervening atoms between the metal chelator and the binding peptide. In some embodiments, a linker comprises 6 to 18 intervening atoms between the metal chelator and the binding peptide. In some embodiments, a linker comprises 10 to 20 intervening atoms between the metal chelator and the binding peptide. The intervening atoms can comprise 1 or more carbons, and optionally one or more heteroatoms such as O and N. In some embodiments, the intervening atoms comprise 2 to 20, 2 to 50, 5 to 15, 5 to 25, 10 to 40, 30 to 60, or 10 to 20 carbons. In some embodiments, the intervening atoms comprise 0, 1, 2, 3, 4, 5, or 6 nitrogen atoms. In some embodiments, the intervening atoms comprise 0, 1, 2, 3, 4, 5, 6, 7 or 8 oxygen atoms. In some embodiments, the intervening atoms comprise 1 to 6 nitrogen and 0 to 4 oxygen atoms.

[0145] A linker can comprise one or more amino acid residues. In some embodiments, the linker comprises 1 to 3, 1 to 5, 1 to 10, 5 to 10, or 5 to 20 amino acid residues. In some embodiments, the linker comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid residues. In some embodiments, the linker comprises 1 to 5 amino acid residues. For example, the linker can comprise one or more lysine (K) residues such as K, KK, or KKK sequences. In some embodiments, the linker comprises an ornithine, a lysine, a homolysine, an aspartate, a beta-aspartate, a glutamate, a 2-aminosuberic acid, a glycine, a beta-alanine, or a combination thereof. In some embodiments, the linker comprises a lysine, an aspartate, a beta- aspartate, a glutamate, or a derivative thereof. In some embodiments, the linker comprises an ornithine, aAttorney Docket No.01277-0079-00PCT lysine, or a homolysine. In some embodiments, the linker comprises an aspartic acid, a beta-aspartate, a glutamic acid, or a 2-aminosuberic acid. In some embodiments, the linker comprises a glycine or a beta- alanine.

[0146] A herein-described linker can attach to the cyclic peptide at any suitable position. The linker can be bonded to the peptide, the metal chelator, or both, for example, through a chemically reactive group. Exemplary chemically reactive groups include, but are not limited to, a free amino, imino, hydroxyl, thiol or carboxyl group (e.g., to the N- or C-terminus, to the epsilon amino group of one or more lysine residues, the free carboxylic acid group of one or more glutamic acid or aspartic acid residues, or to the sulfhydryl group of one or more cysteinyl residues). The site to which the linker is bound to the peptide can be a natural or unnatural amino acid of the peptide and / or it can be introduced into the peptide, e.g., by DNA recombinant technology (e.g., by introducing a cysteine or protease cleavage site in the amino acid sequence) or by protein biochemistry (e.g., reduction, pH adjustment or proteolysis). Exemplary methods for attaching the linker includes carbodiimide reaction, reactions using bifunctional agents such as dialdehydes or imidoesters, Schiff base reaction, Suzuki-Miyaura cross-coupling reactions, Isothiocyanates as coupling agents, and click chemistry.

[0147] The linker can have a prescribed length thereby linking the metal chelator (and optionally radionuclide) and the peptide while allowing an appropriate distance therebetween. In some embodiments, the linker has 1 to 100 atoms, 1 to 60 atoms, 1 to 30 atoms, 1 to 15 atoms, 1 to 10 atoms, 1 to 5, or 2 to 20 atoms in length. In some embodiments, the linker has 1 to 10 atoms in length.

[0148] The linker can comprise flexible and / or rigid regions. Exemplary flexible linker regions include those comprising Gly and Ser residues (“GS” linker), glycine residues, alkylene chain, PEG chain, etc. Exemplary rigid linker regions include those comprising alpha helix-forming sequences (e.g., EAAAK (SEQ ID NO: 119)), proline-rich sequences, and regions rich in double and / or triple bonds.

[0149] In some embodiments, a linker may be further added to the (cyclic) peptide. Examples of the linker include the foregoing amino acid linker (peptide linker), a chemical linker, a fatty acid linker, a nucleic acid linker, a sugar chain linker, or the like, or it may be a complex, for example, a chemical linker, a peptide linker, or the like. Examples of the chemical linker include a PEG (polyethylene glycol) linker. For example, the PEG linker may comprise between 1 to 24 ethylene glycol units. Furthermore, the linker may be a fatty acid linker containing a divalent chemical moiety derived from a fatty acid. In some embodiments, the linker comprises at least one amino acid, and, for example, a glycine-rich peptide such as a peptide having a sequence [Gly-Gly-Gly-Gly-Ser]n(in the formula, n is 1, 2, 3, 4, 5, or 6)(SEQ ID NO: 120).

[0150] The linker can be cleavable, e.g., under physiological conditions, e.g., under intracellular conditions, such that cleavage of the linker releases the chelator and radionuclide in the intracellular environment. The linker can be, e.g., a peptidyl linker that is cleaved by an intracellular peptidase or protease enzyme, including, but not limited to, a lysosomal or endosomal protease. In some embodiments, the peptidyl linker is at least two amino acids long or at least three amino acids long. Cleaving agents can include cathepsins B and D and plasmin. In other embodiments, the linker is notAttorney Docket No.01277-0079-00PCT cleavable. In some embodiments, the linker is pH-sensitive, i.e., sensitive to hydrolysis at certain pH values. For example, the pH-sensitive linker can be hydrolyzable under acidic conditions. For example, a linker can be an acid-labile linker that is hydrolyzable in the lysosome (e.g., a hydrazone, semicarbazone, thiosemicarbazone, cis-aconitic amide, orthoester, acetal, ketal, or the like). Such linkers can be relatively stable under neutral pH conditions, such as those in the blood, but are unstable at below pH 5.5 or 5.0, the approximate pH of the lysosome. In some embodiments, the hydrolyzable linker is a thioether linker.

[0151] In some embodiments, the linker comprises one or more of substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. In some embodiments, the linker comprises substituted or unsubstituted C1-C30alkylene. In some embodiments, a linker of the present disclosure is a bond. In some embodiments, a linker of the present disclosure comprises a substituted or unsubstituted C1-12heteroalkylene. In some embodiments, a linker of the present disclosure comprises a substituted or unsubstituted C1-8heteroalkylene. In some embodiments, a linker of the present disclosure comprises a substituted or unsubstituted C1-4heteroalkylene. In some embodiments, the heteroalkylene is substituted with one or more Re, wherein each Reis independently halogen, -CN, -OH, oxo, -O-C1-C6alkyl, -SF5, -S(=O)C1-C6alkyl, - S(=O)2C1-C6alkyl, -S(=O)2NH2, -S(=O)2-halogen, -S(=O)2NHC1-C6alkyl, -S(=O)2N(C1-C6alkyl)2, -NH2, - NHC1-C6alkyl, -N(C1-C6alkyl)2, -NHC(=NH)NH2, -NHC(=O)OC1-C6alkyl, -C(=O)C1-C6alkyl, - C(=O)OH, C1-C6alkyl-C(=O)OH, -C(=O)OC1-C6alkyl, -C(=O)NH2, -C(=O)N(C1-C6alkyl)2, - C(=O)NHC1-C6alkyl, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl. In some embodiments, the heteroalkylene is substituted with one or more Re, wherein each Reis independently -OH, oxo, -O-C1-C6alkyl, -NH2, -NHC1-C6alkyl, -N(C1-C6alkyl)2, - C(=O)C1-C6alkyl, -C(=O)OH, C1-C6alkyl-C(=O)OH, -C(=O)OC1-C6alkyl, -C(=O)NH2, - C(=O)N(C1-C6alkyl)2, or -C(=O)NHC1-C6alkyl.

[0152] In some embodiments, the linker comprises polyethylene glycol such as (-CH2-CH2-O-)1-10.

[0153] In some embodiments, the linker comprises a conjugation moiety such as a click chemistry residue. In some embodiments, the conjugation moiety is a reaction product of a conjugation group. In some embodiments, the linker is attached to the peptide, to the metal chelator, or both via click chemistry, thereby forming a click chemistry residue. For example, the peptide can comprise an azide group (at N- or C-terminus or at a non-terminal amino acid) that reacts with an alkyne group to form the linker of a conjugate. For another example, the peptide can comprise an alkyne group (at N- or C- terminus or at a non-terminal amino acid) that reacts with an azide to form the linker of a conjugate. The metal chelator and the linker can be attached similarly. In some embodiments, the linker comprises an azide moiety, an alkyne moiety, or both. In some embodiments, the linker comprises a triazole. In some embodiments, the linker comprises 1,4-di-substituted 1,2,3-triazole. In some embodiments, the clickAttorney Docket No.01277-0079-00PCTsome embodiments, the click chemistry residue is a DIBO-azide residue, BARAC-azide residue, DBCO- azide residue, DIFO-azide residue, COMBO-azide residue, BCN-azide residue, or DIMAC-azide residue. In some embodiments, the linker comprises a residue of nitrone dipole cycloaddition. In some embodiments, the linker comprises a residue of tetrazine ligation. In some embodiments, the linker comprises a residue of quadricyclane ligation. Exemplary groups of click chemistry residue are shown in Hein at al., “Click Chemistry, A Powerful Tool for Pharmaceutical Sciences,” Pharmaceutical Research volume 25, pages2216–2230 (2008); Thirumurugan et al, “Click Chemistry for Drug Development and Diverse Chemical–Biology Applications,” Chem. Rev.2013, 113, 7, 4905–4979; US20160107999A1; US10266502B2; and US20190204330A1, each of which is incorporated by reference in its entirety.

[0154] In some embodiments, the linker has a structure ofFormula (V-1) wherein each L is independently -O-, –NRL-, –N(RL)2+-, -OP(=O)(ORL)O-, -S-, -S(=O)-, - S(=O)2-, =CH-, -C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)O-, -C(=O)NRL-, -NRLC(=O)-, -OC(=O)NRL-, - NRLC(=O)O-, -NRLC(=O)NRL-, -NRLC(=S)NRL-, -CRL=N-, -N=CRL, -NRLS(=O)2-, -S(=O)2NRL-, - C(=O)NRLS(=O)2-, -S(=O)2NRLC(=O)-, substituted or unsubstituted C3-C15cycloalkyl, substituted or unsubstituted C1-C12heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C1-C30alkylene, substituted or unsubstituted C2-C30alkenylene, substituted or unsubstituted C2-C30alkynylene, substituted or unsubstituted C1-C30heteroalkylene, -(C1- C30alkylene)-O-, -O-(C1-C30alkylene)-, -(C1-C30alkylene)-NRL-, -NRL-(C1-C30alkylene)-, -(C1-C30alkylene)-N(RL)2+-, -N(RL)2+-(C1-C30alkylene)-, or a click chemistry residue; and each RLis independently hydrogen, substituted or unsubstituted C1-C4alkyl, substituted or unsubstituted C1-C4heteroalkyl, substituted or unsubstituted C2-C6alkenyl, substituted or unsubstituted C2-C5alkynyl, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted C2-C7heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and n is 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20).Attorney Docket No.01277-0079-00PCT

[0155] In some embodiments, the linker has a structurewherein each L is independently -O-, –NRL-, –N(RL)2+-, -OP(=O)(ORL)O-, -S-, -S(=O)-, -S(=O)2-, -CH=CH-, =CH-, -C≡C- , -C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)O-, -C(=O)NRL-, -NRLC(=O)-, -OC(=O)NRL-, -NRLC(=O)O-, -NRLC(=O)NRL-, -NRLS(=O)2-, -S(=O)2NRL-, -C(=O)NRLS(=O)2-, or -S(=O)2NRLC(=O)-.

[0156] In some embodiments, the linker of Formula (V-1) has a structure of Formula (V-1a), Formula (V-1a) wherein each of L1and L3is independently -O-, –NRL-, –N(RL)2-, -OP(=O)(ORL)O-, -S-, -S(=O)-, -L2is absent, substituted or unsubstituted C1-C30alkylene, or substituted or unsubstituted C1-C30heteroalkylene.

[0157] In some embodiments, the linker comprises a structure of Formula (V1b),Formula (V-1b) wherein each of L1and L5is independently -O-, –NRL-, –N(RL)2-, -OP(=O)(ORL)O-, -S-, -S(=O)-, - S(=O)2-, -CH=CH-, =CH-, -C≡C-, -C(=O)-, -C(=O)C1-C6alkylene -, -C(=O)O-, -OC(=O)-, - OC(=O)O-, -C(=O)NRL-, -NRLC(=O)-, -OC(=O)NRL-, -NRLC(=O)O-, -NRLC(=O)NRL-, - NRLS(=O)2-, -S(=O)2NRL-, -C(=O)NRLS(=O)2-, -S(=O)2NRLC(=O)-, substituted or unsubstituted C4-C6cycloalkyl, or substituted or unsubstituted 4- to 6- membered heterocycloalkyl; and L2, L3and L4are each independently absent, substituted or unsubstituted C4-C10cycloalkyl, substituted or unsubstituted 4- to 6- membered heterocycloalkyl, substituted or unsubstituted C1- C30alkylene, or substituted or unsubstituted C1-C30heteroalkylene.

[0158] In some embodiments, L1is -NH- or substituted or unsubstituted 4- to 6- membered heterocycloalkyl.

[0159] In some embodiments, L2is absent. In some embodiments, L2is substituted or unsubstituted C1- C30alkylene, or substituted or unsubstituted C1-C30heteroalkylene. In some embodiments, L2is substituted or unsubstituted C1-C30alkylene. In some embodiments, L2is substituted or unsubstituted C1- C30heteroalkylene. In some embodiments, L2is substituted or unsubstituted C1-C18alkylene, or substituted or unsubstituted C1-C18heteroalkylene. In some embodiments, L2is optionally substituted. In some embodiments, L2is optionally substituted with one or more substituents selected from -OH, -SH, oxo, amino, C1-C6alkyl, C1-C6hydroxyalkyl, C1-C6haloalkyl, C1-C6aminoalkyl, -C(=O)ORL, -C1-Attorney Docket No.01277-0079-00PCT C6alkylene-C(=O)ORL, -OC(=O) RL, -OC(=O)ORL, -C(=O)N(RL)2, -NRLC(=O)RL, -OC(=O)N(RL)2, and -NRLC(=O)ORL. In some embodiments, L2is C1-C30heteroalkylene that is optionally substituted with one or more substituents selected from -OH, -SH, oxo, amino, C1-C6alkyl, C1-C6hydroxyalkyl, C1-C6haloalkyl, and C1-C6aminoalkyl. In some embodiments, L2is optionally substituted with C1-C6alkyl which is further optionally substituted with one or more substituents chosen from -OH, -SH, oxo, amino, C6-C10aryl, 6- to 10- membered heteroaryl, -C(=O)ORL, -OC(=O)RL, -OC(=O)ORL, -C(=O)N(RL)2, - NRLC(=O)RL, -OC(=O)N(RL)2, and -NRLC(=O)ORL.

[0160] In some embodiments, L3is -NH-. In some embodiments, L3is substituted or unsubstituted C4-C6cycloalkyl or substituted or unsubstituted 4- to 6- membered heterocycloalkyl. In some embodiments, L3is absent.

[0161] In some embodiments, L4is absent. In some embodiments, L4is substituted or unsubstituted C4- C6cycloalkyl, substituted or unsubstituted 4- to 6- membered heterocycloalkyl, substituted or unsubstituted C1-C30alkylene, or substituted or unsubstituted C1-C30heteroalkylene.

[0162] In some embodiments, L5is -NH-, -C(=O)-, or -C(=O)C1-C6alkylene -. In some embodiments, L5is -NH-. In some embodiments, L5is -C(=O)-. In some embodiments L5is -C(=O)C1-C6alkylene-.

[0163] In some embodiments for Formula (V-1b), L1is -NH- or substituted or unsubstituted 4- to 6- membered heterocycloalkyl; L5is -NH- -C(=O)-, or -C(=O)C1-C6alkylene -; L2, L3and L4are each independently absent, substituted or unsubstituted C4-C10cycloalkyl, substituted or unsubstituted 4- to 6- membered heterocycloalkyl, substituted or unsubstituted C1-C12alkylene, or substituted or unsubstituted C1-C30heteroalkylene, wherein L1is connected to the metal chelator and L5is connected to the peptide. In some embodiments, the cycloalkyl and heterocycloalkyl are unsubstituted and the alkylene and heteroalkylene are optionally substituted with 1 to 3 groups selected from the group consisting of oxo, - C(=O)ORL, and -C1-C6alkylene-C(=O)ORL.

[0164] In some embodiments for Formula (V-1b), L2is unsubstituted C1-C12alkylene, and L3and L4are absent. In some embodiments for Formula (V-1b), L2is unsubstituted C1-C12heteroalkylene, and L3and L4are absent.

[0165] In some embodiments, the linker comprises substituted or unsubstituted C1-C30alkylene, C1-C12alkylene, C1-C8alkylene, C1-C6alkylene, or C2-C6alkylene. In some embodiments, the linker comprises C2-C6alkylene. In some embodiments, the linker comprises C4-C6alkylene.

[0166] In some embodiments, the linker L (or L1, L2, L3, L4, or L5) is substituted with one or more Re, wherein each Reis independently halogen, -CN, -OH, oxo, -O-C1C6alkyl, -SF5, -S(=O)C1C6alkyl, - S(=O)2C1C6alkyl, -S(=O)2NH2, -S(=O)2-halogen, -S(=O)2NHC1C6alkyl, -S(=O)2N(C1C6alkyl)2, -NH2, - NHC1C6alkyl, -N(C1C6alkyl)2, -NHC(=NH)NH2, -NHC(=O)OC1C6alkyl, -C(=O)C1C6alkyl, -C(=O)OH, C1C6alkyl-C(=O)OH, -C(=O)OC1C6alkyl, -C(=O)NH2, -C(=O)N(C1C6alkyl)2, -C(=O)NHC1C6alkyl, C1- C6alkyl, C1C6haloalkyl, C1C6hydroxyalkyl, C1C6aminoalkyl, or C1C6heteroalkyl. In some embodiments, each Reis independently -OH, oxo, -O-C1C6alkyl, -NH2, -NHC1C6alkyl, -N(C1C6alkyl)2, - C(=O)C1C6alkyl, -C(=O)OH, C1C6alkyl-C(=O)OH, -C(=O)OC1C6alkyl, -C(=O)NH2, - C(=O)N(C1C6alkyl)2, or -C(=O)NHC1C6alkyl.Attorney Docket No.01277-0079-00PCT

[0167] In some embodiments, each of L1is independently -O-, –NRL-, –N(RL)2-, -OP(=O)(ORL)O-, -S-, -S(=O)-, -S(=O)2-, =CH-, -C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)O-, -C(=O)NRL-, -NRLC(=O)-, - OC(=O)NRL-, -NRLC(=O)O-, -NRLC(=O)NRL-, -NRLC(=S)NRL-, -CRL=N-, -N=CRL, -NRLS(=O)2-, - S(=O)2NRL-, -C(=O)NRLS(=O)2-, -S(=O)2NRLC(=O)-, substituted or unsubstituted C3-C15cycloalkyl, substituted or unsubstituted C1-C12heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C1-C30alkylene, substituted or unsubstituted C2-C30alkenylene, substituted or unsubstituted C2-C30alkynylene, or substituted or unsubstituted C1-C30heteroalkylene, In some embodiments, L1is -O-, –NRL-, -OP(=O)(ORL)O-, -S-, -S(=O)-, -S(=O)2-, - C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)O-, -C(=O)NRL-, -NRLC(=O)-, -OC(=O)NRL-, -NRLC(=O)O-, - NRLC(=O)NRL-, -NRLC(=S)NRL-, -NRLS(=O)2-, -S(=O)2NRL-, -C(=O)NRLS(=O)2-, or - S(=O)2NRLC(=O)-. In some embodiments, L1is -O-, –NH-, -S(=O)-, -S(=O)2-, or -C(=O)-. In some embodiments, L1is -C(=O)NH- or -NHC(=O)-. In some embodiments, L1is substituted or unsubstituted C3-C15cycloalkyl, or substituted or unsubstituted C1-C12heterocycloalkyl. In some embodiments, L1is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl. In some embodiments, L1is substituted or unsubstituted C1-C30alkylene. In some embodiments, L1is substituted or unsubstituted C2- C30alkenylene. In some embodiments, L1is substituted or unsubstituted C1-C30heteroalkylene. In some embodiments, L1is substituted or unsubstituted C5-C25heteroalkylene. In some embodiments, L1is substituted or unsubstituted C5-C12heteroalkylene.

[0168] In some embodiments, each of L2is independently -O-, –NRL-, –N(RL)2-, -OP(=O)(ORL)O-, -S-, -S(=O)-, -S(=O)2-, =CH-, -C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)O-, -C(=O)NRL-, -NRLC(=O)-, - OC(=O)NRL-, -NRLC(=O)O-, -NRLC(=O)NRL-, -NRLC(=S)NRL-, -CRL=N-, -N=CRL, -NRLS(=O)2-, - S(=O)2NRL-, -C(=O)NRLS(=O)2-, -S(=O)2NRLC(=O)-, substituted or unsubstituted C3-C15cycloalkyl, substituted or unsubstituted C1-C12heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C1-C30alkylene, substituted or unsubstituted C2-C30alkenylene, substituted or unsubstituted C2-C30alkynylene, or substituted or unsubstituted C1-C30heteroalkylene, In some embodiments, L2is -O-, –NRL-, -OP(=O)(ORL)O-, -S-, -S(=O)-, -S(=O)2-, - C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)O-, -C(=O)NRL-, -NRLC(=O)-, -OC(=O)NRL-, -NRLC(=O)O-, - NRLC(=O)NRL-, -NRLC(=S)NRL-, -NRLS(=O)2-, -S(=O)2NRL-, -C(=O)NRLS(=O)2-, or - S(=O)2NRLC(=O)-. In some embodiments, L2is -O-, –NH-, -S(=O)-, -S(=O)2-, or -C(=O)-. In some embodiments, L2is -C(=O)NH- or -NHC(=O)-. In some embodiments, L2is substituted or unsubstituted C3-C15cycloalkyl, or substituted or unsubstituted C1-C12heterocycloalkyl. In some embodiments, L2is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl. In some embodiments, L2is substituted or unsubstituted C1-C30alkylene. In some embodiments, L2is substituted or unsubstituted C2- C30alkenylene. In some embodiments, L2is substituted or unsubstituted C1-C30heteroalkylene. In some embodiments, L2is substituted or unsubstituted C5-C25heteroalkylene. In some embodiments, L2is substituted or unsubstituted C5-C12heteroalkylene.

[0169] In some embodiments, each of L3is independently -O-, –NRL-, –N(RL)2-, -OP(=O)(ORL)O-, -S-, -S(=O)-, -S(=O)2-, =CH-, -C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)O-, -C(=O)NRL-, -NRLC(=O)-, -Attorney Docket No.01277-0079-00PCT OC(=O)NRL-, -NRLC(=O)O-, -NRLC(=O)NRL-, -NRLC(=S)NRL-, -CRL=N-, -N=CRL, -NRLS(=O)2-, - S(=O)2NRL-, -C(=O)NRLS(=O)2-, -S(=O)2NRLC(=O)-, substituted or unsubstituted C3-C15cycloalkyl, substituted or unsubstituted C1-C12heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C1-C30alkylene, substituted or unsubstituted C2-C30alkenylene, substituted or unsubstituted C2-C30alkynylene, or substituted or unsubstituted C1-C30heteroalkylene, In some embodiments, L3is -O-, –NRL-, -OP(=O)(ORL)O-, -S-, -S(=O)-, -S(=O)2-, - C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)O-, -C(=O)NRL-, -NRLC(=O)-, -OC(=O)NRL-, -NRLC(=O)O-, - NRLC(=O)NRL-, -NRLC(=S)NRL-, -NRLS(=O)2-, -S(=O)2NRL-, -C(=O)NRLS(=O)2-, or - S(=O)2NRLC(=O)-. In some embodiments, L3is -O-, –NH-, -S(=O)-, -S(=O)2-, or -C(=O)-. In some embodiments, L3is -C(=O)NH- or -NHC(=O)-. In some embodiments, L3is substituted or unsubstituted C3-C15cycloalkyl, or substituted or unsubstituted C1-C12heterocycloalkyl. In some embodiments, L3is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl. In some embodiments, L3is substituted or unsubstituted C1-C30alkylene. In some embodiments, L3is substituted or unsubstituted C2- C30alkenylene. In some embodiments, L3is substituted or unsubstituted C1-C30heteroalkylene. In some embodiments, L3is substituted or unsubstituted C5-C25heteroalkylene. In some embodiments, L3is substituted or unsubstituted C5-C12heteroalkylene. In some embodiments, L3is absent.

[0170] In some embodiments, each of L4is independently -O-, –NRL-, –N(RL)2-, -OP(=O)(ORL)O-, -S-, -S(=O)-, -S(=O)2-, =CH-, -C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)O-, -C(=O)NRL-, -NRLC(=O)-, - OC(=O)NRL-, -NRLC(=O)O-, -NRLC(=O)NRL-, -NRLC(=S)NRL-, -CRL=N-, -N=CRL, -NRLS(=O)2-, - S(=O)2NRL-, -C(=O)NRLS(=O)2-, -S(=O)2NRLC(=O)-, substituted or unsubstituted C3-C15cycloalkyl, substituted or unsubstituted C1-C12heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C1-C30alkylene, substituted or unsubstituted C2-C30alkenylene, substituted or unsubstituted C2-C30alkynylene, or substituted or unsubstituted C1-C30heteroalkylene, In some embodiments, L4is -O-, –NRL-, -OP(=O)(ORL)O-, -S-, -S(=O)-, -S(=O)2-, - C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)O-, -C(=O)NRL-, -NRLC(=O)-, -OC(=O)NRL-, -NRLC(=O)O-, - NRLC(=O)NRL-, -NRLC(=S)NRL-, -NRLS(=O)2-, -S(=O)2NRL-, -C(=O)NRLS(=O)2-, or - S(=O)2NRLC(=O)-. In some embodiments, L4is -O-, –NH-, -S(=O)-, -S(=O)2-, or -C(=O)-. In some embodiments, L4is -C(=O)NH- or -NHC(=O)-. In some embodiments, L4is substituted or unsubstituted C3-C15cycloalkyl, or substituted or unsubstituted C1-C12heterocycloalkyl. In some embodiments, L4is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl. In some embodiments, L4is substituted or unsubstituted C1-C30alkylene. In some embodiments, L4is substituted or unsubstituted C2- C30alkenylene. In some embodiments, L4is substituted or unsubstituted C1-C30heteroalkylene. In some embodiments, L4is substituted or unsubstituted C5-C25heteroalkylene. In some embodiments, L4is substituted or unsubstituted C5-C12heteroalkylene. In some embodiments, L4is absent.

[0171] In some embodiments, each of L5is independently -O-, –NRL-, –N(RL)2-, -OP(=O)(ORL)O-, -S-, -S(=O)-, -S(=O)2-, =CH-, -C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)O-, -C(=O)NRL-, -NRLC(=O)-, - OC(=O)NRL-, -NRLC(=O)O-, -NRLC(=O)NRL-, -NRLC(=S)NRL-, -CRL=N-, -N=CRL, -NRLS(=O)2-, - S(=O)2NRL-, -C(=O)NRLS(=O)2-, -S(=O)2NRLC(=O)-, substituted or unsubstituted C3-C15cycloalkyl,Attorney Docket No.01277-0079-00PCT substituted or unsubstituted C1-C12heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C1-C30alkylene, substituted or unsubstituted C2-C30alkenylene, substituted or unsubstituted C2-C30alkynylene, or substituted or unsubstituted C1-C30heteroalkylene, In some embodiments, L5is -O-, –NRL-, -OP(=O)(ORL)O-, -S-, -S(=O)-, -S(=O)2-, - C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)O-, -C(=O)NRL-, -NRLC(=O)-, -OC(=O)NRL-, -NRLC(=O)O-, - NRLC(=O)NRL-, -NRLC(=S)NRL-, -NRLS(=O)2-, -S(=O)2NRL-, -C(=O)NRLS(=O)2-, or - S(=O)2NRLC(=O)-. In some embodiments, L5is -O-, –NH-, -S(=O)-, -S(=O)2-, or -C(=O)-. In some embodiments, L5is -C(=O)NH- or -NHC(=O)-. In some embodiments, L5is substituted or unsubstituted C3-C15cycloalkyl, or substituted or unsubstituted C1-C12heterocycloalkyl. In some embodiments, L5is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl. In some embodiments, L5is substituted or unsubstituted C1-C30alkylene. In some embodiments, L5is substituted or unsubstituted C2- C30alkenylene. In some embodiments, L5is substituted or unsubstituted C1-C30heteroalkylene. In some embodiments, L5is substituted or unsubstituted C5-C25heteroalkylene. In some embodiments, L5is substituted or unsubstituted C5-C12heteroalkylene. In some embodiments, L5is absent.

[0172] In some embodiments, the linker comprises one or more selected from AEEA, AEEP, AEEEP,and AEEEEP groups. In some embodiments, the linker comprises (AEEA). In some embodiments, the linker comprises(AEEP). In someembodiments, the linker comprises (AEEEA). In some embodiments, the

[0173] In some embodiments, a linker of the present disclosure is or comprises ,Attorney Docket No.01277-0079-00PCT. In some embodiments, a linker of the present disclosure is or comprises

[0174] In some embodiments, a linker of the present disclosure comprises 1 to 20 groups independentlyselected from-O-, -S-, -C(=O)O-, -OC(=O)-, -C(=O)NRa-, -NRaC(=O)-, -S(=O)2NRa-, -NRaS(=O)2-, -NRaC(=O)NRa-, - NRaC(=O)O-, -OC(=O)NRa-, arylene, heteroarylene, wherein each Rais independently hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl, C2- C9heterocycloalkyl, aryl, or heteroaryl, and wherein each Rbis independently hydrogen, halogen, -CN, -NO2, -ORa, -SRa, C1C6alkyl, C1C6haloalkyl, C1C6hydroxyalkyl, C1C6aminoalkyl, C1C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl, C2- C9heterocycloalkyl, aryl, or heteroaryl. In some embodiments, a linker of the present disclosure comprises 1 to 5, 1 to 3, or 1 to 10 groups as described above.

[0175] In some embodiments, the linker is a bond. Metal Chelator

[0176] In one aspect, described herein are conjugates that comprise a metal chelator that is configured toAttorney Docket No.01277-0079-00PCT bind with a radionuclide. The metal chelator can refer to a moiety of the conjugate that is configured to bind with a radionuclide. In some embodiments, a conjugate described herein comprises two or more independent metal chelators, e.g., 2, 3, 4, 5, or more metal chelators. In some embodiments, a conjugate described herein comprises two metal chelators, which can be the same or different. In some embodiments, a conjugate described herein comprises two or more metal chelators. In some embodiments, the conjugate comprises two radionuclides bound to the metal chelators. The metal chelator can be attached to the linker or the peptide through any suitable group / atom of the chelator.

[0177] In some embodiments, the metal chelator is capable of binding a radioactive atom. The binding can be direct, e.g., the metal chelator can make hydrogen bonds or electrostatic interactions with the radioactive atom. The binding can also be indirect, e.g., the metal chelator binds to a molecule that comprises a radioactive atom. In some embodiments, the metal chelator comprises, or is, a macrocycle. In some embodiments, the metal chelator comprises, or is, 2,2′,2′′,2′′′-(1,4,7,10-Tetraazacyclododecane- 1,4,7,10-tetrayl)tetraacetic acid (DOTA) or 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA). In some embodiments, the metal chelator comprises a macrocycle, e.g., a macrocycle comprising an O and / or a N, DOTA, NOTA, one or more amines, one or more ethers, one or more carboxylic acids, EDTA, DTPA, TETA, DO3A, PCTA, or desferrioxamine.

[0178] In some embodiments, the metal chelator comprises a plurality of amines. In some embodiments, the metal chelator includes 4 or more N, 4 or more carboxylic acid groups, or a combination thereof. In some embodiments, the metal chelator does not comprise S. In some embodiments, the metal chelator comprises a ring. In some embodiments, the ring comprises an O and / or an N. In some embodiments, the metal chelator is a ring that includes 3 or more N, 3 or more carboxylic acid groups, or a combination thereof. In some embodiments, the metal chelator is polydentate.

[0179] In some embodiments, a metal chelator described herein is selected from: DOTA, DOTA-GA, pBn-DOTA, pBn-SCN-DOTA, NH2-DOTA, NH2-DOTA-GA, p-NCS-Bn-DOTA-GA, p-NH2-Bn-oxo- DO3A, p-SCN-Bn-oxo-DO3A, NOTA, NODA-GA, NH2-NODA-GA, p-NCS-Bn-NODA-GA, p-NH2- Bn-NOTA, p-SCN-Bn-NOTA, NCS-MP-NODA, NH2-MPAA-NODA, PCTA, p-NH2-Bn-PCTA, p- SCN-Bn-PCTA, p-SCN-Bn-HEHA, H2-MACROPA-NCS, H1-MACROPA, H2-MACROPA-NH2, H4- OCTAPA, tetra-(S, S, S, S)-Me-DOTA, tetra-(S, S, S, S)-Et-DOTA, tetra-(S, S, S, S)-iBu-DOTA, or maleimide-nBu-DOTA.

[0180] In some embodiments, the metal chelatorAttorney Docket No.01277-0079-00PCTembodiments, a metal chelator described herein has a structureAttorney Docket No.01277-0079-00PCTa metal chelator described herein has a structure

[0181] In some embodiments, a metal chelator described herein comprises a cyclic chelating agent. Exemplary cyclic chelating agents include, but are not limited to, AAZTA, BAT, BAT-TM, Crown, Cyclen, DO2A, CB-DO2A, DO3A, H3HP-DO3A, Oxo-DO3A, p-NH2-Bn-Oxo-DO3A, DOTA, DOTA- 3py, DOTA-PA, DOTA-GA, DOTA-4AMP, DOTA-2py, DOTA-1py, p-SCN-Bn-DOTA, CHX-A″- EDTA, MeO-DOTA-NCS EDTA, DOTAMAP, DOTAGA, DOTAGA-anhydride, DOTMA, DOTASA, DOTAM, DOTP, CB-Cyclam, TE2A, CB-TE2A, CB-TE2P, DM-TE2A, MM-TE2A, NOTA, NOTP, HEHA, HEHA-NCS, p-SCN-Bn-HEHA, DTPA, CHX-A″-DTPA, p-NH2-Bn-CHX-A″-DTPA, p-SCN- DTPA, p-SCN-Bz-Mx-DTPA, 1B4M-DTPA, p-SCN-Bn1B-DTPA, p-SCN-Bn-1B4M-DTPA, p-SCN- Bn-CHX-A″-DTPA, PEPA, p-SCN-Bn-PEPA, TETPA, DOTPA, DOTMP, DOTPM, t-Bu-calix[4]arene- tetracarboxylic acid, macropa, macropa-NCS, macropid, H3L1, H3L4, H2azapa, H5decapa, bispa2, H4pypa, H4octapa, H4CHXoctapa, p-SCN-Bn-H4octapa, p-SCN-Bn-H4octapa, TTHA, p-NO2-Bn-neunpa, H4octox, H2macropa, H2bispa2, H4phospa, H6phospa, p-SCN-Bn-H6phospa, TETA, p-NO2-Bn-TETA, TRAP, TPA, HBED, SHBED, HBED-CC, (HBED-CC)TFP, DMSA, DMPS, DHLA, lipoic acid, TGA, BAL, Bis-thioseminarabazones, p-SCN-NOTA, nNOTA, NODAGA, CB-TE1A1P, 3P-C-NETA-NCS, 3p-C-DEPA, 3P-C-DEPA-NCS, TCMC, PCTA, NODIA-Me, TACN, pycup1A1B, pycup2A, THP, DEDPA, H2DEDPA, p-SCN-Bn-H2DEDPA, p-SCN-Bn-TCMC, motexafin, NTA, NOC, 3p-C-NETA, p- NH2-Bn-TE3A, SarAr, DiAmSar, SarAr-NCS, AmBaSar, BaBaSar, TACN-TM, CP256, C-NE3TA, C- NE3TA-NCS, NODASA, NETA-monoamide, C-NETA, NOPO, BPCA, p-SCN-Bn-DFO, DFO-ChX- Mal, DFO, DFO-IAC, DFO-BAC, DiP-LICAM, EC, SBAD, BAPEN, TACHPYR, NEC-SP, Lpy, L1, L2, L3, and EuK-106. In some embodiments, the metal chelator is DOTA, TRITA, TETA, DOTA-MA, DO3A-HP, DOTMA, DOTA-pNB, DOTP, DOTMP, DOTEP, DOTMPE, F-DOTPME, DOTPP,Attorney Docket No.01277-0079-00PCT DOTBzP, DOTA-monoamide, p-NCS-DOTA, p-NCS-PADOTA, BAT, DO3TMP-Monoamide, p-NCS- TRITA, NOTA, or CHX-A″-DTPA. In some embodiments, a metal chelator described herein comprises an acyclic chelating agent. Exemplary acyclic chelating agents include, but are not limited to, DTA, CyEDTA, EDTMP, DTPMP, DTPA, CyDTPA, Cy2DTPA, DTPA-MA, DTPA-BA, and BOPA. In some embodiments, a metal chelator described herein comprises DOTA, DOTP, DOTMA, DOTAM, DTPA, NTA, EDTA, DO3A, DO2A, NOC, NOTA, TETA, TACN, DiAmSar, CB-Cyclam, CB-TE2A, DOTA- 4AMP, or NOTP. In some embodiments, a metal chelator described herein comprises H4pypa, H4octox, H4octapa, p-NO2-Bn-neunpa, p-SCN–Bn–H4neunpa, TTHA,tBu4pypa-C7-NHS, H4neunpa, H2macropa, HP-DO3A, BT-DO3A, DO3A-Nprop, DO3AP, DO2A2P, DOA3P, DOTP, DOTPMB, DOTAMAE, DOTAMAP, DO3AMBu, DOTMA, TCE-DOTA, DEPA, PCTA, p-NO2-Bn-PCTA, p-NO2-Bn-DOTA, symPC2APA, symPCA2PA, asymPC2APA, asymPCA2PA, TRAP, AAZTA, DATAm, THP, HEHA, or HBED.

[0182] In some embodiments, the metal chelator is DO3A. In some embodiments, the metal chelator is PEPA. In some embodiments, the metal chelator is EDTA. In some embodiments, the metal chelator is CHX-A″-DTPA. In some embodiments, the metal chelator is HEHA. In some embodiments, the metal chelator is DOTMP. In some embodiments, the metal chelator is t-Bu-calix[4]arene-tetracarboxylic acid. In some embodiments, the metal chelator is macropa. In some embodiments, the metal chelator is macropa-NCS. In some embodiments, the metal chelator is H4pypa. In some embodiments, the metal chelator is H4octapa. In some embodiments, the metal chelator is H4CHXoctapa. In some embodiments, the metal chelator is DOTP. In some embodiments, the metal chelator is crown. In some embodiments, the metal chelator is NOTA. In some embodiments, the metal chelator is NODAGA.

[0183] In some embodiments, the metal chelator is DOTA. In some embodiments, the metal chelator is a chiral derivative of DOTA. Exemplary chiral DOTA chelators are described in Dai et al., Nature Communications (2018) 9:857. In some embodiments, the metal chelator is 2,2',2'',2'''-((2S,5S,8S,11S)- 2,5,8,11-tetramethyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetraacetic acid. In some embodiments, the metal chelator has a structuresome embodiments, the metal chelator is 2,2',2'',2'''-((2S,5S,8S,11S)-2,5,8,11-tetraethyl-1,4,7,10-tetraazacyclododecane-1,4,7,10- tetrayl)tetraacetic acid. In some embodiments, the metal chelator has a structure ofAttorney Docket No.01277-0079-00PCT.

[0184] In some embodiments, the metal chelator has a structurewherein each Reis independently selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylcycloalkyl, alkylheterocycloalkyl, alkylaryl, alkylheteroaryl, or an amino acid side chain. In some embodiments, the metal chelator has a structurewherein each Reis independently selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylcycloalkyl, alkylheterocycloalkyl, alkylaryl, alkylheteroaryl, or an amino acid side chain.

[0185] In some embodiments, the conjugate comprises DOTA. In some embodiments, the conjugate comprises a DOTA derivative such as p-SCN-Bn-DOTA and MeO-DOTA-NCS. In some embodiments, the conjugate comprises two independent metal chelators, and at least one or both are DOTA. The structures of some exemplary metal chelators are illustrated in FIGs.6-25 (without showing the attachment points). Exemplary metal chelators are also illustrated in FIGs.1A, 2A, 3A, 4A, and 5A (attachment point shown as a squiggly line) and FIGs.1B, 2B, 3B, 4B and 5B (except that a part of the linker or the peptide covalently connected to the metal chelator is shown in the dashed circle). In some embodiments, a conjugate comprises a metal chelator of FIG.1A. In some embodiments, a conjugate comprises a metal chelator of FIG.2A. In some embodiments, a conjugate comprises a metal chelator of FIG.3A. In some embodiments, a conjugate comprises a metal chelator of FIG.4A. In some embodiments, a conjugate comprises a metal chelator of FIG.5A. Exemplary metal chelators are further described in WO2012 / 174136; US20130183235A1; US20120219495A1; US5334371, EP292689 A2,Attorney Docket No.01277-0079-00PCT WO2023202655 A1, Ramogidaand et al., EJNMMI radiopharm. chem.4, 21 (2019); Thiele et al., Cancer Biotherapy and Radiopharmaceuticals 2018; Li et al., Bioconjugate Chem.2019, 30, 5, 1539–1553; and Baranyai et al., Eur. J. Inorg. Chem.36–56 (2020), each of which is incorporated by reference in its entirety.

[0186] A metal chelator such as DOTA can interact with a radionuclide (e.g.,177Lu or225Ac) via one or more functional groups and / or atoms. For example, a metal chelator can interact with a radionuclide via nitrogen and / or oxygen atoms. As another example, a metal chelator can interact with a radionuclide via carbonyl, carboxylic acid, amino, and / or amide groups of the metal chelator. In some embodiments, the interaction of a metal chelator and a radionuclide of the conjugates disclosed herein can be illustrated assome embodiments, the interaction of a metal chelator and a radionuclide of the conjugates disclosed herein can be illustratedembodiments, the interaction of a metal chelator and a radionuclide of the conjugates disclosed hereinsome embodiments, the interaction of a metal chelator and a radionuclide of the conjugates disclosed herein can be illustrated asAttorney Docket No.01277-0079-00PCTsome embodiments, the interaction of a metal chelator and a radionuclide of the conjugates disclosed herein can be illustrated asradionuclide of the conjugates disclosed herein can be illustratedsome embodiments, the radionuclide exists in a positive oxidation state e.g.,225Ac3+,177Lu3+. In some embodiments, for example in certain aqueous conditions, the radionuclide exists in a salt form, e.g., as225Ac3+,177Lu3+. In some embodiments, for example in certain acidic aqueous conditions, the radionuclide exists in a salt form, e.g., as225Ac3+,177Lu3+. In some embodiments, the conjugate is in a salt form. In some embodiments, one or more of the carboxylic acid groups of the conjugate may exist as carboxylate anions. In some embodiments, one or more of the carboxylate anions of the conjugate may coordinate to the radionuclide. A person of ordinary skill would appreciate that the dissociation of an acid can depend on the pH value of the environment and its pK value. Accordingly, in some embodiments, a conjugate described herein can exist in a completely ionized, partially ionized or non-ionized form. Radionuclide

[0187] In one aspect, disclosed herein are radiopharmaceutical conjugates comprising a radionuclide. In some embodiments, the radionuclide is chelated or bound to a metal chelator. In some embodiments, theAttorney Docket No.01277-0079-00PCT radionuclide is covalently bound to the conjugate. Generally, the type of radionuclide used in a therapeutic radiopharmaceutical can be tailored to the specific type of cancer, the type of targeting moiety (e.g., binding peptide), etc. Radionuclides that undergo α-decay produce particles composed of two neutrons and two protons, and radionuclides that undergo β-decay emit energetic electrons from their nuclei. Some radionuclides can also undergo electron capture and emit auger electrons. In some embodiments, the conjugate comprises an alpha particle-emitting radionuclide. Alpha radiation can cause direct, irreparable double-strand DNA breaks compared with gamma and beta radiation, which can cause single-stranded breaks via indirect DNA damage. The range of these particles in tissue and the half-life of the radionuclide can also be considered in designing the radiopharmaceutical conjugate. Table 3 below illustrates some properties of exemplary radionuclides. Table 3. Exemplary radionuclidesAttorney Docket No.01277-0079-00PCT

[0188] In some embodiments, the radiopharmaceutical conjugate described herein comprises a radionuclide selected from Table 3.

[0189] In some embodiments, the radiopharmaceutical conjugate described herein comprises one or more independent radionuclides. In some embodiments, the radiopharmaceutical conjugate comprises two radionuclides. In some embodiments, each of the one or more radionuclides is bound to the metal chelator of the radiopharmaceutical conjugate. In some embodiments, two radionuclides of the radiopharmaceutical conjugate are bound to the same metal chelator. In some embodiments, two radionuclides of the radiopharmaceutical conjugate are bound to two independent metal chelators. In some embodiments, each of the one or more radionuclides is an alpha particle-emitting radionuclide.

[0190] In some embodiments, the radiopharmaceutical conjugate described herein comprises an alpha particle-emitting radionuclide. In some embodiments, the radiopharmaceutical conjugate comprises an alpha-particle emitting radionuclide bound to the metal chelator. In some embodiments, the alpha particle-emitting radionuclide is actinium-225 (225Ac), radium-223 (223Ra), radium-224 (224Ra), bismuth- 209 (209Bi), bismuth-213 (213Bi), gadolinium-148 (148Gd), terbium-149 (149Tb), polonium-213 (213Po), francium-223 (223Fr), thorium-227 (227Th), thorium-229 (229Th), or lead-212 (212Bb). In some embodiments, the alpha particle-emitting radionuclide is selected from225Ac,211At,223Ra,209Bi,213Bi,148Gd,149Tb,213Po,223Fr,227Th,229Th, and212Pb. In some embodiments, the alpha particle-emitting radionuclide is selected from225Ac,223Ra,209Bi,213Bi,148Gd,149Tb,213Po,223Fr,227Th,229Th, and212Pb. In some embodiments, the alpha particle-emitting radionuclide is225Ac. In some embodiments, the alpha particle-emitting radionuclide is213Bi. In some embodiments, the alpha particle-emitting radionuclide is212Bi. In some embodiments, the alpha particle-emitting radionuclide is212Pb. In some embodiments, the alpha particle-emitting radionuclide is224Ra. In some embodiments, the alpha particle-emitting radionuclide is223Ra. In some embodiments, the alpha particle-emitting radionuclide is227Th. In some embodiments, the alpha particle-emitting radionuclide is149Tb. In some embodiments, the conjugate comprises225Ac. In some embodiments, the conjugate comprises two225Ac radionuclides. In some embodiments, the radionuclide is no-carrier added (i.e., non-carrier-added or n.c.a.)177Lu. In some embodiments, the radionuclide is no-carrier added (i.e., non-carrier-added or n.c.a.)225Ac. In some embodiments, the radionuclide is177Lu free of long-lived radioactive contaminants and byproducts. In some embodiments, the conjugate comprises two177Lu radionuclides. In some embodiments, the radionuclide is a non-carrier-added radionuclide. In some embodiments, the radionuclide is a pseudo- radiometal. In some embodiments, the pseudo-radiometal is aluminum -[18F]fluoride ([18F]AlF) complex.

[0191] In some embodiments, the radiopharmaceutical conjugate described herein comprises aAttorney Docket No.01277-0079-00PCT radionuclide selected from62Cu,64Cu,67Cu,90Y,109Pd,111Ag,134Ce,149Pm,153Sm,166Ho,99mTc,67Ga,68Ga,111In,90Y,177Lu,186Re,188Re,197Au,198Au,199Au,105Rh,165Ho,161Tb,149Pm,153Pm,44Sc,47Sc,213Po,212Pb,209Bi,212Bi,213Bi,225Ac,117mSn,67Ga,149Tb,152Tb,167Tm,175Yb,223Ra,223Fr,227Th,229Th,201Tl,148Gd,160Gd,148Nd,89Sr, and89Zr. In some embodiments, the radionuclide is selected from62Cu,64Cu,67Cu,68Ga,89Zr,90Y,99mTc,105Rh,111In,134Ce,148Gd,149Tb,152Tb,153Pm,167Tm,175Yb,177Lu,209Bi,212Pb,213Po,213Bi,223Ra,223Fr,227Th,225Ac, and229Th. In some embodiments, the radionuclide is225Ac. In some embodiments, the radionuclide is a decay daughter of225Ac such as221Fr,217At,213Bi,213Po,209Tl,209Pb, or209Bi. In some embodiments, the radiopharmaceutical conjugate comprises two225Ac radionuclides. In some embodiments, the radionuclide is177Lu. In some embodiments, the radiopharmaceutical conjugate comprises two177Lu radionuclides.

[0192] In some embodiments, the radiopharmaceutical conjugate described herein comprises a beta particle-emitting radionuclide. In some embodiments, the radiopharmaceutical conjugate comprises a beta particle-emitting radionuclide bound to the metal chelator. In some embodiments, the beta particle- emitting radionuclide is Cu-67, Lu-177, Y-90, Rh-105, Yb-175, Tm-167, Tb-161, Pm-153, Sm-153, or In-111. In some embodiments, the beta particle-emitting radionuclide is copper-67, rhodium-105, ytterbium-175, thulium-167, promethium-153, yttrium-90, samarium-153, or lutetium-177. In some embodiments, the beta particle emitting radionuclide is copper-67, yttrium-90, samarium-153, or lutetium-177. In some embodiments, the beta particle emitting radionuclide is lutetium-177.

[0193] In some embodiments, the radiopharmaceutical conjugate described herein comprises a gamma particle-emitting radionuclide. In some embodiments, the radiopharmaceutical conjugate comprises a gamma particle-emitting radionuclide bound to the metal chelator. In some embodiments, the gamma particle-emitting radionuclide is indium-111 or tin-117m.

[0194] In some embodiments, the radiopharmaceutical conjugate described herein comprises a positron particle-emitting radionuclide. In some embodiments, the radiopharmaceutical conjugate comprises a positron particle-emitting radionuclide bound to the metal chelator. In some embodiments, the positron- emitting radionuclide is gallium-68, copper-61, copper-62, copper-64, zirconium-89, or terbium-152. In some embodiments, the radionuclide is zirconium-89. In some embodiments, the radionuclide is gallium- 68.

[0195] In some embodiments, a conjugate described herein comprises a radionuclide suitable for imaging or diagnostic purposes. In some embodiments, the radionuclide suitable for imaging is selected from62Cu,64Cu,89Zr,134Ce,152Tb,68Ga,111In, and99mTc. In some embodiments, the radionuclide is suitable PET imaging. In some embodiments, the radionuclide suitable for PET imaging is selected from62Cu,64Cu,89Zr,134Ce,152Tb, and68Ga. In some embodiments, the radionuclide is suitable for SPECT imaging. In some embodiments, the radionuclide suitable for SPECT imaging is selected from111In and99mTc.

[0196] In some embodiments, radiopharmaceutical conjugates described herein do not contain any hot radionuclide, i.e., a cold conjugate. For example, in some cases, a radionuclide can be replaced with a surrogate (e.g.,225Ac replaced with lanthanum) for testing and experimental purposes. In someAttorney Docket No.01277-0079-00PCT embodiments, hot lutetium (Lu-177) is replaced with a cold lutetium (Lu-175).

[0197] In some embodiments, a radiopharmaceutical conjugate disclosed herein comprises a pseudo- radiometal, for example, an aluminum-18F complex. In some embodiments, the aluminum-18F complex is bound to a metal chelator. Conjugates Comprising Non-Radioactive Drugs

[0198] In one aspect, described herein is a conjugate comprising an SSTR binding peptide as described herein (e.g., a peptide of SEQ ID NO: 1-85), a non-radioactive drug, and optionally a linker. In some embodiments, the conjugate further comprises both a metal chelator and optionally a radionuclide bound to the metal chelator, and a non-radioactive drug. In some embodiments, the conjugate comprises an SSTR binding peptide herein (e.g., a peptide of SEQ ID NO: 1-85), a non-radioactive drug, and optionally a linker connecting the SSTR binding peptide to the non-radioactive drug. The non-radioactive drug can be a toxin. In some embodiments, the toxin is selected from pseudomonas exotoxin (PE), deBouganin, Bouganin, diphtheria toxin (DT) and ricin. In some embodiments, the non-radioactive drug can be a chemotherapy agent.

[0199] The non-radioactive drug can be a cytotoxic drug. Exemplary cytotoxic drugs include aplidin, azaribine, anastrozole, azacytidine, bleomycin, bortezomib, bryostatin-1, busulfan, calicheamycin, camptothecin, 10-hydroxycamptothecin, carmustine, celebrex, chlorambucil, cisplatin, irinotecan (CPT- 11), SN-38, carboplatin, cladribine, cyclophosphamide, cytarabine, dacarbazine, docetaxel, dactinomycin, daunomycin glucuronide, daunorubicin, dexamethasone, diethylstilbestrol, doxorubicin, 2- pyrrolinodoxorubicin (2P-DOX), cyano-morpholino doxorubicin, doxorubicin glucuronide, epirubicin glucuronide, ethinyl estradiol, estramustine, etoposide, etoposide glucuronide, etoposide phosphate, floxuridine (FUdR), 3′,5′-O-dioleoyl-FudR (FUdR-dO), fludarabine, flutamide, fluorouracil, fluoxymesterone, gemcitabine, hydroxyprogesterone caproate, hydroxyurea, idarubicin, ifosfamide, L- asparaginase, leucovorin, lomustine, mechlorethamine, medroprogesterone acetate, megestrol acetate, melphalan, mercaptopurine, 6-mercaptopurine, methotrexate, mitoxantrone, mithramycin, mitomycin, mitotane, phenyl butyrate, prednisone, procarbazine, paclitaxel, pentostatin, PSI-341, semustine streptozocin, tamoxifen, taxanes, taxol, testosterone propionate, thalidomide, thioguanine, thiotepa, teniposide, topotecan, uracil mustard, velcade, vinblastine, vinorelbine, vincristine, ricin, abrin, ribonuclease, onconase, rapLR1, DNase I, Staphylococcal enterotoxin-A, pokeweed antiviral protein, gelonin, diphtheria toxin, Pseudomonas exotoxin, Pseudomona endotoxin, or combinations of these.

[0200] In some embodiments, the non-radioactive drug is selected from duocarmycin and its analogues, dolastatins, combretastatin, calicheamicin, N-acetyl-□-calicheamycin (CMC), a calicheamycin derivative, maytansine and analogues thereof, DM-I, auristatin E, auristatin EB (AEB), auristatin EFP (AEFP), monomethyl auristatin E (MMAE), monomethyl auristatin F (MMAF), tubulysin, disorazole, the epothilones, Paclitaxel, docetaxel, Topotecan, echinomycin, estramustine, cemadotine, eleutherobin, methopterin, actinomycin, daunorubicin, the daunorubicin conjugates, mitomycin C, mitomycin A, vincristine, retinoic acid, camptothecin, a camptothecin derivative, SN38, maytansine, a derivative of theAttorney Docket No.01277-0079-00PCT maytansinoid type, DM1, DM4, TK1, amanitin, a pyrrolobenzodiazepine, a pyrrolobenzodiazepine dimer, methotrexate, ilomedine, aspirin, an IMIDs, lenalidomide, pomalidomide.

[0201] In some embodiments, the non-radioactive drug is a polypeptide, a small molecule compound, a cell, a polynucleotide, a magnetic nanocluster, a nanoparticle, or a boron cluster.

[0202] In some embodiments, the non-radioactive drug is a polypeptide. In some embodiments, the non- radioactive drug is an antibody, a nanobody, or a functional fragment thereof. In some embodiments, the non-radioactive drug is a peptide ligand.

[0203] In some embodiments, the non-radioactive drug is a small molecule compound. In some embodiments, the small molecule therapeutic is a kinase inhibitor, an apoptosis inducer, a PROTAC, or a molecular glue. In some embodiments, the non-radioactive drug is an antineoplastic agent. In some embodiments, the antineoplastic agent is selected from an auristatin, a maytansinoid, a tubulysin, a cryptophycin, a hemisaterlin, a cemadotin, a rhizoxin, a discodermolide, a pyrrolobenzodiazepine, a duocarmycin, a calicheamicin, a camptothecin, an indolinobenzodiazepine, or an amatoxin. In some embodiments, the non-radioactive drug is a cell therapy such as an immune cell therapy or an engineered cell therapy.

[0204] In some embodiments, the non-radioactive drug is a polynucleotide such as a DNA or RNA oligonucleotide. In some embodiments, the non-radioactive drug is an aptamer. In some embodiments, the non-radioactive drug is a ligand which binds to a second protein. In some embodiments, the second protein is CD137. In some embodiments, the ligand is a vitamin. Amino Acids

[0205] The structures of exemplary unnatural amino acids that are present in Table 1, 2, 2A, 2B, and 2C can be found below. As described in Table 1, 2, or other tables, abbreviations have the following meanings: Upper case and lower case “D” means D-amino acids, e.g., D-Trp or dTrp refers to D-tryptophan; Me refers to a methyl group, e.g., NMe-Hcy represents N-Methyl- homocysteine (i.e., methyl-homocysteine); Ala or A refer to alanine; Asn or N refer to asparagine; Glu or E refer to glutamic acid; Asp or D refer to aspartic acid; Cys or C refer to cysteine; Gln or Q refer to glutamine; Gly or G refer to glycine; His or H refer to histidine; Ile or I refer to isoleucine; Leu or L refer to leucine; Lys or K refer to lysine; Phe or F refer to phenylalanine; Pro or P refer to proline; Ser or S refer to serine; Thr or T refer to threonine; Trp or W refer to tryptophan; Tyr or Y refer to tyrosine; and Val or V refer to valine.

[0206] Unless otherwise stated in the present specification, the following abbreviations for non-natural amino acids are used according to the following meanings: (3-Azetidine)-hAla 2-amino-4-(azetidin-3-yl)butanoic acid, such as (S)-2-amino-4-(azetidin-3- yl)butanoic acid; (5-Cl) D-Trp (R)-2-amino-3-(5-chloro-1H-indol-3-yl)propanoic acid; (5-Me) D-Trp (R)-2-amino-3-(5-methyl-1H-indol-3-yl)propanoic acid;Attorney Docket No.01277-0079-00PCT (5-MeO) D-Trp (R)-2-amino-3-(5-methoxy-1H-indol-3-yl)propanoic acid; (6-Me) D-Trp (R)-2-amino-3-(6-methyl-1H-indol-3-yl)propanoic acid; (7-Me) D-Trp (R)-2-amino-3-(7-methyl-1H-indol-3-yl)propanoic acid; (D / L)Hly 2,6-diamino-6-hydroxyhexanoic acid; (R-βBenzyl) D-Trp (2R,3R)-2-amino-3-(1H-indol-3-yl)-4-phenylbutanoic acid; (R-βBenzyl) Trp (2S,3R)-2-amino-3-(1H-indol-3-yl)-4-phenylbutanoic acid; (R-βCyclopropyl) D- (2R,3R)-2-amino-3-cyclopropyl-3-(1H-indol-3-yl)propanoic acid; Trp (R-βCyclopropyl) Trp (2S,3R)-2-amino-3-cyclopropyl-3-(1H-indol-3-yl)propanoic acid; (R-βIsobutyl) D-Trp (2R,3R)-2-amino-3-(1H-indol-3-yl)-5-methylhexanoic acid; (R-βIsobutyl) Trp (2S,3R)-2-amino-3-(1H-indol-3-yl)-5-methylhexanoic acid; (R-βIsopropyl) D-Trp (2R,3R)-2-amino-3-(1H-indol-3-yl)-4-methylpentanoic acid; (R-βIsopropyl) Trp (2S,3R)-2-amino-3-(1H-indol-3-yl)-4-methylpentanoic acid; (R-βMe) D-Trp (2R,3R)-2-amino-3-(1H-indol-3-yl)butanoic acid; (R-βMe) Phe (2S,3R)-2-amino-3-phenylbutanoic acid; (R-βMe) Trp (2S,3R)-2-amino-3-(1H-indol-3-yl)butanoic acid; (R-βNeopentyl) D-Trp (2R,3R)-2-amino-3-(1H-indol-3-yl)-5,5-dimethylhexanoic acid; (R-βNeopentyl) Trp (2S,3R)-2-amino-3-(1H-indol-3-yl)-5,5-dimethylhexanoic acid; (R-βPhenyl) D-Trp (2R,3R)-2-amino-3-(1H-indol-3-yl)-3-phenylpropanoic acid; (R-βPhenyl) Trp (2S,3R)-2-amino-3-(1H-indol-3-yl)-3-phenylpropanoic acid; (R-βPropyl) D-Trp (2R,3R)-2-amino-3-(1H-indol-3-yl)hexanoic acid; (R-βPropyl) Trp (2S,3R)-2-amino-3-(1H-indol-3-yl)hexanoic acid; (R-βSecbutyl) D-Trp (2R,3R)-2-amino-3-(1H-indol-3-yl)-4-methylhexanoic acid; (R-βSecbutyl) Trp (2S,3R)-2-amino-3-(1H-indol-3-yl)-4-methylhexanoic acid; (S-βBenzyl) D-Trp (2R,3S)-2-amino-3-(1H-indol-3-yl)-4-phenylbutanoic acid; (S-βBenzyl) Trp (2S,3S)-2-amino-3-(1H-indol-3-yl)-4-phenylbutanoic acid; (S-βCyclopropyl) D- (2R,3S)-2-amino-3-cyclopropyl-3-(1H-indol-3-yl)propanoic acid; Trp (S-βCyclopropyl) Trp (2S,3S)-2-amino-3-cyclopropyl-3-(1H-indol-3-yl)propanoic acid; (S-βIsobutyl) D-Trp (2R,3S)-2-amino-3-(1H-indol-3-yl)-4-methylpentanoic acid; (S-βIsobutyl) Trp (2S,3S)-2-amino-3-(1H-indol-3-yl)-4-methylpentanoic acid; (S-βIsopropyl) D-Trp (2R,3S)-2-amino-3-(1H-indol-3-yl)-4-methylpentanoic acid; (S-βIsopropyl) Trp (2S,3S)-2-amino-3-(1H-indol-3-yl)-4-methylpentanoic acid; (S-βMe) D-Trp (2R,3S)-2-amino-3-(1H-indol-3-yl)butanoic acid; (S-βMe) Phe (2S,3S)-2-amino-3-phenylbutanoic acid; (S-βMe) Trp (2S,3S)-2-amino-3-(1H-indol-3-yl)butanoic acid; (S-βNeopentyl) D-Trp (2R,3S)-2-amino-3-(1H-indol-3-yl)-5,5-dimethylhexanoic acid;Attorney Docket No.01277-0079-00PCT (S-βNeopentyl) Trp (2S,3S)-2-amino-3-(1H-indol-3-yl)-5,5-dimethylhexanoic acid; (S-βPhenyl) D-Trp (2R,3S)-2-amino-3-(1H-indol-3-yl)-3-phenylpropanoic acid; (S-βPhenyl) Trp (2S,3S)-2-amino-3-(1H-indol-3-yl)-3-phenylpropanoic acid; (S-βPropyl) D-Trp (2R,3S)-2-amino-3-(1H-indol-3-yl)hexanoic acid; (S-βPropyl) Trp (2S,3S)-2-amino-3-(1H-indol-3-yl)hexanoic acid; (S-βSecbutyl) D-Trp (2R,3S)-2-amino-3-(1H-indol-3-yl)-4-methylhexanoic acid; (S-βSecbutyl) Trp (2S,3S)-2-amino-3-(1H-indol-3-yl)-4-methylhexanoic acid; (βGeminal methyl) D- (R)-2-amino-3-(1H-indol-3-yl)-3-methylbutanoic acid; Trp (βGeminal methyl) Trp (S)-2-amino-3-(1H-indol-3-yl)-3-methylbutanoic acid; 2-aza-Trp 2-amino-3-(1H-indazol-3-yl)propanoic acid, such as (R)-2-amino-3-(1H- indazol-3-yl)propanoic acid; 2Nal L-3-(2-naphthyl)alanine; 3,3-diPhe 2-amino-3,3-diphenylpropanoic acid, such as (S)-2-amino-3,3- diphenylpropanoic acid; 3,5-diF Tyr 2-amino-3-(3,5-difluoro-4-hydroxyphenyl)propanoic acid, such as (S)-2- amino-3-(3,5-difluoro-4-hydroxyphenyl)propanoic acid; 3MeO-Phe 2-amino-3-(3-methoxyphenyl)propanoic acid, such as (S)-2-amino-3-(3- methoxyphenyl)propanoic acid; 3N-Tyr 2-amino-3-(6-hydroxypyridin-3-yl)propanoic acid, such as (S)-2-amino-3- (6-hydroxypyridin-3-yl)propanoic acid; 3Pal 2-amino-3-(pyridin-3-yl)propanoic acid, such as (S)-2-amino-3-(pyridin-3- yl)propanoic acid; 4Amp (Amp) 4-aminomethylphenylalanine;DAgl(N-Beta- (R)-2-amino-2-(N-methylbenzamido)acetic acid; Me,benzoyl)LAgl(N-Beta- (S)-2-amino-2-(N-methylbenzamido)acetic acid; Me,benzoyl) 4-aminomethyl Phe 2-amino-3-(4-(aminomethyl)phenyl)propanoic acid, such as (S)-2-amino-3- (4-(aminomethyl)phenyl)propanoic acid; 4Aph 4-aminophenyl propanoic acid; 4-aza-Trp 2-amino-3-(1H-pyrrolo[3,2-b]pyridin-3-yl)propanoic acid, such as (R)-2- amino-3-(1H-pyrrolo[3,2-b]pyridin-3-yl)propanoic acid; 4Iamp (S)-2-amino-3-(4-((isopropylamino)methyl)phenyl)propanoic acid; 4MeO-Phe 2-amino-3-(4-methoxyphenyl)propanoic acid, such as (S)-2-amino-3-(4- methoxyphenyl)propanoic acid; 4-oxa Lys O-(2-aminoethyl)-serine, such as O-(2-aminoethyl)-L-serine;Attorney Docket No.01277-0079-00PCT 4-oxa NMe-Lys O-(2-aminoethyl)-N-methyl-serine, such as O-(2-aminoethyl)-N-methyl-L- serine; 4Pal 2-amino-3-(pyridin-4-yl)propanoic acid, such as (S)-2-amino-3-(pyridin-4- yl)propanoic acid; 5-aza-Trp 2-amino-3-(1H-pyrrolo[3,2-c]pyridin-3-yl)propanoic acid, such as (R)-2- amino-3-(1H-pyrrolo[3,2-c]pyridin-3-yl)propanoic acid; 5FY / 5F-Tyr 2-amino-3-(3-fluoro-4-hydroxyphenyl)propanoic acid, such as (S)-2-amino- 3-(3-fluoro-4-hydroxyphenyl)propanoic acid; 6-aza-Trp 2-amino-3-(1H-pyrrolo[2,3-c]pyridin-3-yl)propanoic acid, such as (R)-2- amino-3-(1H-pyrrolo[2,3-c]pyridin-3-yl)propanoic acid; 7-aza-Trp 2-amino-3-(1H-pyrrolo[2,3-b]pyridin-3-yl)propanoic acid, such as (R)-2- amino-3-(1H-pyrrolo[2,3-b]pyridin-3-yl)propanoic acid; Alt allothreonine, such as L-allothreonine; Aph(Hor) 2-amino-3-(4-(2,6-dioxohexahydropyrimidine-4- carboxamido)phenyl)propanoic acid, such as (2S)-2-amino-3-(4-(2,6- dioxohexahydropyrimidine-4-carboxamido)phenyl)propanoic acid; azaLys amino(4-aminobutyl)carbamic acid; Aza-Trp azatryptophan; Bzt 2-amino-3-(benzo[b]thiophen-3-yl)propanoic acid, such as (S)-2-amino-3- (benzo[b]thiophen-3-yl)propanoic acid; Cba 2-amino-3-cyclobutylpropanoic acid, such as (S)-2-amino-3- cyclobutylpropanoic acid; Cba3N 2-amino-3-(azetidin-3-yl)propanoic acid, such as (S)-2-amino-3-(azetidin-3- yl)propanoic acid; Cbg 2-amino-2-cyclobutylacetic acid, such as (S)-2-amino-2-cyclobutylacetic acid; Cbm Carbamoyl; Cha 2-amino-3-cyclohexylpropanoic acid, such as (S)-2-amino-3- cyclohexylpropanoic acid; Cha4N 2-amino-3-(piperidin-4-yl)propanoic acid, such as (S)-2-amino-3-(piperidin- 4-yl)propanoic acid; Cha4NH2 2-amino-3-(4-aminocyclohexyl)propanoic acid, such as (S)-2-amino-3-(4- aminocyclohexyl)propanoic acid; Chg4N 2-amino-2-(piperidin-4-yl)acetic acid, such as (S)-2-amino-2-(piperidin-4- yl)acetic acid; Cpg 2-amino-2-cyclopentylacetic acid, such as (S)-2-amino-2-cyclopentylacetic acid;Attorney Docket No.01277-0079-00PCT D-6F-Trp (R)-2-amino-3-(6-fluoro-1H-indol-3-yl)propanoic acid; D-Aph(Cbm) (R)-2-amino-3-(4-ureidophenyl)propanoic acid; D-Lys D-lysine; D-Phg (R)-2-amino-2-phenylacetic acid; D-Tpi (R)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylic acid; D-Trp D-tryptophan; D-Tyr D-tyrosine; F2CON 2-amino-3-(2-carbamoylphenyl)propanoic acid, such as (S)-2-amino-3-(2- carbamoylphenyl)propanoic acid; F3CON 2-amino-3-(3-carbamoylphenyl)propanoic acid, such as (S)-2-amino-3-(3- carbamoylphenyl)propanoic acid; F4COO 4-(2-amino-2-carboxyethyl)benzoic acid, such as (S)-4-(2-amino-2- carboxyethyl)benzoic acid; G(cPr) 2-amino-2-cyclopropylacetic acid, such as (S)-2-amino-2-cyclopropylacetic acid; L-DOPA 2-amino-3-(3,4-dihydroxyphenyl)propanoic acid, such as (S)-2-amino-3- (3,4-dihydroxyphenyl)propanoic acid; Lys(diMe) N6,N6-dimethyl-lysine, such as N6,N6-dimethyl-L-lysine; Lys(iPr) N6-isopropyl-lysine, such as N6-isopropyl-L-lysine; Lys(Me) N6-methyl-lysine, such as N6-methyl-L-lysine; Lys(triMe) N6,N6,N6-trimethyl-lysine, such as N6,N6,N6-trimethyl-L-lysine; Mpd 2-amino-3-(methyl(phenyl)amino)propanoic acid, such as (S)-2-amino-3- (methyl(phenyl)amino)propanoic acid; mTyr 2-amino-3-(3-hydroxyphenyl)propanoic acid, such as (S)-2-amino-3-(3- hydroxyphenyl)propanoic acid; Nlys (4-aminobutyl)glycine; NMe-Ala methyl-alanine, such as methyl-L-alanine; NMe-Amp 2-(methylamino)heptanedioic acid, such as (S)-2-(methylamino)heptanedioic acid; NMe-Asp methyl-L-aspartate, such as methyl-L-aspartate; NMe-Azidolysine N6-diazo-N2-methyl-L-lysine, such as N6-diazo-N2-methyl-lysine; NMe-Cha4N 2-amino-3-(piperidin-4-yl)propanoic acid, such as (S)-2-amino-3-(piperidin- 4-yl)propanoic acid; NMe-Chg4N 2-amino-2-(piperidin-4-yl)acetic acid, such as (S)-2-amino-2-(piperidin-4- yl)acetic acid; NMe-Cys methyl-cysteine, such as methyl-L-cysteine;Attorney Docket No.01277-0079-00PCT NMe-Dab 4-amino-2-(methylamino)butanoic acid, such as (S)-4-amino-2- (methylamino)butanoic acid; NMe-Dap 3-amino-2-(methylamino)propanoic acid, such as (S)-3-amino-2- (methylamino)propanoic acid; NMe-D-Hcy methyl-D-homocysteine; NMe-dLys methyl-D-lysine; NMe-D-Trp methyl-D-tryptophan; NMe-Glu methyl-glutamate, such as methyl-L-glutamate; NMe-Hcy methyl-homocysteine, such as methyl-L-homocysteine; NMe-hGlu 2-(methylamino)hexanedioic acid, such as (S)-2-(methylamino)hexanedioic acid; NMe-hHcy 5-mercapto-2-(methylamino)pentanoic acid, such as (S)-5-mercapto-2- (methylamino)pentanoic acid; NMe-hLys 7-amino-2-(methylamino)heptanoic acid, such as (S)-7-amino-2- (methylamino)heptanoic acid; NMe-Hse methyl-homoserine, such as methyl-L-homoserine; NMe-Hse(Se) methyl-homoselenocysteine, such as methyl-L-homoselenocysteine; NMe-Lys methyl-lysine, such as methyl-L-lysine; NMe-Nle methyl-norleucine, such as methyl-L-norleucine NMe-Orn 5-amino-2-(methylamino)pentanoic acid, such as (S)-5-amino-2- (methylamino)pentanoic acid; NMe-Phe methyl-phenylalanine, such as Methyl-L-phenylalanine; NMe-propargyl alanine 2-methyl-2-(methylamino)pent-4-ynoic acid; NMe-propargyl glycine 2-(methylamino)pent-4-ynoic acid; Nva(NH-NH2) 2-amino-5-hydrazineylpentanoic acid, such as (S)-2-amino-5- hydrazineylpentanoic acid; Phg 2-amino-2-phenylacetic acid, such as (S)-2-amino-2-phenylacetic acid; Pic4 4-aminopiperidine-4-carboxylic acid; PipzaA 2-amino-3-(piperazin-1-yl)propanoic acid, such as (S)-2-amino-3-(piperazin- 1-yl)propanoic acid; Ser(3-azetidine) O-(azetidin-3-yl)-serine, such as O-(azetidin-3-yl)-L-serine; Ser(Ph) O-phenyl-serine, such as O-phenyl-L-serine; threo(2R,3S)CβMe O-methyl-D-threonine; Tme O-methyl-threonine, such as O-methyl-L-threonine; trans-Hyp L-hydroxyproline; Tyr(OBn) 2-amino-3-(4-(benzyloxy)phenyl)propanoic acid, such as (S)-2-amino-3-(4- (benzyloxy)phenyl)propanoic acid; andAttorney Docket No.01277-0079-00PCT Tyr(Phe) 2-amino-3-(4-phenoxyphenyl)propanoic acid, such as (S)-2-amino-3-(4- phenoxyphenyl)propanoic acid.

[0207] Amino acids used in the disclosed peptides can be substituted with similar amino acids. In some embodiments, an amino acid can be substituted with another amino acid with similar hydrophobicity. In some embodiments, an amino acid can be substituted with another amino acid with similar hydrophilicity. In some embodiments, an amino acid can be substituted with another amino acid with similar size. In some embodiments, an amino acid can be substituted with another amino acid with similar charge. In some embodiment, an amino acid can be substituted with another amino acid with a similar functional group. In some embodiments, an amino acid can be substituted with another amino acid with the same functional group.

[0208] In some embodiments, an amino acid described herein can be replaced with a derivative thereof. Examples of an amino acid substitution or derivative include derivatives having an amine, amide, ester, or carboxyl group as the C-terminus and / or N-terminus thereof. Additional examples of amino acid / peptide derivatives include those obtained by modification such as phosphorylation, alkylation (e.g., methylation), acetylation, adenylylation, ADP-ribosylation, or glycosylation and fused protein obtained by fusion with another peptide or protein. These derivatives can be prepared by those skilled in the art in a known manner or a method based thereon. An amino acid derivative further encompasses the amino acids that have the same functional groups but with different lengths of the side chain (e.g., LysAc vs. OrnAc and cysteine vs. homocysteine). An amino acid derivative further encompasses amino acids with a different aromatic moiety compared to the canonical amino acid (e.g., the indole in tryptophan vs the 7- azaindole in 7-AzaTrp; the phenyl in phenylalanine vs the pyridine in 4Py). An amino acid derivative further encompasses amino acids with optional substituents, i.e., optionally substituted amino acid.

[0209] In some embodiments, a derivative of an amino acid is selected from amino acids having one, two or three substituents based on the amino acid, and wherein the substituents are independently selected from halogen, -CN, -NH2, -NH(C1-C3alkyl), -N(C1-C3alkyl)2, oxo, -OH, -CO2H, -CO2-C1- C3alkyl, -C(=O)NH2, -C(=O)NH(C1-C3alkyl), -C(=O)N(C1-C3alkyl)2, -S(=O)2NH2, -S(=O)2NH(C1- C3alkyl), -S(=O)2N(C1-C3alkyl)2, C1-C6alkyl, C1-C6heteroalkyl, C1-C6alkoxy, C6-C10aryl, C3-C6cycloalkyl, 6- to 10- membered heterocycloalkyl, and 6- to 10- membered heteroaryl. In some embodiments, the derivative is selected from amino acids having one or two substituents based on the amino acid, and wherein the substituents are independently selected from halogen, -CN, -NH2, -NH(C1- C3alkyl), -N(C1-C3alkyl)2, oxo, -OH, -CO2H, -CO2-C1-C3alkyl, -C(=O)NH2, -C(=O)NH(C1-C3alkyl), - C(=O)N(C1-C3alkyl)2, and C1-C6alkyl. In some embodiments, the derivative is selected from amino acids having one or two substituents based on the amino acid, and wherein the substituents are independently selected from halogen, -CN, -NH2, -NH(C1-C3alkyl), -N(C1-C3alkyl)2, and C1-C6alkyl. In some embodiments, the derivative is selected from amino acids having one or two substituents based on the amino acid, and wherein the substituents are independently selected from C1-C6alkyl.

[0210] In some embodiments, a derivative of an amino acid is selected from amino acids that have theAttorney Docket No.01277-0079-00PCT similar hydrophilicity or hydrophobicity compared to the amino acid. Thus, in some embodiments, a positively charged amino acid can be a derivative of another positively charged amino acid. In some embodiments, a negatively charged amino acid can be a derivative of another negatively charged amino acid. In some embodiments, a zwitterionic amino acid can be a derivative of another zwitterionic amino acid.

[0211] In some embodiments, a hydrophilic amino acid has an electrically charged side chain. In some embodiments, a hydrophilic amino acid has a positive charge. In some embodiments, a hydrophilic amino acid has a negative charge. In some embodiments, a hydrophilic amino acid is zwitterionic (e.g., KCOpipzaa). In some embodiments, a hydrophilic amino acid comprises a -OH, COOH, -NH- or NH2moiety. In some embodiments, a hydrophilic amino acid comprises -OH, -C(O)OH, -NHC(=NH)NH2, - NHC(O)NH2, -C(O)NH2, or -NHC(O)CH3.In some embodiments, a hydrophilic amino acid comprises a side chain of C1C6hydroxyalkyl, C1C6aminoalkyl, -C0-6alkylene-NH-C(=NH)-NH2, -C0-6alkylene-CO- NH2, -C0-6alkylene-COOH, or -NH-CO-C1-6alkyl.

[0212] In some embodiments, a hydrophobic amino acid is not charged. In some embodiments, a hydrophobic amino acid contains at least 2 contiguous carbon atoms. In some embodiments, a hydrophobic amino acid comprises at least 3 contiguous carbon atoms, either linear or branched. In some embodiments, a hydrophobic amino acid comprises at least 4 contiguous carbon atoms, either linear or branched. In some embodiments, a hydrophobic amino acid comprises at least 5 contiguous carbon atoms, either linear or branched. In some embodiments, a hydrophobic amino acid comprises an ethylene moiety in the side chain. In some embodiments, a hydrophobic amino acid comprises a propylene moiety in the side chain. In some embodiments, a hydrophobic amino acid comprises a butylene moiety in the side chain. In some embodiments, a hydrophobic amino acid comprises phenyl moiety. In some embodiments, a hydrophobic amino acid comprises a heteroaryl moiety. In some embodiments, a hydrophobic amino acid is Trp, Tyr, Phe, or derivatives thereof.

[0213] In some embodiments, a derivative of an amino acid is selected from amino acids that have the same functional group as the amino acid, and wherein the derivative has a different length of a side chain compared to the amino acid. In some embodiments, a derivative of an amino acid is selected from amino acids that have the same charge compared to the amino acid. In some embodiments, a derivative of an amino acid is selected from amino acids that have the same polarity compared to the amino acid. In some embodiments, an amino acid comprising an aromatic group can be a derivative of another amino acid having an aromatic group. In some embodiments, an amino acid comprising a phenyl can be a derivative of another amino acid having a phenyl. In some embodiments, an amino acid comprising a heteroaryl can be a derivative of another amino acid having a heteroaryl.

[0214] In some embodiments, an amino acid comprising a cycloalkyl group can be a derivative of another amino acid having a cycloalkyl group. In some embodiments, an amino acid comprising a heterocycloalkyl group can be a derivative of another amino acid having a heterocycloalkyl group.

[0215] In some embodiments, a derivative of an amino acid is selected from amino acids that have similar polarity and / or charge with the amino acid. For example, in some embodiments, a polar,Attorney Docket No.01277-0079-00PCT uncharged amino acid can be a derivative of another polar, uncharged amino acid (e.g., Hgn, Q, S, T, Qglucamine),

[0216] In some embodiments, a derivative of an amino acid has the same number of hydrogen donor as the amino acid. In some embodiments, a derivative of an amino acid has the same number of hydrogen acceptor as the amino acid.

[0217] In some embodiments, the derivative has a molecular weight that does not vary for more than 14, 28, 30, 45 or 60 g / mol compared to the amino acid. In some embodiments, the derivative has a molecular weight that does not vary for more than 14 g / mol compared to the amino acid. In some embodiments, the derivative has a molecular weight that does not vary for more than 50 g / mol compared to the amino acid. In some embodiments, the derivative has a molecular weight that does not vary for more than 28 g / mol compared to the amino acid.

[0218] An amino acid derivative further encompasses amino acids wherein a functional group is substituted with another functional group having similar properties, e.g., a cysteine can be substituted with a homocysteine. In some embodiments, an aryl functional group can be substituted with an aryl or heteroaryl group. In some embodiments, a heteroaryl functional group can be substituted with an aryl or heteroaryl group. In some embodiments, an amino functional group can be substituted with an NH(alkyl) group.

[0219] As used herein, the expression “conservative amino acid substitution” refers to a substitution of functionally equivalent or similar amino acids. A conservative amino acid substitution in a peptide brings about a static change to the amino acid sequence of the peptide. For example, one or two or more amino acids having similar polarity act functionally equivalent to each other and bring about a static change in the amino acid sequence of the peptide. In general, a substitution within a certain group may be considered conservative regarding structure and function. However, as is clear to a person having ordinary skill in the art, the role played by a defined amino acid residue may be determined by its implication in the three-dimensional structure of the molecule containing the amino acid. For example, a cysteine residue in an oxidized-type (disulfide) form may have a lower polarity than that of a reduced- type (thiol) form. The long aliphatic part of the arginine side chain may constitute structurally and functionally important features. Furthermore, the side chain (tryptophan, tyrosine, phenylalanine) including an aromatic ring may contribute to ion-aromatic interaction or cation-pi interaction. In such a case, even if the amino acids having these side chains are substituted for amino acids belonging to the acidic or non-polar groups, they may be structurally and functionally conservative. There is a possibility that residues such as proline, glycine, cysteine (disulfide form) have a direct effect on the three- dimensional structure of the main chain and often may not be substituted without structural distortion.

[0220] Conservative amino acid substitution, as shown below, includes specific substitution based on the similarity of side chains (for example, substitutions are described in Lehninger, Biochemistry, Revised 2nd Edition, published in 1975, pp. 73 to 75: L. Lehninger, Biochemistry, 2nd edition, pp. 73 to 75, Worth Publisher, New York (1975)), incorporated herein by reference, and typical substitution.

[0221] Hydrophobic amino acids include amino acids that exhibit hydrophobicity, including alanineAttorney Docket No.01277-0079-00PCT (also referred to as “Ala” or simply “A”), glycine (also referred to as “Gly” or simply “G”), valine (also referred to as “Val” or simply “V”), leucine (also referred to as “Leu” or simply “L”), isoleucine (also referred to as “Ile” or simply “I”), proline (also referred to as “Pro” or simply “P”), phenylalanine (also referred to as “Phe” or simply “F”), tryptophan (also referred to as Trp” or simply “W”), tyrosine (also referred to as “Tyr” or simply “Y”), and methionine (also referred to as “Met” or simply “M”).

[0222] Exemplary hydrophobic amino acids may be further divided into the following groups: ^ Aliphatic amino acids: Amino acids having a fatty acid or hydrogen in the side chain, including e.g., Ala, Gly, Val, Ile, and Leu. ^ Aliphatic / branched-chain amino acids: Amino acids having a branched fatty acid in the side chain, including e.g., Val, Ile, and Leu. ^ Aromatic amino acids: Amino acids having an aromatic ring in the side chain, including e.g., Trp, Tyr, and Phe.

[0223] In some embodiments, a hydrophobic amino acid has a C1-C8alkyl, cycloalkyl, or heterocycloalkyl, wherein the alkyl, cycloalkyl, and heterocycloalkyl are each independently, optionally substituted. In some embodiments, a hydrophobic amino acid has a C1-C8alkyl, cycloalkyl, or heterocycloalkyl, wherein the alkyl, cycloalkyl, and heterocycloalkyl are each unsubstituted. In some embodiments, a hydrophobic amino acid has a C3-C6unsubstituted alkyl.

[0224] Hydrophilic amino acids include amino acids that exhibit hydrophilicity, including e.g., serine (also referred to as “Ser” or simply “S”), threonine (also referred to as “Thr” or simply “T”), cysteine (also referred to as “Cys” or simply “C”), asparagine (also referred to as “Asn” or simply “N”), glutamine (also referred to as “Gln” or simply “Q”), aspartic acid (also referred to as “Asp” or simply “D”), glutamic acid (also referred to as “Glu” or simply “E”), Elysine (also referred to as “Lys” or simply “K”), arginine (also referred to as “Arg” or simply “R”), and histidine (also referred to as “His” or “H”).

[0225] Exemplary hydrophilic amino acids may be further divided into the following groups: ^ Acidic amino acids: Amino acids whose side chains exhibit acidity, including Asp and Glu. ^ Basic amino acids: Amino acids whose side chains exhibit basicity, including Lys, Arg, and His. ^ Neutral amino acids: Amino acids whose side chains exhibit neutrality, including Ser, Thr, Asn, Gln, and Cys.

[0226] Exemplary hydrophilic amino acids include, for example, D, Q, E, S, N, T, C, H, or a derivative thereof.

[0227] Examples of the amino acids include natural protein L-amino acids, unnatural amino acids, and chemically synthesized compounds having properties known in the art as characteristics of an amino acid. Examples of the unnatural amino acids include, but not limited to, α,α-disubstituted amino acids (such as α-methylalanine), N-alkyl-α-amino acids, N-alkyl-β-amino acids, D-amino acids, β-amino acids, and α-hydroxy acids, each having a backbone structure different from that of natural amino acids; amino acids (such as norleucine and homohistidine) having a side-chain structure different from that of natural amino acids; amino acids (such as “homo” amino acids, homophenylalanine, and homohistidine) havingAttorney Docket No.01277-0079-00PCT extra methylene in the side chain thereof; and amino acids (such as cysteic acid) obtained by substituting a carboxylic acid functional amino group in the side chain thereof by a sulfonic acid group.

[0228] The peptides described herein can comprise one or more unnatural amino acids. Unnatural amino acids include, but are not limited to, (1) amino acids corresponding to an amino acid residue on a polypeptide subjected to modification after expression (ex. phosphorylated tyrosine, acetylated lysine, or farnesylated cysteine), (2) amino acids that cannot be used in expression on a ribosome but occur naturally, and (3) artificial amino acids that do not occur naturally (unnatural amino acids). Non-limiting examples of unnatural amino acids include: p-acetyl-L-phenylalanine, p-iodo-L-phenylalanine, p- methoxyphenylalanine, O-methyl-L-tyrosine, p-propargyloxyphenylalanine, p-propargyl-phenylalanine, L-3-(2-naphthyl)alanine, 3-methyl-phenylalanine, O-4-allyl-L-tyrosine, 4-propyl-L-tyrosine, tri-O-acetyl- GlcNAcp-serine, L-Dopa, fluorinated phenylalanine, isopropyl-L-phenylalanine, p-azido-L- phenylalanine, p-acyl-L-phenylalanine, p-benzoyl-L-phenylalanine, Boronophenylalanine, O- propargyltyrosine, L-phosphoserine, phosphonoserine, phosphonotyrosine, p-bromophenylalanine, selenocysteine, p-amino-L- phenylalanine, isopropyl-L-phenylalanine, and azido-lysine (AzK). In some embodiments, the unnatural amino acid is an unnatural analogue of a tyrosine amino acid; an unnatural analogue of a glutamine amino acid; an unnatural analogue of a phenylalanine amino acid; an unnatural analogue of an alanine amino acid; an unnatural analogue of a serine amino acid; an unnatural analogue of a threonine amino acid; an alkyl, aryl, acyl, azido, cyano, halo, hydrazine, hydrazide, hydroxyl, alkenyl, alkynl, ether, thiol, sulfonyl, seleno, ester, thioacid, borate, boronate, phospho, phosphono, phosphine, heterocyclic, enone, imine, aldehyde, hydroxylamine, keto, or amino substituted amino acid; or a combination thereof. In some embodiments, the unnatural amino acid is an amino acid with a photoactivatable cross-linker; a spin-labeled amino acid; a fluorescent amino acid; a metal binding amino acid; a metal-containing amino acid; a photocaged and / or photoisomerizable amino acid; a biotin or biotin-analogue containing amino acid; a keto containing amino acid; an amino acid comprising polyethylene glycol or polyether; a heavy atom substituted amino acid; a chemically cleavable or photocleavable amino acid; an amino acid with an elongated side chain; an amino acid containing a toxic group; a sugar substituted amino acid; a carbon-linked sugar-containing amino acid; a redox-active amino acid; an a-hydroxy containing acid; an amino thio acid; an α, α-disubstituted amino acid; a β- amino acid; a cyclic amino acid other than proline or histidine, or an aromatic amino acid other than phenylalanine, tyrosine or tryptophan.

[0229] Unnatural amino acids include, for example, N-alkyl amino acids in which a natural amino acid described above is N-alkylated, e.g., those modified with lower alkyl groups (for example, of C1 to C5, C1 to C3, and C1) in which the nitrogen forming a peptide bond is branched or not branched. Exemplary N-alkyl amino acids include, e.g., N-ethyl amino acid, N-butyl amino acid, and N-methyl amino acid. Also included are amino acids to which a functional group is further added to the side chain of a natural amino acid or substituted for another functional group (for example, an amino acid having a substitution or an addition in a part such as an arylene group, an alkylene group, or the like of the side chain; an amino acid wherein the arylene group or the alkyl group of the side chain has an increased C-number; anAttorney Docket No.01277-0079-00PCT amino acid having a substitution in the aromatic ring of the side chain; a heterocyclic or condensed cyclic amino acid; or the like). Exemplary N-alkyl amino acids further include, e.g., N-alkyllysine and N- methyllysine.

[0230] In a non-limiting manner, unnatural amino acids include, but are not limited to N-methyl amino acids, (3-Azetidine)-hAla, (5-Cl) D-Trp, (5-Me) D-Trp, (5-MeO) D-Trp, (6-Me) D-Trp, (7-Me) D-Trp, (D / L)Hly, (R-βBenzyl) D-Trp, (R-βBenzyl) Trp, (R-βCyclopropyl) D-Trp, (R-βCyclopropyl) Trp, (R- βIsobutyl) D-Trp, (R-βIsobutyl) Trp, (R-βIsopropyl) D-Trp, (R-βIsopropyl) Trp, (R-βMe) D-Trp, (R- βMe) Phe, (R-βMe) Trp, (R-βNeopentyl) D-Trp, (R-βNeopentyl) Trp, (R-βPhenyl) D-Trp, (R-βPhenyl) Trp, (R-βPropyl) D-Trp, (R-βPropyl) Trp, (R-βSecbutyl) D-Trp, (R-βSecbutyl) Trp, (S-βBenzyl) D-Trp, (S-βBenzyl) Trp, (S-βCyclopropyl) D-Trp, (S-βCyclopropyl) Trp, (S-βIsobutyl) D-Trp, (S-βIsobutyl) Trp, (S-βIsopropyl) D-Trp, (S-βIsopropyl) Trp, (S-βMe) D-Trp, (S-βMe) Phe, (S-βMe) Trp, (S- βNeopentyl) D-Trp, (S-βNeopentyl) Trp, (S-βPhenyl) D-Trp, (S-βPhenyl) Trp, (S-βPropyl) D-Trp, (S- βPropyl) Trp, (S-βSecbutyl) D-Trp, (S-βSecbutyl) Trp, (βGeminal methyl) D-Trp, (βGeminal methyl) Trp, 2-aza-Trp, 3,3-diPhe, 3,5-diF Tyr, 3MeO-Phe, 3N-Tyr, 3Pal, 4-aminomethyl Phe, 4-aza-Trp, 4MeO- Phe, 4-oxa Lys, 4-oxa NMe-Lys, 4Pal, 5-aza-Trp, 5FY / 5F-Tyr, 6-aza-Trp, 7-aza-Trp, Alt, Aph(Hor), azaLys, Aza-Trp, Bzt, Cba, Cba3N, Cbg, Cha, Cha4N, Cha4NH2, Chg4N, Cpg, D-6F-Trp, D-Aph(Cbm), D-Lys, D-Phg, D-Tpi, D-Trp, D-Tyr, F2CON, F3CON, F4COO, G(cPr), L-DOPA, Lys(diMe), Lys(iPr), Lys(Me), Lys(triMe), Mpd, mTyr, Nlys, NMe-Ala, NMe-Amp, NMe-Asp, NMe-Azidolysine, NMe- Cha4N, NMe-Chg4N, NMe-Cys, NMe-Dab, NMe-Dap, NMe-D-Hcy, NMe-dLys, NMe-D-Trp, NMe- Glu, NMe-Hcy, NMe-hGlu, NMe-hHcy, NMe-hLys, NMe-Hse, NMe-Hse(Se), NMe-Lys, NMe-Nle, NMe-Orn, NMe-Phe, NMe-propargyl alanine, NMe-propargyl glycine, Nva(NH-NH2), Phg, Pic4, PipzaA, Ser(3-azetidine), Ser(Ph), Tme, trans-Hyp, Tyr(OBn), Tyr(Phe), and the like. Note that D-amino acids such as d-alanine may be classified as D-amino acids, but they may also be classified according to the properties of their side chains, and N-methyl amino acids may be classified as N-alkyl amino acids and may also be classified according to the property of the side chain.

[0231] In some embodiments, the unnatural amino acids incorporated into the peptides include one or more of: 1) a ketone functional group (as found in para or meta acetyl-phenylalanine) that can be specifically reacted with hydrazines, hydroxylamines and their derivatives (Addition of the keto functional group to the genetic code of Escherichia coli. Wang L, Zhang Z, Brock A, Schultz P G. Proc Natl Acad Sci USA.2003 Jan.7; 100(1):56-61; Bioorg Med Chem Lett.2006 Oct.15; 16(20):5356-9. Genetic introduction of a diketone-containing amino acid into proteins. Zeng H, Xie J, Schultz P G), 2) azides (as found in p-azido-phenylalanine) that can be reacted with alkynes via copper catalyzed “click chemistry” or strain promoted (3+2) cycloadditions to form the corresponding triazoles (Addition of p- azido-L-phenylalanine to the genetic code of Escherichia coli. Chin J W, Santoro S W, Martin A B, King D S, Wang L, Schultz P G. J Am Chem Soc.2002 Aug.7; 124(31):9026-7; Adding amino acids with novel reactivity to the genetic code of Saccharomyces cerevisiae. Deiters A, Cropp T A, Mukherji M, Chin J W, Anderson J C, Schultz P G. J Am Chem Soc.2003 Oct.1; 125(39):11782-3), or azides that can be reacted with aryl phosphines, via a Staudinger ligation (Selective Staudinger modification of proteinsAttorney Docket No.01277-0079-00PCT containing p-azidophenylalanine. Tsao M L, Tian F, Schultz P G. Chembiochem.2005 December; 6(12):2147-9), to form the corresponding amides, 3) alkynes that can be reacted with azides to form the corresponding triazole (In vivo incorporation of an alkyne into proteins in Escherichia coli. Deiters A, Schultz P G. Bioorg Med Chem Lett.2005 Mar.1; 15(5):1521-4), and 4) boronic acids (boronates) than can be specifically reacted with compounds containing more than one appropriately spaced hydroxyl group or undergo palladium mediated coupling with halogenated compounds (Angew Chem Int Ed Engl. 2008; 47(43):8220-3. A genetically encoded boronate-containing amino acid., Brustad E, Bushey M L, Lee J W, Groff D, Liu W, Schultz P G). Isomers / Stereoisomers

[0232] In some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein possess one or more double bonds. The compounds presented herein include cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the corresponding mixtures thereof. In some situations, the compounds described herein possess one or more chiral centers and each center exists in the R configuration or S configuration. The compounds described herein include diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof. In additional embodiments of the compounds and methods provided herein, mixtures of enantiomers and / or diastereoisomers, resulting from a single preparative step, combination, or interconversion are useful for the applications described herein. In some embodiments, the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers, and recovering the optically pure enantiomers. In some embodiments, dissociable complexes are preferred. In some embodiments, the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities. In some embodiments, the diastereomers are separated by chiral chromatography, or preferably, by separation / resolution techniques based upon differences in solubility. In some embodiments, the optically pure enantiomer is then recovered, along with the resolving agent. Tautomers

[0233] A "tautomer" refers to a molecule wherein a proton shift from one atom of a molecule to another atom of the same molecule is possible. The compounds presented herein, in certain embodiments, exist as tautomers. In circumstances where tautomerization is possible, a chemical equilibrium of the tautomers will exist. The exact ratio of the tautomers depends on several factors, including physical state, temperature, solvent, and pH. Some examples of tautomeric equilibrium include:Attorney Docket No.01277-0079-00PCT

[0234] In some instances, the compounds disclosed herein exist in tautomeric forms. The structures of said compounds are illustrated in the one tautomeric form for clarity. The alternative tautomeric forms are expressly included in this disclosure. Labeled Compounds

[0235] In some embodiments, the peptides and conjugates described herein exist in their isotopically- labeled forms. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled peptides and conjugates as pharmaceutical compositions. Thus, in some embodiments, the peptides and conjugates disclosed herein include isotopically-labeled compounds, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into peptides and conjugates described herein, or a solvate, or stereoisomer thereof, include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, and chloride, such as2H,3H,13C,14C,l5N,18O,17O,31P,32P,35S,18F, and36Cl, respectively. Peptides and conjugates described herein, and the pharmaceutically acceptable salts, solvates, or stereoisomers thereof which contain the aforementioned isotopes and / or other isotopes of other atoms are within the scope of this disclosure. Certain isotopically-labeled peptides and conjugates, for example those into which radioactive isotopes such as3H and14C are incorporated, are useful in drug and / or substrate tissue distribution assays. Tritiated, i.e.,3H and carbon-14, i.e.,14C, isotopes are notable for their ease of preparation and detectability. Further, substitution with heavy isotopes such as deuterium, i.e.,2H, produces certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements. In some embodiments, the isotopically labeled peptide or conjugate, or aAttorney Docket No.01277-0079-00PCT pharmaceutically acceptable salt, solvate, or stereoisomer thereof is prepared by any suitable method.

[0236] In some embodiments, the peptides and conjugates described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels. Pharmaceutically acceptable salts

[0237] In some embodiments, the peptides and conjugates described herein exist as their pharmaceutically acceptable salts. In some embodiments, the peptides and conjugates disclosed herein include their pharmaceutically acceptable salts.

[0238] In some embodiments, the peptides and conjugates described herein possess acidic or basic groups and therefore react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt. In some embodiments, these salts are prepared in situ during the final isolation and purification of the conjugates disclosed herein, or by separately reacting a purified conjugate in its free form with a suitable acid or base, and isolating the salt thus formed.

[0239] Examples of pharmaceutically acceptable salts include those salts prepared by reaction of the compounds described herein with a mineral acid, organic acid, or inorganic base, such salts including acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyn-1,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-1,6-dioate, hydroxybenzoate, γ-hydroxybutyrate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate, metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogenphosphate, 1-napthalenesulfonate, 2-napthalenesulfonate, nicotinate, nitrate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, tosylate, undeconate, and xylenesulfonate.

[0240] Further, the peptides and conjugates described herein can be prepared as pharmaceutically acceptable salts formed by reacting the free base form of the conjugate with a pharmaceutically acceptable inorganic or organic acid, including, but not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, and the like; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p- toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3-(4- hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 2- naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4’-Attorney Docket No.01277-0079-00PCT methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and muconic acid.

[0241] In some embodiments, the peptides and conjugates described herein which comprise a free acid group react with a suitable base, such as the hydroxide, carbonate, bicarbonate, or sulfate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine. Representative salts include the alkali or alkaline earth salts, like lithium, sodium, potassium, calcium, and magnesium, and aluminum salts, and the like. Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N+(C1-4alkyl)4, and the like.

[0242] Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like. It should be understood that the compounds described herein also include the quaternization of any basic nitrogen-containing groups they contain. In some embodiments, water or oil-soluble or dispersible products are obtained by such quaternization. Solvates

[0243] In some embodiments, the peptides and conjugates described herein exist as solvates... Accordingly, one aspect of the present disclosure pertains to solvates of peptides and conjugates of the present disclosure and / or their pharmaceutical acceptable salts, as described herein, that can be isolated and characterized by methods known in the art, such as, thermogravimetric analysis (TGA), TGA-mass spectroscopy, TGA-Infrared spectroscopy, powder X-ray diffraction (PXRD), Karl Fisher titration, high resolution X-ray diffraction, and the like. Preparation of the Peptides and Conjugates

[0244] The disclosure provides methods of preparing and making the peptides and conjugates described herein.

[0245] The compounds used in the reactions described herein are made according to organic synthesis techniques known to those skilled in this art, starting from commercially available chemicals and / or from compounds described in the chemical literature. “Commercially available chemicals” are obtained from standard commercial sources including ABX advanced biochemical compounds GmbH (Radeberg, Germany), Acros Organics (Pittsburgh, PA), Aldrich Chemical (Milwaukee, WI, including Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK), Avidity Science (U.S.A.), Avocado Research (Lancashire, U.K.), BDH, Inc. (Toronto, Canada), Bionet (Cornwall, U.K.), Chem Service Inc. (West Chester, PA), Crescent Chemical Co. (Hauppauge, NY), Eastman Organic Chemicals, Eastman Kodak Company (Rochester, NY), Fisher Scientific Co. (Pittsburgh, PA), Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan, UT), ICN Biomedicals, Inc. (Costa Mesa, CA), ITM (Munich, Germany), Key Organics (Cornwall, U.K.), Lancaster Synthesis (Windham, NH), Maybridge Chemical Co. Ltd.Attorney Docket No.01277-0079-00PCT (Cornwall, U.K.), Parish Chemical Co. (Orem, UT), Pfaltz & Bauer, Inc. (Waterbury, CN), Polyorganix (Houston, TX), Pierce Chemical Co. (Rockford, IL), Riedel de Haen AG (Hanover, Germany), Sigma- Aldrich (U.S.A.), Spectrum Quality Product, Inc. (New Brunswick, NJ), TCI America (Portland, OR), Trans World Chemicals, Inc. (Rockville, MD), VWR (Radnor, PA, USA), Wako Chemicals USA, Inc. (Richmond, VA), and Wuxi-Apptech Inc. (Shanghai, China). Pharmaceutical Compositions

[0246] The peptides and conjugates described herein, including e.g., pharmaceutically acceptable salt or solvate thereof, can be administered per se as a pure chemical or as a component of a pharmaceutically acceptable formulation. In some embodiments, a peptide or conjugate described herein is combined with a pharmaceutically suitable or acceptable carrier selected on the basis of a chosen route of administration and standard pharmaceutical practice as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21stEd. Mack Pub. Co., Easton, PA (2005)). Provided herein is a pharmaceutical composition comprising at least one peptide or conjugate described herein, or a stereoisomer, pharmaceutically acceptable salt, amide, ester, solvate, or N-oxide thereof, together with one or more pharmaceutically acceptable carriers. The carrier(s) (or excipient(s)) is acceptable or suitable if the carrier is compatible with the other ingredients of the composition and not deleterious to the recipient (i.e., the subject or patient) of the composition.

[0247] In one aspect, the disclosure provides a pharmaceutical composition comprising a herein described peptide or conjugate, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient or carrier.

[0248] The peptides, conjugates, and pharmaceutical compositions of the current disclosure can be administered by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intravenous, intrathecal, epidural, and intranasal, etc. Method of Treatment

[0249] In one aspect, the disclosure provides methods of treating a disease or condition in a subject in need thereof. The methods can comprise administering a peptide or radiopharmaceutical conjugate to the subject in need thereof. The methods can provide a therapeutic and / or prophylactic benefit to a subject in need thereof comprising administering a peptide or radiopharmaceutical conjugate described herein.

[0250] The methods can comprise administering to a subject a radiopharmaceutical conjugate that comprises a therapeutically effective amount of a conjugate or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the subject has cancer. In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is an SSTR-associated cancer. In some embodiments, the cancer is an SSTR1-associated cancer. In some embodiments, the cancer is an SSTR2-associated cancer. In some embodiments, the cancer is an SSTR3-associated cancer. In some embodiments, the cancer is an SSTR4-associated cancer. In some embodiments, the cancer is an SSTR5-associated cancer. In someAttorney Docket No.01277-0079-00PCT embodiments, the cancer is a somatostatin receptor-positive (SSTR+) cancer.

[0251] In some embodiments, the cancer is a neuroendocrine cancer, a lymphatic cancer, a pancreatic cancer, a pituitary cancer, a breast cancer, a lung cancer, a stomach cancer, medulloblastoma, or neuroblastoma. In some embodiments, the cancer is a glioblastoma. In some embodiments, the cancer is a neuroendocrine cancer. In some embodiments, the neuroendocrine cancer is a neuroendocrine lung cancer or a neuroendocrine pancreatic cancer. In some embodiments, the neuroendocrine cancer is a Carcinoid tumor in the lungs, gastrointestinal tract or thymus, Pancreatic neuroendocrine tumor (e.g., Gastrinoma, Insulinoma, Glucagonoma, VIPoma) Medullary thyroid carcinoma, Merkel cell carcinoma, Pheochromocytoma of the adrenal gland, Adrenal cancer, Small cell carcinoma (such as in the lungs), or Large cell carcinoid tumor (such as in the lungs). In some embodiments, the cancer is a SSTR2+ lung neuroendocrine tumor. In some embodiments, the cancer is somatostatin receptor-positive (SSTR+) gastroenteropancreatic neuroendocrine tumor (GEP-NET). In some embodiments, the cancer is small cell lung cancer (SCLC). In some embodiments, the cancer is somatostatin receptor expressing (SSTR+) extensive stage small cell lung cancer (ES-SCLC).

[0252] In addition to the methods of treatment described above, the radiopharmaceutical conjugates described herein can be used to image, and / or as part of a treatment for diseases. Conjugates for imaging applications, e.g., single-photon emission computed tomography (SPECT) and positron emission tomography (PET), can comprise a radionuclide suitable for use as imaging isotopes such as the isotopes in Table 3 labeled “Dx”. Accordingly, the conjugate can be administered as a companion diagnostic.

[0253] In one aspect, provided herein are methods for diagnosing a patient harboring a somatostatin receptor (SSTR) expressing cancer or tumor comprising administering to the patient a radiopharmaceutical described herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition comprising the same. In one aspect, provided herein are methods for imaging an SSTR expressing cancer or tumor comprising administering to the patient a radiopharmaceutical described herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition comprising the same. In some embodiments, the method further comprises selecting or confirming that a tumor in the patient expresses SSTR. In some embodiments, the SSTR expressing cancer is an SSTR2 expressing cancer. In some embodiments, the method further comprises measuring the concentration of the radiopharmaceutical accumulated in the patient. In some embodiments, the method further comprises measuring the amount of radiation emitted from the radionuclide. In some embodiments, the method further comprises analyzing the elimination or clearance profile of the radiopharmaceutical in the patient. In some embodiments, the method further comprises measuring an elimination half-life of the radiopharmaceutical in the patient. In some embodiments, the method further comprises analyzing the clearance profile of the radiopharmaceutical in the patient. In some embodiments, the method of imaging or diagnosing cancer comprises administering a radiopharmaceutical that comprises a radionuclide of Table 3 labeled “Dx”, such as68Ga. For example, radiopharmaceuticals of the present disclosure can be administered for patient selection purposes, such as to confirm the tumor has the appropriate expression of the SSTR target (e.g., SSTR2). As anotherAttorney Docket No.01277-0079-00PCT example, radiopharmaceuticals of the present disclosure can be administered to a patient so that the patient’s care team can make sure the radiopharmaceutical is cleared from the body in a suitable timeframe so that undesired irradiation of other tissues is minimized.

[0254] In some embodiments, a method described herein comprises administering to a patient two radiopharmaceuticals of the present disclosure. In some embodiments, the two radiopharmaceuticals can have the same targeting ligand. In some embodiments, a method described herein comprises administering (i) a radiopharmaceutical of the present disclosure that comprises a radionuclide of Table 3 labeled “Dx”, and followed by (i) a radiopharmaceutical of the present disclosure that comprises a radionuclide of Table 3 labeled “Tx”. In some embodiments, the method comprises administering a68Ga labeled conjugate described herein followed by the administering of an225Ac labeled conjugate described herein.

[0255] In some embodiments, the radiopharmaceutical conjugates described herein can be administered alone or in combination with one or more additional therapeutic agents. For example, the combination therapy can include a composition comprising a radiopharmaceutical conjugate described herein co- formulated with, and / or co-administered with, one or more additional therapeutic agents, e.g., one or more anti-cancer agents, e.g., cytotoxic or cytostatic agents, immune checkpoint inhibitors, hormone treatment, vaccines, and / or immunotherapies. In some embodiments, the radiopharmaceutical conjugate is administered in combination with other therapeutic treatment modalities, including surgery, cryosurgery, and / or chemotherapy. Such combination therapies may advantageously utilize lower dosages of the administered therapeutic agents, thus avoiding possible toxicities or complications associated with the various monotherapies. In some embodiments, the additional anti-cancer agent is a local or regional cancer treatment. In some embodiments, the local or regional cancer treatment comprises microwave ablation. In some embodiments, the local or regional cancer treatment comprises radiofrequency ablation (RFA). In some embodiments, the local or regional cancer treatment comprises ultrasound ablation. In some embodiments, the local or regional cancer treatment comprises magnetic resonance guided focused ultrasound ablation.

[0256] When administered in combination, two (or more) different treatments can be delivered to the subject during the course of the subject's affliction with the disorder, e.g., the two or more treatments are delivered after the subject has been diagnosed with the disorder and before the disorder has been cured or eliminated. In some embodiments, the delivery of one treatment is still occurring when the delivery of the second begins, so that there is overlap. This is sometimes referred to herein as “simultaneous” or “concurrent delivery.” In some embodiments, the delivery of one treatment ends before the delivery of the other treatment begins. In some embodiments of either case, the treatment is more effective because of combined administration. For example, the second treatment is more effective, e.g., an equivalent effect is seen with less of the second treatment, or the second treatment reduces symptoms to a greater extent, than would be seen if the second treatment were administered in the absence of the first treatment, or the analogous situation is seen with the first treatment. In some embodiments, delivery is such that the reduction in a symptom, or other parameter related to the disorder is greater than what would be observedAttorney Docket No.01277-0079-00PCT with one treatment delivered in the absence of the other. The effect of the two treatments can be partially additive, wholly additive, or greater than additive. The delivery can be such that an effect of the first treatment delivered is still detectable when the second is delivered.

[0257] Co-administration of amino acids with a radiopharmaceutical described herein may reduce kidney update of the radiopharmaceutical. Reducing kidney uptake and / or increasing clearance of the radiopharmaceutical is a desired property in radiopharmaceutical therapeutics. In some embodiments, a radiopharmaceutical conjugate described herein is concurrently administered with an intravenous infusion of one or more amino acids. In some embodiments, a radiopharmaceutical conjugate described herein is administered after an intravenous infusion of one or more amino acids. In some embodiments, the infusion of the one or more amino acids is administered at least 30 minutes prior to administering a radiopharmaceutical conjugate described herein. In some embodiments, the infusion of the one or more amino acids is administered at least 6 hours, 3 hours, 1 hour, 30 minutes, 20 minutes, 10 minutes, or 5 minutes prior to administering a radiopharmaceutical conjugate described herein. In some embodiments, the infusion of the one or more amino acids is administered 10 to 60 minutes prior to administering a radiopharmaceutical conjugate described herein.

[0258] The radiopharmaceutical conjugates of the current disclosure can be administered by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal and epidural and intranasal, and, if desired for local treatment, intralesional administration. The term parenteral as used herein includes e.g., subcutaneous, intravenous, intramuscular, intrasternal, intraperitoneal, and infusion techniques. The term parenteral also includes injections, into the eye or ocular, intravitreal, intrabuccal, transdermal, intranasal, into the brain, including intracranial and intradural, into the joints, including ankles, knees, hips, shoulders, elbows, wrists, and the like, and in suppository form. The radiopharmaceutical conjugates can be administered orally. The radiopharmaceutical conjugates can be administered by systemic administration. The radiopharmaceutical conjugates can be administered parenterally. The radiopharmaceutical conjugates can be administered intravenously. The radiopharmaceutical conjugates can be administered locally at a targeted site.

[0259] The radiopharmaceutical conjugates described herein can be administered via parenteral injection as liquid solution.

[0260] The radiopharmaceutical conjugates can be administered in a manner appropriate to the disease to be treated. An appropriate dose and a suitable duration and frequency of administration can be determined by such factors as the condition of the subject, the type and severity of the subject's disease, the particular form of the active ingredient, and the method of administration. In some embodiments, an appropriate dose and treatment regimen provides the composition(s) in an amount sufficient to provide therapeutic and / or prophylactic benefit (e.g., an improved clinical outcome), or a lessening of symptom severity. Optimal doses are generally determined using experimental models and / or clinical trials. The optimal dose depends upon the body mass, weight, or blood volume of the subject. In some embodiments, the radiopharmaceutical conjugate can be administered as part of a first-line therapy. InAttorney Docket No.01277-0079-00PCT some embodiments, the radiopharmaceutical conjugate can be administered as part of a first-line therapy with existing standard of care, for example, immune checkpoint blockers and DNA damaging agents.

[0261] In one aspect, disclosed herein is a method of increasing renal clearance of a cyclic somatostatin receptor binding peptide comprising a one or more lysine residues (e.g., a lysine residue present in a peptide of SEQ ID NO: 1-85), the method comprising independently replacing the one or more lysine residues with the non-natural lysine derivative described herein. In some embodiments, one lysine from a somatostatin binding peptide selected from SEQ ID NO: 1-85 is replaced with a non-natural lysine derivative described herein. In some embodiments, the cyclic somatostatin receptor binding peptide comprising the non-natural lysine derivative has increased renal clearance compared to the peptide where the lysine is not replaced.

[0262] In one aspect, disclosed herein is a method of increasing renal clearance of a radiopharmaceutical conjugate comprising a cyclic somatostatin receptor binding peptide comprising a one or more lysine residues (e.g., a lysine residue present in a peptide of SEQ ID NO: 1-85), the method comprising independently replacing the one or more lysine residues with the non-natural lysine derivative described herein. In some embodiments, one lysine from a somatostatin binding peptide selected from SEQ ID NO: 1-85 is replaced with a non-natural lysine derivative described herein. In some embodiments, the radiopharmaceutical conjugate comprising the cyclic somatostatin receptor binding peptide comprising the non-natural lysine derivative has increased renal clearance compared to the peptide where the lysine is not replaced.

[0263] Although the present disclosure and its advantages have been described in detail, it should be understood that various changes, substitutions and alterations can be made herein without departing from the spirit and scope of the disclosure as defined in the appended claims.

[0264] The present disclosure is further illustrated in the following Examples which are given for illustration purposes only and are not intended to limit the disclosure in any way. EXAMPLES A: Synthesis of the Conjugates

[0265] Unless otherwise stated in the present specification, the following abbreviations are used according to the following meanings: Alloc allyloxycarbonyl aq. aqueous Biotin-OSu biotin N-hydroxysuccinimide ester (CAS 35013-72-0) Boc tert-butyloxycarbonyl ClAcOH chloroacetic acid ClAcOSu N-succinimidyl 2-chloroacetate (CAS 27243-15-8) DCM dichloromethane (CAS 75-09-2) DIC N,N’-diisopropylcarbodiimide (CAS 693-13-0) DIPEA, DIEA N,N-diisopropylethylamine (CAS 7087-68-5)Attorney Docket No.01277-0079-00PCT DMEM Dulbecco's Modified Eagle Medium DMF N,N-dimethylformamide (CAS 68-12-2) DODT 2,2’-(ethylenedioxy)diethanethiol (CAS 14970-87-7) EDCI-HCl N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (CAS 25952-53-8) EDTA ethylenediaminetetraacetic acid EMEM Eagle's minimal essential medium eq equivalent Et ethyl Et3N, TEA triethylamine (CAS 121-44-8) FBS fetal bovine serum Fmoc 9-fluorenylmethoxycarbonyl hr hour HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate (CAS 148893-10-1) HOSu N-hydroxysuccinimide (CAS 6066-82-6) iPrOH, IPA isopropanol M molar min minutes NHS N-hydroxysuccinimide (CAS 6066-82-6) NMP N-methylpyrrolidone (CAS 872-50-4) Pd(PPh3)4tetrakis(triphenylphosphine)palladium(0) (CAS 14221-01-3) PG protecting group Ph phenyl RP reverse phase rpm rotations per minute rt room temperature SAPE Streptavidin, R-Phycoerythrin conjugate SPPS solid phase peptide synthesis Su succinimidyl SulfoCy5- sulfo Cyanine5 (CAS 2791287-13-1) SulfoCy5-OSu, (CAS 146368-14-1) SulfoCy5-NHS see SulfoCy5-OSu tert tertiary TFA trifluoroacetic acid (CAS 76-05-1) TIS triisopropylsilane (CAS 6485-79-6) tr retention time Trt tritylAttorney Docket No.01277-0079-00PCT PyAOP (7-azabenzotriazol-1-yloxy)trispyrrolidinophosphonium hexafluorophosphate (CAS 156311-83-0) MeCN acetonitrile AcOH acetic acid Et2O diethyl ether AA amino acid Me methyl HFIP 1,1,1,3,3,3-hexafluoro-2-propanol (CAS 920-66-1) PhSiH3phenylsilane (CAS 694-53-1) tBu tertiary butyl DMSO dimethylsulfoxide Mpe 3-Methyl-pent-3-yl Example A1. Analytical Conditions and Peptide Synthesis

[0266] Certain exemplary peptides of the disclosure may be synthesized using standard synthetic methods for peptide synthesis, including solid phase peptide synthesis. For example, synthesis of certain cyclic peptides may be found in International Publication No. WO 2022 / 115778 and US Application Publication No. US 2023 / 0158179, the entire disclosures of which are hereby incorporated by reference.

[0267] Solid phase peptide synthesis (SPPS) is performed in a standard manual reaction vessel under nitrogen.2-CTC resin is purchased from Sunresin New Materials Co. (China). Fmoc protected amino acids are purchased from GL Biochem (China). HBTU and HATU are purchased from Highfine Biotech Co. (China). Piperidine is purchased from Damao Chemical Reagent Factory (China). The peptides and their derivatives are purified on a Gilson GX-281 preparative HPLC system using reverse-phase C18 columns (Gemini, 5 µm, 110 Å + luna, 10 µm, 100 Å) at 30 °C. HPLC solvents consist of H2O containing 0.075% trifluoroacetic acid (mobile phase A) and acetonitrile (mobile phase B).

[0268] High performance liquid chromatography (HPLC) analyses are performed on an Agilent 1260 series equipped with a binary pump G7112A, micro vacuum degasser, standard autosampler ALS G7129A, thermostatted column compartment TCC G7116A, variable wavelength detector VWD G7114A, and data are analyzed by OpenLab CDS 2.2 network workstation software from Agilent Technologies. HPLC solvents consist of H2O containing 0.1% trifluoroacetic acid (mobile phase A) and acetonitrile containing 0.075% trifluoroacetic acid (mobile phase B). Conditions: a Phenomenex Gemini- NX C-18 (5 µm, 110 Å, 4.6 × 250 mm) column is used with a flow rate of 1.0 mL / min.

[0269] LC-MS analyses are carried out on an Agilent 1200 series coupled to an Agilent MSD G6125C, equipped with a binary pump G7112A, micro vacuum degasser, standard autosampler ALS G7129A, thermostatted column compartment TCC G7116A, variable wavelength detector VWD G7114A, and data are analyzed by OpenLab CDS 2.3 standalone workstation software from Agilent Technologies. HPLC solvents consist of H2O containing 0.1% trifluoroacetic acid (mobile phase A) and acetonitrile containing 0.075% trifluoroacetic acid (mobile phase B). Conditions: a Waters Xbridge C-18 (3.5 µm,Attorney Docket No.01277-0079-00PCT 3.1× 30mm) column was used with a flow rate of 1.2 mL / min. Example A2: Radiolabeling Protocols General protocol for cold labeling of empty-chelator conjugates with Lu, La and Ga metals

[0270] To a solution of peptide conjugated to an empty-chelator (1 equiv.) in 1M Na2CO3aqueous buffer (pH = 5-6) is added LuCl3,LaCl3,or GaCl3(5 equiv.). The resulting mixture is stirred at 40-60 °C for 1 h. After filtration, the crude product is purified by preparative HPLC to afford the corresponding cold metal labeled peptide. General protocol for177Lu Radiolabeling of empty-DOTA conjugate

[0271] A 35 mCi aliquot of177LuCl3is added to the reaction vessel followed by addition of 10% ethanol in 0.4M NaOAc buffer (1.0 mL; pH=5.0) and the empty-DOTA conjugate (1.0 µg / µL, 32 µL). The resulting mixture is heated and mixed with a thermal mixer at 70°C for 0.5h. After 0.5h, the reaction mixture is allowed to cool at room temperature for 3 min. Then the reaction mixture is diluted with 4.8 mL of a pre-mixed formulation buffer. To assess the radiochemical purity, 60 µCi of the177Lu labeled product is injected on a rad-HPLC. At the end of the synthesis (EOS), the radiochemical purity and specific activity is determined. HPLC column: Aeris 3.6 µm PEPTIDE XB-C18100, LC Column, 150 x 4.6 mm (00F-4507-E0). Flow 1.0mL / min. HPLC column Aeris 3.6 µm PEPTIDE XB-C18100, LC Column, 150 x 4.6 mm (00F-4507-E0). Solvent A is H2O / 0.05% TFA and solvent B is CH3CN / 0.05% TFA. Elution is conducted at flow rate of 1.0 mL / min with gradient from 5 to 95% B over 16 min. General protocol for225Ac Radiolabeling of empty-DOTA conjugate

[0272] A225Ac(NO3)3powder is diluted with 0.5M HCl to achieve a concentration of 10 µCi / µL. 100µCi aliquot of the 10 µCi / µL225Ac-chloride solution is added to the reaction vessel followed by addition of 10% ethanol in 0.4M NaOAc buffer (200 µL, pH=6.2) and 27.5 µg of the empty-DOTA conjugate (1.0 µg / µL, 27.5 µL). The resulting mixture is heated and mixed with a thermal mixer at 90°C for 0.5 h. After 0.5h, the reaction mixture is allowed to cool at room temperature for 3 min. The reaction mixture is diluted with 1.0 mL of a pre-mixed formulation buffer. The radiochemical purity is determined at 5 µCi / nmol by radio thin-layer chromatography (radio-TLC). TLC plate: Agilent Technologies Chromatography paper (Cat number A120B12); mobile phase: 50mM DTPA, pH=5.56. General protocol for64Cu Radiolabeling of empty-NOTA conjugate

[0273] 64CuCl2in 0.1M HCl is reconstituted with 0.4M NaOAc pH=6.2 to achieve a concentration of 0.2 mCi / µL. A 7.14 mCi aliquot of the64CuCl2solution is added to the reaction vessel followed by addition of 10% ethanol in 0.4M NaOAc buffer (200 µL; pH=6.2) and the empty-NOTA conjugate (1.0 µg / µL, 6.0 µL). The resulting mixture is heated and mixed with a thermal mixer at 50°C for 0.5h. After 0.5h, the reaction mixture is allowed to cool at room temperature for 3 min. Then the reaction ia diluted with 4.8 mL of a pre-mixed formulation buffer. To assess the radiochemical purity, 10 µCi of the productAttorney Docket No.01277-0079-00PCT was injected on a rad-HPLC. At the end of the synthesis (EOS), the radiochemical purity and specific activity is determined. HPLC column: Aeris 3.6 µm PEPTIDE XB-C18100, LC Column, 150 x 4.6 mm (00F-4507-E0). Solvent A is H2O / 0.05% TFA and solvent B is CH3CN / 0.05% TFA. Elution is conducted at flow rate of 1.0 mL / min with gradient from 5 to 95% B over 16 min. General protocol for68Ga Radiolabeling of empty-DOTA conjugate

[0274] A 10 mCi aliquot of68GaCl3in 0.1M HCl (1.1 mL) is added to the reaction vessel followed by addition of 1.0 M NaOAc, pH 5.5 ,175 µL, and empty DOTA conjugate (0.75 µg / µL; 42µL). The resulting mixture is heated and mixed with a thermal mixer at 95°C for 10 min. After 10 min, the reaction mixture is allowed to cool at room temperature for 3 minutes. Then the reaction mixture is diluted with 4 mL of a pre-mixed formulation buffer. To assess the radiochemical purity, 10 μCi of the product is injected on a rad-HPLC. At the end of the synthesis (EOS), the radiochemical purity and specific activity is determined. HPLC column: Aeris 3.6 μm PEPTIDE XB-C18100, LC Column, 150 x 4.6 mm (00F- 4507-E0). Solvent A is H2O / 0.05% TFA and solvent B is CH3CN / 0.05% TFA. Elution is conducted at flow rate of 1.0 mL / min with gradient from 5 to 95% B over 16 min. Example B: Biological examples Example B1: SSTR binding affinity measured by radioligand binding competition assay

[0275] Macrocyclic peptides in this invention were tested for binding to SSTR protein by a radioligand binding competition assay. For radioligand binding assay, competition binding is performed in duplicate in the wells of a 96 well plate containing binding buffer (HEPES 25 mM pH 7.4, MgCl25mM, CaCl21 mM, BSA 0.5%, Saponine 10 µg / ml)), membrane extracts (0.6 µg protein / well), radiotracer ([125I]- Tyr11-Somatostatin, Perkin Elmer NEX389) and test compound. Nonspecific binding is determined by co-incubation with 200-fold excess of cold competitor (SST28). The samples are incubated in a final volume of 0.1 ml for 60 min at room temperature and then filtered over UniFilter-96 GF / C (Revvity 6055690) filter plates. Filters are washed six times with 0.5 ml of ice-cold washing buffer (HEPES 25 mM pH 7.4, MgCl25mM, CaCl21 mM) and 50 µl of Microscint 20 (Packard) are added in each well. The plates are incubated 15 min on an orbital shaker and then counted with a TopCountTMfor 1 min / well. For IC50 to Ki determination, the Cheng Prusoff equation is used: Ki = IC50 / (1+ [tracer] / Kd). [Tracer] is 0.1 nM as mentioned above. Conjugate SSTR2 binding affinity is shown in Table 4, wherein 0 < A < 1.0nM and 1.0nM ≤ B < 3.33nM. Table 4.Attorney Docket No.01277-0079-00PCTExample B2: Peptide Conjugate Biodistribution Measured by Tissue PK

[0276] Macrocyclic peptides and conjugates of this invention were tested for tissue distribution by measuring concentrations in tissues by MS using in vivo animal models. Peptide metal chelates were dosed to animals and tissues were collected at specific time points based off the peptide PK profile. The samples were then analyzed by MS and the results reported as %ID / g (% injected dose / gram). Radiopharmaceutical conjugates of the present disclosure have improved tissue distribution for radiopharmaceutical therapeutics.

[0277] Peptide metal chelate doses were suspended in phosphate-buffered saline (PBS) containing 0.1% Tween 80. An injection volume of 100 µL per mouse was used, and blood and tissue samples were collected, weighed, and stored frozen at -80 °C until analysis. Tissue samples were digested with concentrated nitric acid in a microwave digestion apparatus. The sample digest was diluted with internal standard and analyzed using inductively coupled plasma mass spectrometry (ICP-MS). ICP-MS is an elemental analysis technique used to measure elements by using argon plasma to convert the sample into ions that are then measured using the mass spectrometer. Calibration standards were used for quantification of element(s) of interest by constructing a multipoint standard curve covering the range of analyte concentrations anticipated in the samples (typical range is 500 ppt to 0.1 ppt). A single quadrupole instrument (iCAP RQ, Thermo Fisher) ICP-MS was coupled with a Teledyne CETAC autosampler and used for the sample analysis.

[0278] The %ID / g of conjugate in kidney tissue at the 2-hour time point (2h) was quantified for various conjugates, and the results are shown in Table 5. Lower kidney tissue % ID / g values indicate lower distribution to the kidney after administration of the conjugate. Table 5.Attorney Docket No.01277-0079-00PCT

[0279] The present technology may be used in bio-related industries and the pharmaceutical industry.

[0280] All references cited in this specification, and their references, are incorporated by reference herein in their entirety where appropriate for teachings of additional or alternative details, features, and / or technical background.

[0281] While the disclosure has been particularly shown and described with reference to particular embodiments, it will be appreciated that variations of the above-disclosed and other features and functions, or alternatives thereof, may be desirably combined into many other different systems or applications. Also, that various presently unforeseen or unanticipated alternatives, modifications, variations, or improvements therein may be subsequently made by those skilled in the art which are also intended to be encompassed by the following claims.

Claims

Attorney Docket No.01277-0079-00PCT CLAIMS 1. A cyclic peptide, or a pharmaceutically acceptable salt thereof, comprising a non-natural tryptophan- lysine dipeptide moiety, wherein the non-natural tryptophan-lysine dipeptide moiety comprises: (i) a non-natural lysine derivative, wherein the non-natural lysine derivative is a non- natural amino acid having a side chain comprising an amine; and wherein the cyclic peptide or a pharmaceutically acceptable salt thereof has an avidity for a somatostatin receptor.

2. The cyclic peptide of claim 1, or a pharmaceutically acceptable salt thereof, wherein the non-natural tryptophan-lysine dipeptide moiety comprises (i) the non-natural lysine derivative and (ii) a non- natural tryptophan derivative, wherein the non-natural tryptophan derivative is an amino acid comprising an aromatic moiety.

3. A cyclic peptide, or a pharmaceutically acceptable salt thereof, comprising a non-natural tryptophan- lysine dipeptide moiety, wherein the cyclic peptide or a pharmaceutically acceptable salt thereof comprises a sequence that has one or more amino acid replacements based on a sequence having any one of SEQ ID NO: 1-77, and wherein the one or more replacements comprise: (i) a replacement of a lysine in the sequence with a non-natural lysine derivative, wherein the non-natural lysine derivative is a non-natural amino acid having a side chain comprising an amine.

4. The cyclic peptide of claim 3, or a pharmaceutically acceptable salt thereof, wherein the one or more replacements comprise the replacement of a lysine in the sequence with a non-natural lysine derivative and replacement of a tryptophan in the sequence with a non-natural tryptophan derivative, wherein the non-natural tryptophan derivative is an amino acid comprising an aromatic moiety.

5. A cyclic peptide, or a pharmaceutically acceptable salt thereof, comprising a non-natural lysine derivative, wherein the non-natural lysine derivative is a non-natural amino acid having a side chain comprising an amine, and wherein the cyclic peptide or a pharmaceutically acceptable salt thereof has an avidity for a somatostatin receptor.

6. The peptide of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein the peptide is monocyclic.

7. The peptide of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein the peptide comprises 5-40 amino acids in the cyclic portion of the peptide.

8. The peptide of claim 7, or a pharmaceutically acceptable salt thereof, wherein the peptide consists of 5-40 amino acids in the cyclic portion of the peptide.Attorney Docket No.01277-0079-00PCT 9. The peptide of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein the peptide comprises 6-14 amino acids in the cyclic portion of the peptide.

10. The peptide of claim 9, or a pharmaceutically acceptable salt thereof, wherein the peptide consists of 6-14 amino acids in the cyclic portion of the peptide.

11. The peptide of any one of claims 1-10, or a pharmaceutically acceptable salt thereof, wherein the non-natural tryptophan derivative is an amino acid comprising an optionally substituted N-containing 5- to 10- membered heteroaryl.

12. The peptide of any one of claims 1-11, or a pharmaceutically acceptable salt thereof, wherein the non-natural tryptophan derivative is a non-natural amino acid comprising an optionally substituted N-containing 5- to 10- membered heteroaryl.

13. The peptide of any one of claims 1-11, or a pharmaceutically acceptable salt thereof, wherein the non-natural tryptophan derivative is D-Trp, NMe-D-Trp, (S-βMe)D-Trp, (S-βMe)Trp, (R-βMe)D- Trp, (R-βMe)Trp, Aza-Trp, Aza-D-Trp, D-6F-Trp, or D-Aph(Cbm), each of which is further optionally substituted.

14. The peptide of any one of claims 1-13, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, wherein the non-natural tryptophan derivative is D-Trp, (S- βMe)D-Trp, (S-βMe)-Trp, (R-βMe)D-Trp, or (R-βMe)-Trp.

15. The peptide of any one of claims 1-14, or a pharmaceutically acceptable salt thereof, wherein the non-natural tryptophan derivative is(S-βMe)D-Trp.

16. The peptide of any one of claims 1-14, or a pharmaceutically acceptable salt thereof, wherein the non-natural tryptophan derivative is D-Trp.

17. The peptide of any one of claims 1-16, or a pharmaceutically acceptable salt thereof, wherein the non-natural tryptophan derivative has a structure of:, wherein: R31is hydrogen or C1-C5alkyl optionally substituted with one to three substituents independently selected from Rf; each Rfis independently halogen, -CN, -NO2, -ORa, -SRaor -NRcRd; LX3is a bond, -O-, -S-, -NR33-, C1-C3alkylene, or C1-C3heteroalkylene, wherein the alkylene or heteroalkylene is optionally substituted with one or more RX3a; ring A3 is an aryl or heteroaryl;Attorney Docket No.01277-0079-00PCT each R32is independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1- C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, halogen, -CN, -NO2, -ORa, -SRa, -SF5, -NRcRd, - (=O)2RcRd, -S(=O)(=NRa)Ra, -N=S(=O)RcRd, -NRaS(=O)2Ra, amidinyl, - (=O)2RcRd, -C(=O)Ra, -C(=O)ORa, -OC(=O)Ra, -OC(=O)ORa, - (=O)Ra, -NRaC(=O)ORa, -NRaC(=O)NRcRd, -C(=O)NRcRd, -RcRd, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, wherein each of the alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more R32a; or two R32are taken together to form =O, =S, or =N(Ra); m3 is 0, 1, 2, 3, 4, or 5; each R32ais independently halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1- C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -CN, -NO2, -ORa, -SRa, -NRcRd, - S(=O)Ra, -S(=O)2Ra, -SF5, -S(=O)2NRcRd, -S(=O)(=NRa)Ra, -N=S(=O)RcRd, -NRaS(=O)2Ra, amidinyl, -NRaC(=NH)(NRa)2, -NRaS(=O)2NRcRd, -C(=O)Ra, -C(=O)ORa, -OC(=O)Ra, - OC(=O)ORa, -OC(=O)NRcRd, -NRaC(=O)Ra, -NRaC(=O)ORa, -NRaC(=O)NRcRd, -C(=O)NRcRd, -P(=O)(ORc)(ORd), -P(=O)RcRd, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, =O, =S, or =N(Ra), wherein each of the alkyl, heteroalkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more Re; R33is hydrogen or C1-C3alkyl; R34is hydrogen or C1-C3alkyl; RX3ais halogen, -CN, -NO2, -ORa, -NRcRd, C1-C6alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1-C6alkylene(heteroaryl), wherein each of the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more Re; or two RX3agroups attached to the same or different atoms are taken together to form a cycloalkyl or heterocycloalkyl ring, each of which is optionally substituted with one or more Re; each Rais independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1-C6alkylene(heteroaryl), wherein each of the alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more Re; each Reis independently halogen, -CN, -OH, oxo, -O-C1-C6alkyl, -SF5, -S(=O)C1-C6alkyl, - S(=O)2C1-C6alkyl, -S(=O)2NH2, -S(=O)2-halogen, -S(=O)2NHC1-C6alkyl, -S(=O)2N(C1-C6alkyl)2, -NH2, -NHC1-C6alkyl, -N(C1-C6alkyl)2, -NHC(=NH)NH2, -NHC(=O)OC1-C6alkyl, -C(=O)C1- C6alkyl, -C(=O)OH, C1-C6alkyl-C(=O)OH, -C(=O)OC1-C6alkyl, -C(=O)NH2, -C(=O)N(C1- C6alkyl)2, -C(=O)NHC1-C6alkyl, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1- C6aminoalkyl, or C1-C6heteroalkyl; andAttorney Docket No.01277-0079-00PCT each Rcand Rdare independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1-C6alkylene(heteroaryl), wherein each of the alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more Re; or Rcand Rdare taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more Re; wherein represents the point of attachment to the rest of the peptide.

18. The peptide of claim 17, or a pharmaceutically acceptable salt thereof, wherein ring A3 is a C6- C10aryl or a 5- to 10- membered heteroaryl.

19. The peptide of claim 17 or 18, or a pharmaceutically acceptable salt thereof, wherein ring A3 is a phenyl, naphthyl, pyridinyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, pyrimidazolyl, pyrazolo[1,5-a]pyridinyl, quinolinyl, or isoquinolinyl.

20. The peptide of any one of claims 17-19, or a pharmaceutically acceptable salt thereof, wherein ring A3 is phenyl or naphthyl.

21. The peptide of any one of claims 17-19, or a pharmaceutically acceptable salt thereof, wherein ring A3 is indolyl or azaindolyl.

22. The peptide of any one of claims 17-21, or a pharmaceutically acceptable salt thereof, wherein m3 is 0 or 1.

23. The peptide of claim 17, or a pharmaceutically acceptable salt thereof, wherein the non-natural tryptophan derivative has a structure of:, wherein: Y31is N, CH, or CR32; Y32is N, CH, or CR32; Y33is N, CH, or CR32; Y34is N, CH, or CR32; Y35is N, or C; Y36is N or C; Y37is N, CH, or CR32; and Y38is S, N or NH;Attorney Docket No.01277-0079-00PCT provided that no more than two of Y31, Y32, Y33, Y34, Y35, Y36, and Y37are N.

24. The peptide of claim 23, or a pharmaceutically acceptable salt thereof, wherein Y31is N.

25. The peptide of claim 23, or a pharmaceutically acceptable salt thereof, wherein Y31is CH.

26. The peptide of any one of claims 23-25, or a pharmaceutically acceptable salt thereof, wherein Y32is N.

27. The peptide of any one of claims 23-25, or a pharmaceutically acceptable salt thereof, wherein Y32is CH.

28. The peptide of any one of claims 23-27, or a pharmaceutically acceptable salt thereof, wherein Y33is N.

29. The peptide of any one of claims 23-27, or a pharmaceutically acceptable salt thereof, wherein Y33is CH.

30. The peptide of any one of claims 23-29, or a pharmaceutically acceptable salt thereof, wherein Y34is N.

31. The peptide of any one of claims 23-29, or a pharmaceutically acceptable salt thereof, wherein Y34is CH.

32. The peptide of any one of claims 23-31, or a pharmaceutically acceptable salt thereof, wherein Y35is N.

33. The peptide of any one of claims 23-31, or a pharmaceutically acceptable salt thereof, wherein Y35is C.

34. The peptide of any one of claims 23-33, or a pharmaceutically acceptable salt thereof, wherein Y36is N.

35. The peptide of any one of claims 23-33, or a pharmaceutically acceptable salt thereof, wherein Y36is C.

36. The peptide of any one of claims 23-35, or a pharmaceutically acceptable salt thereof, wherein Y37is N.

37. The peptide of any one of claims 23-35, or a pharmaceutically acceptable salt thereof, wherein Y37is CH.

38. The peptide of any one of claims 17-37, or a pharmaceutically acceptable salt thereof, wherein each R32is independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1- C6heteroalkyl, halogen, -CN, -NO2, -ORa, -SRa, -SF5, or -NRcRd, wherein each of the alkyl and heteroalkyl is optionally substituted with one or more R32a.

39. The peptide of claim 38, or a pharmaceutically acceptable salt thereof, wherein each R32is independently C1-C6alkyl, C1-C6haloalkyl, halogen, -CN, -ORa, -SRa, or -NRcRd, wherein each of the alkyl and heteroalkyl is optionally substituted with one or more R32a.

40. The peptide of any one of claims 17-39, or a pharmaceutically acceptable salt thereof, wherein R31is hydrogen or methyl.Attorney Docket No.01277-0079-00PCT 41. The peptide of any one of claims 17-40, or a pharmaceutically acceptable salt thereof, wherein LX3is C1-C3alkylene, optionally substituted with one to three RX3aselected from C1-C3alkyl (e.g., methyl), phenyl, C1-C3alkylene(phenyl), and C3-C6cycloalkyl.

42. The peptide of any one of claims 17-40, or a pharmaceutically acceptable salt thereof, wherein LX3is -CH2-, -CH(CH3)-, -C(CH3)2-, -CH(iPr)-, or-CH(benzyl).

43. The peptide of claim 17, or a pharmaceutically acceptable salt thereof, wherein the non-natural tryptophan derivative iswherein each R32is independently C1-C6alkyl, C1-C6haloalkyl, halogen, -CN, -ORa, -SRa, or -NRcRd; and m3 is 0, 1, or 2.

44. The peptide of any one of claims 1-43, wherein the amine comprises a primary amine, a secondary amine, or a tertiary amine.

45. The peptide of claim 44, wherein the amine comprises a secondary amine or a tertiary amine.

46. The peptide of any one of claims 1-45, or a pharmaceutically acceptable salt thereof, wherein the non-natural lysine derivative is a non-natural lysine derivative having a side chain comprising an amine, and wherein the side chain comprises azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl.

47. The peptide of any one of claims 1-46, or a pharmaceutically acceptable salt thereof, wherein the non-natural lysine derivative is Cba3N, Chg4N, Cha4N, Cha4NH2, Ser(3-azetidine), PipzaA, 3- Azetidine-hAla, or Pic4.

48. The peptide of any one of claims 1-45, wherein the non-natural lysine derivative is NMe-Lys, Lys(Me), Lys(diMe), Lys(iPr), Chg4N, Cha4N, 4-oxa-Lys, or 3-Azetidine-hAla.

49. The peptide of any one of claims 1-45, wherein the non-natural lysine derivative is Cba3N, Chg4N, Cha4N, Cha4NH2, Ser(3-azetidine), PipzaA, 3-Azetidine-hAla, Pic4, NMe-Lys, Lys(Me), Lys(diMe), Lys(iPr), or 4-oxa-Lys.

50. The peptide of any one of claims 1-45, or a pharmaceutically acceptable salt thereof, wherein the non-natural lysine derivative is PipzaA, 3-Azetidine-hAla, Lys(Me), Chg4N or Cha4N.

51. The peptide of any one of claims 1-44, or a pharmaceutically acceptable salt thereof, wherein the non-natural lysine derivative has a structure of:Attorney Docket No.01277-0079-00PCT, wherein, R41is hydrogen or C1-C5alkyl optionally substituted with one to three substituents independently selected from Rf; each Rfis independently halogen, -CN, -NO2, -ORa, -SRaor -NRcRd; LX4is a bond, -O-, -S-, -NR43-, C1-C6alkylene, C1-C6heteroalkylene, C3-C6cycloalkyl, or 3- to 6- membered heterocycloalkyl, wherein the alkylene, heteroalkylene, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more RX4a; R42is -NR44R45, a heterocycloalkyl comprising one or more ring nitrogen atoms, or cycloalkylene- NR44R45, wherein the heterocycloalkyl and cycloalkylene are optionally substituted with one or more R42a; each R42ais independently halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1- C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -CN, -NO2, -ORa, -SRa, -NRcRd, -alkenyl, and alkynyl is optionally substituted with one or more Re; R43is hydrogen or C1-C3alkyl; R44and R45are each independently hydrogen, C1-C3alkyl, aryl, heteroaryl, -C1-C3alkylene-aryl, -C1- C3alkylene-heteroaryl, or -NH2; or R44and R45are taken together to form a 3- to 6- membered heterocycloalkyl, wherein each of the alkyl, aryl, heteroaryl, and heterocycloalkyl are optionally substituted with one or more R42a; each RX4ais independently halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1- C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -CN, -NO2, -ORa, -SRa, -NRcRd, - S(=O)Ra, -S(=O)2Ra, -SF5, -S(=O)2NRcRd, -S(=O)(=NRa)Ra, -N=S(=O)RcRd, -NRaS(=O)2Ra, amidinyl, -NRaC(=NH)(NRa)2, -NRaS(=O)2NRcRd, -C(=O)Ra, -C(=O)ORa, -OC(=O)Ra, - OC(=O)ORa, -OC(=O)NRcRd, -NRaC(=O)Ra, -NRaC(=O)ORa, -NRaC(=O)NRcRd, -C(=O)NRcRd, -P(=O)(ORc)(ORd), -P(=O)RcRd, =O, =S, or =N(Ra), wherein each of the alkyl, heteroalkyl, alkenyl, and alkynyl is optionally substituted with one or more Re; or or two RX4agroups attached to the same or different atoms are taken together to form a cycloalkyl or heterocycloalkyl ring, each of which is optionally substituted with one or more Re; each Rais independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl,Attorney Docket No.01277-0079-00PCT aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1-C6alkylene(heteroaryl), wherein each of the alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more Re; each Reis independently halogen, -CN, -OH, oxo, -O-C1-C6alkyl, -SF5, -S(=O)C1-C6alkyl, - S(=O)2C1-C6alkyl, -S(=O)2NH2, -S(=O)2-halogen, -S(=O)2NHC1-C6alkyl, -S(=O)2N(C1-C6alkyl)2, -NH2, -NHC1-C6alkyl, -N(C1-C6alkyl)2, -NHC(=NH)NH2, -NHC(=O)OC1-C6alkyl, - C(=O)C1-C6alkyl, -C(=O)OH, C1-C6alkyl-C(=O)OH, -C(=O)OC1-C6alkyl, -C(=O)NH2, - C(=O)N(C1-C6alkyl)2, -C(=O)NHC1-C6alkyl, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl; and each Rcand Rdare independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1-C6alkylene(heteroaryl), wherein each of the alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more Re; or Rcand Rdare taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more Re; and wherein represents the point of attachment to the rest of the peptide.

52. The peptide of claim 51, or a pharmaceutically acceptable salt thereof, wherein R42is a 4- to 8 membered N-containing heterocycloalkyl, which is optionally substituted with one or more R42a.

53. The peptide of claim 51 or 52, or a pharmaceutically acceptable salt thereof, wherein R42is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, which is optionally substituted with one to four R42a.

54. The peptide of claim 51 or 52, or a pharmaceutically acceptable salt thereof, wherein R42is azetidinyl, piperidinyl, or piperazinyl, each of which is optionally substituted with one to four R42a.

55. The peptide of claim 51, or a pharmaceutically acceptable salt thereof, wherein R42is, each of which is optionally substituted with 1 or 2 substituents selected from R42a.

56. The peptide of claim 51, or a pharmaceutically acceptable salt thereof, wherein R42is -NR44R45.

57. The peptide of claim 51 or 56, wherein R44and R45are each independently hydrogen, methyl, ethyl, isopropyl, phenyl, -C1-C3alkylene-phenyl, or -NH2.

58. The peptide of any one of claims 51-57, or a pharmaceutically acceptable salt thereof, wherein LX4is a bond.Attorney Docket No.01277-0079-00PCT 59. The peptide of any one of claims 51-57, or a pharmaceutically acceptable salt thereof, wherein LX4is a C1-C4alkylene (e.g., -CH2-), wherein the alkylene is optionally substituted with 1 or 2 substituents selected from -F, -CH3, and -OH.

60. The peptide of any one of claims 51-57, or a pharmaceutically acceptable salt thereof, wherein LX4is a C1-C4heteroalkylene (e.g., -CH2OCH2CH2-).

61. The peptide of any one of claims 51-60, or a pharmaceutically acceptable salt thereof, wherein R41is hydrogen or methyl.

62. The peptide of claim 61, or a pharmaceutically acceptable salt thereof, wherein R41is hydrogen.

63. The peptide of claim 61, or a pharmaceutically acceptable salt thereof, wherein R41is methyl.

64. The peptide of claim 51, or a pharmaceutically acceptable salt thereof, wherein the non-natural lysine ,Attorney Docket No.01277-0079-00PCT 65. The peptide of claim 51, or a pharmaceutically acceptable salt thereof, wherein the non-natural lysine66. A conjugate, or a pharmaceutically acceptable salt thereof, comprising a cyclic peptide, or a pharmaceutically acceptable salt thereof, of any one of claims 1 to 65, a metal chelator, and optionally a linker that covalently connects the cyclic peptide and the metal chelator.

67. The conjugate of claim 66, or a pharmaceutically acceptable salt thereof, wherein the metal chelator comprises DOTA, DOTA-GA, pBn-DOTA, pBn-SCN-DOTA, NH2-DOTA, NH2-DOTA-GA, p- NCS-Bn-DOTA-GA, p-NH2-Bn-oxo-DO3A, p-SCN-Bn-oxo-DO3A, NOTA, NODA-GA, NH2- NODA-GA, p-NCS-Bn-NODA-GA, p-NH2-Bn-NOTA, p-SCN-Bn-NOTA, NCS-MP-NODA, NH2- MPAA-NODA, PCTA, p-NH2-Bn-PCTA, p-SCN-Bn-PCTA, p-SCN-Bn-HEHA, H2-MACROPA- NCS, H1-MACROPA, H2-MACROPA-NH2, H4-OCTAPA, tetra-(S, S, S, S)-Me-DOTA, tetra-(S, S, S, S)-Et-DOTA, tetra-(S, S, S, S)-iBu-DOTA, or maleimide-nBu-DOTA.

68. The conjugate of claim 66, or a pharmaceutically acceptable salt thereof, wherein the metal chelatorAttorney Docket No.01277-0079-00PCT69. The conjugate of claim 68, or a pharmaceutically acceptable salt thereof, wherein the metal chelator70. The conjugate of any one of claims 66-69, or a pharmaceutically acceptable salt thereof, wherein the metal chelator is connected to the monocyclic peptide through a linker.

71. The conjugate of any one of claims 66-70, or a pharmaceutically acceptable salt thereof, wherein the linker comprises 3 to 30 intervening non-hydrogen, organic atoms between the metal chelator and the peptide.

72. The conjugate of claim 71, or a pharmaceutically acceptable salt thereof, wherein the linker comprises 3 to 18 intervening non-hydrogen, organic atoms between the metal chelator and the peptide.

73. The conjugate of claim 71 or 72, or a pharmaceutically acceptable salt thereof, wherein the intervening atoms comprise 1 to 6 nitrogen atoms and 0 to 4 oxygen atoms.

74. The conjugate of any one of claims 66-73, or a pharmaceutically acceptable salt thereof, wherein the linker comprises one or more amino acid residues.

75. The conjugate of claim 74, or a pharmaceutically acceptable salt thereof, wherein the linker comprises one or two amino acid residues.

76. The conjugate of any one of claims 66-70, or a pharmaceutically acceptable salt thereof, wherein the linker has a structure of Formula (V-1)Formula (V-1)Attorney Docket No.01277-0079-00PCT wherein each L is independently -O-, –NRL-, –N(RL)2-, -OP(=O)(ORL)O-, -S-, -S(=O)-, -S(=O)2-, NRL-, -NRLC(=O)-, -OC(=O)NRL-, - , -N=CRL, -NRLS(=O)2-, -substituted or unsubstituted C3-15cycloalkyl, substituted or unsubstituted C1-12heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C1-30alkylene, substituted or unsubstituted C2-30alkenylene, substituted or unsubstituted C2-30alkynylene, substituted or unsubstituted C1-30heteroalkylene, -(C1-30alkylene)-O-, -O-(C1-30alkylene)-, -(C1-30alkylene)- NRL-, -NRL-(C1-30alkylene)-, -(C1-30alkylene)-N(RL)2-, or -N(RL)2-(C1-30alkylene)-, or a click chemistry residue; and each RLis independently hydrogen, substituted or unsubstituted C1-4alkyl, substituted or unsubstituted C1-4heteroalkyl, substituted or unsubstituted C2-6alkenyl, substituted or unsubstituted C2-5alkynyl, substituted or unsubstituted C3-8cycloalkyl, substituted or unsubstituted C2-7heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and n is 1 to 20.

77. The conjugate of any one of claims 66-70 and 76, or a pharmaceutically acceptable salt thereof, wherein the linker comprises a structure of Formula (V-1a),Formula (V-1a) wherein each of L1and L3is independently -O-, –NRL-, –N(RL)2-, -OP(=O)(ORL)O-, -S-, - -, -C(=O)O-, - -NRLC(=O)O-, - or -SL(=O)2NR C(=O)-; and L2is absent, substituted or unsubstituted C1-30alkylene, or substituted or unsubstituted C1-30heteroalkylene.

78. The conjugate of claim 77, or a pharmaceutically acceptable salt thereof, wherein L1is -NH-.

79. The conjugate of claim 77 or 78, or a pharmaceutically acceptable salt thereof, wherein L2is substituted or unsubstituted C1-30alkylene, or substituted or unsubstituted C1-30heteroalkylene.

80. The conjugate of claim 79, or a pharmaceutically acceptable salt thereof, wherein L2is substituted or unsubstituted C1-18alkylene, or substituted or unsubstituted C1-18heteroalkylene.

81. The conjugate of any one of claims 77-80, or a pharmaceutically acceptable salt thereof, wherein L2is optionally substituted with one or more substituents selected from -OH, -SH, oxo, amino, C1-6alkyl, C1-6hydroxyalkyl, C1-6haloalkyl, C1-6aminoalkyl, -C(=O)ORL, -C1-C6alkylene-C(=O)ORL, - OC(=O)RL, -OC(=O)ORL, -C(=O)N(RL)2, -NRLC(=O)RL, -OC(=O)N(RL)2, and -NRLC(=O)ORL; andAttorney Docket No.01277-0079-00PCT the C1-6alkyl is further optionally substituted with one or more substituents chosen from -OH, -SH, oxo, amino, C6-C10aryl, 6- to 10- membered heteroaryl, -C(=O)ORL, -OC(=O)RL, -OC(=O)ORL, - C(=O)N(RL)2, -NRLC(=O)RL, -OC(=O)N(RL)2, and -NRLC(=O)ORL.

82. The conjugate of any one of claims 77-81, or a pharmaceutically acceptable salt thereof, wherein L3is -NH- or -C(=O)C1-C6alkylene -.

83. The conjugate of any one of claims 66-70 and 76, or a pharmaceutically acceptable salt thereof, wherein the linker comprises a structure of Formula (V-1b),Formula (V-1b) wherein each of L1and L5is independently -O-, –NRL-, –N(RL)2-, -OP(=O)(ORL)O-, -S-, -S(=O)-, -NRLS(=O)2-, -S(=O)2NRL-, -C(=O)NRLS(=O)2-, -S(=O)2NRLC(=O)-, substituted or unsubstituted C4-C6cycloalkyl, or substituted or unsubstituted 4- to 6- membered heterocycloalkyl; and L2, L3and L4are each independently absent, substituted or unsubstituted C4-C10cycloalkyl, substituted or unsubstituted 4- to 6- membered heterocycloalkyl, substituted or unsubstituted C1- C30alkylene, or substituted or unsubstituted C1-C30heteroalkylene.

84. The conjugate of claim 83, wherein L1is -NH- or substituted or unsubstituted 4- to 6- membered heterocycloalkyl.

85. The conjugate of claim 83 or 84, wherein L5is -NH-, -C(=O)-, or -C(=O)C1-C6alkylene-.

86. The conjugate of any one of claims 66-70, or a pharmaceutically acceptable salt thereof, wherein the linker is a bond.

87. A radiopharmaceutical comprising a conjugate of any one of claims 66-86, or a pharmaceutically acceptable salt thereof, and a radionuclide bound to the metal chelator.

88. The radiopharmaceutical of claim87, or a pharmaceutically acceptable salt thereof, wherein the radionuclide is an alpha particle-emitting radionuclide.

89. The radiopharmaceutical of claim 88, or a pharmaceutically acceptable salt thereof, wherein the alpha particle-emitting radionuclide is Ac-225, Bi-213, Bi-209, Tb-149, Ra-223, Th-227, Fr-223, Gd- 148, Th-229, Pb-212, At-211, or Po-213.

90. The radiopharmaceutical of claim 89, or a pharmaceutically acceptable salt thereof, wherein the alpha particle-emitting radionuclide is Ac-225.

91. The radiopharmaceutical of claim 87, or a pharmaceutically acceptable salt thereof, wherein the radionuclide is a beta particle-emitting radionuclide.

92. The radiopharmaceutical of claim 91, or a pharmaceutically acceptable salt thereof, wherein the beta particle-emitting radionuclide is Cu-67, Lu-177, Y-90, Rh-105, Yb-175, Tm-167, Tb-161, Pm-153, Sm-153, or In-111.Attorney Docket No.01277-0079-00PCT 93. The radiopharmaceutical of claim 92, or a pharmaceutically acceptable salt thereof, wherein the beta particle-emitting radionuclide is lutetium-177.

94. The radiopharmaceutical of claim 87, or a pharmaceutically acceptable salt thereof, wherein the radionuclide is a positron-emitting radionuclide.

95. The radiopharmaceutical of claim 94, or a pharmaceutically acceptable salt thereof, wherein the positron-emitting radionuclide is Ga-68, Cu-62, Cu-64, Zr-89, Tb-152.

96. A pharmaceutical composition comprising the peptide of any one of claims 1-65, conjugate of any one of claims 66-86, or radiopharmaceutical of any one of claims 87-95, and a pharmaceutically acceptable excipient or carrier.

97. A method of treating a somatostatin receptor-positive (SSTR+) tumor in a subject in need thereof, comprising administering to the subject the peptide of any one of claims 1-65, conjugate of any one of claims 66-86, or radiopharmaceutical of any one of claims 87-95, or a pharmaceutically acceptable salt thereof.

98. A method of increasing renal clearance of a cyclic somatostatin receptor binding peptide comprising one or more lysine residues or a radiopharmaceutical or conjugate comprising a cyclic somatostatin receptor binding peptide comprising one or more lysine residues, the method comprising independently replacing the one or more lysine residues with a non-natural lysine derivative.

99. The method of claim 98, wherein the somatostatin receptor binding peptide is selected from SEQ ID NO: 1-85.

100. The method of claim 98 or 99, wherein the cyclic somatostatin receptor binding peptide comprising the non-natural lysine derivative or the radiopharmaceutical or conjugate comprising a cyclic somatostatin receptor binding peptide comprising the non-natural lysine derivative has increased renal clearance compared to the peptide where the lysine is not replaced.

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